AU7168400A - Use of polypeptides or nucleic acids encoding these for the diagnosis or treatment of skin disorders, and their use for the identification of pharmacologically active substances - Google Patents

Description

P/00/011 28/5/91 Regulation 3.2(2)

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: Invention Title: USE OF POLYPEPTIDES OR NUCLEIC ACIDS ENCODING THESE FOR THE DIAGNOSIS OR TREATMENT OF SKIN DISORDERS, AND THEIR USE FOR THE IDENTIFICATION OF PHARMACOLOGICALLY ACTIVE SUBSTANCES The following statement is a full description of this invention, including the best method of performing it known to us 1 Switch Biotech AG 14. November 2000 S29829AU BO/ZW/pvc Use of polypeptides or nucleic acids encoding these for the diagnosis or treatment of skin disorders, and their use for the identification of pharmacologically active substances Description The invention relates to the use of polypeptides or nucleic acids encoding these for the diagnosis and/or prevention and/or treatment of disorders and/or wound healing, and their use for the identification of pharmacologically active substances. In particular, the present invention relates to the use in connection with disorders of skin cells and in wound healing.

Wounds in general heal without therapeutic intervention. However, there are numerous disorders in which wound healing plays a role, such as, for example, S. diabetes mellitus, arterial occlusive diseases, psoriasis, atopic dermatitis, contact dermatitis, Crohn's disease, epidermolysis bullosa, age-related skin changes or innervation disorders. Wound healing disorders lead to a delayed healing of wounds or to chronic wounds. These disorders can be caused by the eeo.

nature of the wound large-area wounds, deep and mechanically expanded operation wounds, burns, trauma, decubitus), medicinal treatment of the patients (e.g.

with corticoids) but also by the nature of the disorder itself. For example, 25% of the patients with Type II diabetes thus frequently suffer from chronic ulcers ("diabetic foot"), of which approximately half necessitate expensive in-patient treatments and nevertheless finally heal poorly. Diabetic foot causes more stays in hospital than any other complication associated with diabetes. The number of these cases in 2 diabetes Type I and II is on the increase and represents 2.5% of all hospital admissions. Moreover, wounds heal more poorly with increasing age of the patients. An acceleration of the natural wound healing process is often desirable as well in order to decrease, for example, the danger of bacterial infections or the rest periods of the patients.

Further disorders can also occur after successful wound closure. While foetal skin wounds heal without scar formation, after injuries in the postnatal period formation of scars always occurs, which often represent a great cosmetic problem. In the case of patients with large-area burn wounds, the quality of life can moreover be dramatically adversely affected, especially as in scarred skin the appendages, such as hair follicles, sweat and sebaceous glands are missing. In the case of appropriate genetic disposition, keloids can also occur, hypertrophic scars which proliferate into the surrounding skin.

20 The process of skin healing requires complex actions and interactions of various cell types which proceed in a coordinated manner. In the wound healing 0 process, the following steps are differentiated: clotting of blood in the area of the wound, the recruitment of inflammatory cells, reepithelialization, the formation of granular tissue and the restructuring of matrix. The exact reaction pattern of the cell types involved during the phases of proliferation, migration, matrix synthesis and contraction are, just like the 30 regulation of genes such as, for example, growth factors, receptors and matrix proteins, little known up to now.

Thus until now only a few satisfactory therapies have been developed in order to be able to intervene in wound healing disorders. Established forms of therapy are restricted to physical assistance of wound healing -3dressings, compresses, gels) or the transplantation of skin tissues, cultured skin cells and/or matrix proteins. In recent years, growth factors have been tested for improving wound healing without, however, improving the conventional therapy decisively.

The diagnosis of wound healing disorders is also based on not very meaningful optical analyses of the skin, since a deeper understanding of the gene regulation during wound healing was lacking until now.

Not very satisfactory therapies have been developed until now for other disorders of regenerative processes *as well. Here too, the knowledge of gene regulation is advantageous for the development of diagnostics and therapies. It has been shown (Finch et al., 1997, Am. J. Pathol. 151: 1619-28; Werner, 1998, Cytokine Growth Factor Rev. 9: 153-165) that genes relevant to wound healing also play a crucial role in dermatological disorders which are based on disorders of the regeneration of the skin, and generally in 20 regenerative processes. Thus the growth factor KGF not only plays a crucial role in the regulation of the proliferation and differentiation of keratinocytes during wound healing, but is also an important factor in the hyperproliferation of the keratinocytes in psoriasis and regeneration processes in the intestine (in Crohn's disease and ulcerative colitis).

It is therefore the object of the present invention to make available polypeptides and/or nucleic acids encoding these which are involved in processes in 30 the case of disorders in mammalian cells, in particular S• in the case of disorders of skin cells and/or wound healing, and whose use decisively improves the diagnosis and/or prevention and/or treatment and also the identification and development of pharmaceuticals which are effective in connection with these disorders.

-4- In the analysis of gene expression during the wound healing process, it was surprisingly possible to identify genes which until now were not connected with diagnosis and/or prevention and/or treatment of disorders or with wound healing or the identification of pharmacologically active substances, but whose regulation is essential for the healing process and which are thus in a causal relationship with diagnosis and/or prevention and/or treatment of disorders or the identification of pharmacologically active substances.

The polypeptides of these genes do not belong to the targets known until now for diagnosis such as, for example, the indication and/or prevention and/or the treatment such as, for example, the modulation of disorders or for the identification of pharmacologically active substances, such that completely novel therapeutic approaches result from this invention.

The object is therefore achieved according to the 20 invention by the use of one or more polypeptides or variants thereof according to one of SEQ ID No. 1 to SEQ ID Nr. 4 and SEQ ID No. 7 to SEQ ID No. 9 and SEQ ID No. 103 to SEQ ID No. 104 and SEQ ID No. 106 or nucleic acids encoding these or variants thereof for the diagnosis and/or prevention and/or treatment of disorders or for the identification of pharmacologically active substances.

The exact biological functions of the polypeptides according to the invention of SEQ ID No. 1 to SEQ ID Nr. 4 or SEQ ID No. 7 to SEQ ID No. 9 or SEQ ID No. 103 oe e to SEQ ID No. 104 and SEQ ID No. 106 are unknown. In the investigations in the context of this invention, it was possible for the first time to find a relationship between the polypeptides described above and disorders, for example skin disorders. The accession numbers of 5 the polypeptide sequences used according to the invention and their cDNAs are listed in Table 2.

The following polypeptides and/or nucleic acids encoding these can be used according to the invention: MBNL from mouse (SEQ ID No. 103; GeneBank: AAF72159) or human (SEQ ID No. 1; GeneBank:CAA74155).

Additionally, the polypeptide KIAA0428 (SEQ ID No.

104; trEMBL: 043311) from human, that is a variant of MBNL (SEQ ID No. 1) can be used.

Wolf-Hirschhorn Syndrome Candidate 2 Protein from mouse (SEQ ID No. 2; trEMBL: Q9Z1V9) or human (SEQ ID No. 3; 095392)The gene encoding this protein in man is located in a 167 kb region, which is regarded critical for the genetic disposition for the Wolf-Hirschhorn Syndrome (Wright et al., 1997, Hum.

Mol. Gener. 6: 317-324).

KIAA0494 from human (SEQ ID No. 4; Seki et al., 1997, DNA Res. 4:345-349).

KIAA0614 from human (SEQ ID No. 7; GenBank: 20 BAA31589) or mouse (SEQ ID No. 106).

KIAA0521 from human (SEQ ID No. 8; GenBank: BAA25447) KIAA0261 from human (SEQ ID No. 9; GeneBank: BAA13391) •In the analysis of gene expression during the wound healing process, it was possible to identify further genes whose already known and described functions were not connected until now with skin disorders, for example with disturbed wound healing, but whose regulation is essential for the wound healing process and which were thus brought for the first time into a causal relationship with skin disorders, for example with disturbed wound healing. The polypeptides 6 of these genes do not belong to the targets of therapies of skin disorders and/or wound healing known until now, such that completely novel therapeutic approaches result from this invention.

The object of the invention is furthermore achieved by the use of at least one polypeptide or variants thereof according to one of SEQ ID No. 5 to SEQ ID No. 6, SEQ ID No. 10 to SEQ ID No. 48, SEQ ID No. 55 to SEQ ID No. 58, SEQ ID No. 89 to SEQ ID 94, SEQ ID No. 105 or SEQ ID No. 109 to SEQ ID No. 114 or nucleic acids encoding these or variants thereof for the diagnosis and/or prevention and/or treatment, for example for the therapeutic and/or prophylactic treatment, of skin disorders or for the identification of pharmacologically active substances.

The following polypeptides and/or nucleic acids encoding these can be used according to the invention: KIAA0585 from man (SEQ ID No. 5; Nagase et al., 20 1998, DNA Res. 5:31-39). A shorter variant of this protein is known from WO 98/57985 as a protein that binds to the "receptor interacting protein" (RIP; a protein involved in the Fas-mediated apoptosis signal transduction pathway). This variant is localized in the 25 nucleus of human cells.

HSPC028 from man (SEQ ID No. 6; GenBank: AAD39844) or mouse (SEQ ID No. 106) The polypeptide from human is known from WO 99/15658 as protein which displays a weak homology to transcription factors.

The protein calnexin from mouse (SEQ ID No. or man (SEQ ID No. 11), which is negatively regulated in resting and differentiating cells (Honore et al., 1994, Electrophoresis 15: 482-90; Olsen et al., 1995, Electrophoresis 16: 2241-8).

7 The CREB-binding protein (CBP) from mouse (SEQ ID No. 12) or man (SEQ ID No. 13), which like the gene for p300 which is described in US 5,658,784 and closely related is described as a coactivator for a large number of transcription factors involved in growth control and differentiation, such as, for example, GATA-1, p53 and E2F (Blobel et al., 1998, Proc. Natl. Acad. Sci. USA 95: 2061-6).

The mas oncogene from mouse (SEQ ID No. 14) or the homologous MRG from man (SEQ ID No. 15) (Monnot et al., 1991, Mol. Endocrinol. 5:1477-1487; Metzger et al.

1995, FEBS Lett. 357: 27-32) which is described in US 5,320,941 in connection with a process for the treatment of tumours. In addition to the polypeptide of mouse known until now, the closely related polypeptide mentioned for the first time in this study having a differing sequence can also be used (SEQ ID No. 109).

The cDNA sequence, that codes for the polypeptide used according to the invention is depicted in the sequence 20 listing according to SEQ ID No. 120.

The acylamino acid-releasing enzyme from man disclosed in JP 3254680 (SEQ ID No. 16), which is activated in tumour cells (Schoenberger et al., 1986, J. Clin. Chem. Clin. Biochem. 24: 375-8).

25 The protein JEM-1 from man identified in acute promyelocytic leukaemia cells and involved in cell maturation (SEQ ID No. 17) (Tong et al., 1998, Leukemia S• 12: 1733-40). In addition the closely related polypeptides of man (SEQ ID No. 110) or mouse (SEQ ID No. 111 and SEQ ID No. 112) mentioned for the first time in this study can also be used, their coding nucleic acids are depicted in the sequence listing according to SEQ ID No. 121 (man) and SEQ ID No. 122 and SEQ ID No. 123 (mouse).

8 The cardiac ankyrin repeat protein (CARP/MARP) from mouse (SEQ ID No. 18) or man (SEQ ID No. 19), which is crucial for the development of cardiac muscle (Zou et al., 1997, Development 124: 793-804). In addition to the sequence of mouse known until now, the polypeptide mentioned for the first time in this study having a differing sequence can also be used (SEQ ID No. 113). The sequence of the nucleic acid encoding this polypeptide is depicted in the sequence listing according to SEQ ID No. 124.

The transcription factor checkpoint suppressor 1 (CHES1) from man (SEQ ID No. 20), which suppresses various mutations in S. cerevisiae in connection with DNA repair and for which a function in cell cycle control is suspected (Pati et al., 1997, Mol. Cell.

Biol 17: 3037-46).

The small GTP binding protein RAB2 from mouse (SEQ ID No. 21) or man (SEQ ID No. 22), which plays an important role in neuronal development (Ayala et al., 20 1990, Neuron 4: 797-805).

The nucleoporin-precursor Nup98-Nup96 from man (SEQ ID No. 23), which is proteolytically processed in vivo to form the nucleoporins Nup96 and Nup98 (Fontoura et al., 1999, J. Cell Biol. 144: 1097-1112). For Nup98 25 a function is described in acute myeloid leukaemia (AML) and it is in a functional relationship with CBP S* and p300 (Kasper et al., 1999, Mol. Cell. Biol. 19: 764-76).

The ribonuclease L inhibitor (Mu-RLI) from mouse 30 (SEQ ID No. 24) or man (SEQ ID No. 25), which in connection with ribonuclease L plays an important role in the antiviral and antiproliferative function of interferons and is regulated tissue-specifically (Benoit et al., 1998, Gene 209: 149-56). In addition to the polypeptides of man (Bisbal et al., 1995, J. Biol.

9 Chem. 270: 13308-17) and mouse (De Coignac et al., 1998, Gene 209: 149-56) known until now, the closely related polypeptides mentioned for the first time in this study and having a differing sequence can also be used (SEQ ID No. 27 and SEQ ID No. 26). The sequences of the nucleic acids encoding these polypeptide variants are depicted in the sequence listing according to SEQ ID No. 118 and SEQ ID No. 117.

The p68 helicase from mouse (SEQ ID No. 28) or man (SEQ ID No. 29), which is described as a DNA or RNA helicase located in the cell nucleus and could be involved in the replication, transcription or RNA processing necessary for cell growth (Ford et al., 1988, Nature 332: 736-8). In addition to the known polypeptide variant from the mouse (SEQ ID No. 28) (Lemaire and Heinlein, 1993, Life Sci. 52: 917-26), the closely related polypeptide mentioned for the first time in this study and having a differing sequence can also be used (SEQ ID No. 30). The sequence of the 20 nucleic acid encoding this polypeptide variant is depicted in the sequence listing according to SEQ ID No. 119.

The keratin-associated protein mKAPl3 (also PMG- 1) (SEQ ID No. 31) and the homologue protein PMG-2 (SEQ 25 ID No. 32) from mouse. The PMG-1 transcript is expressed skin-specifically in the keratogenic zone of the cortical cells of the hair follicles and is specific for the keratinization of the cortical cell layer in mouse hair (Aoki et al., 1998, J. Invest.

Dermatol. 111: 804-9).

The closely related PMG-2, likewise expressed in growing hair follicles was described as a protein, which together with PMG-1 is involved in the differentiation of all epithelial cells which form epidermal appendages (Kuhn et al., 1999, Mech. Dev 86: 193-196). In addition to the known polypeptide of mouse 10 the polypeptides of man mentioned for the first time in this study can also be used (SEQ ID No. 55 (Example 7) and SEQ ID No. 89 to SEQ ID No. 94). The nucleic acids, that encode the above described polypeptides according to SEQ ID No. 89 to SEQ ID No. 94 are indicated in the sequence listing according to SEQ ID No. 95 to SEQ ID No. 100.

The protein MA-3 from mouse (SEQ ID No. 33) or man (SEQ ID No. 34) involved in apoptosis (Matsuhashi et al., 1997, Res. Commun. Biochem. Cell Mol. Biol.

1:109-120; Shibahara et al., 1995, Gene 166: 297-301).

In addition to the known polypeptide from man, the polypeptide from man obtained in this study can also be used (SEQ ID No. 58). The sequence of the nucleic acid coding for this polypeptide variant is indicated in the sequence listing according to SEQ ID No. 116.

The antiproliferative protein BTG1 from mouse (SEQ ID No. 35) or man (SEQ ID No. 36), for which a high expression in dying cells and a function in the 20 regulation of the cell status of advanced atherosclerotic lesions is described (Corjay et al., 1998, Lab. Invest. 78: 847-58).

The CD9 from mouse (SEQ ID No. 37) or man (SEQ ID No. 38) which is expressed in the epidermis in a 25 widespread manner, which forms complexes with beta 1 integrins and for which a role in the regulation of the motility and differentiation of keratinocytes is suspected (Jones et al., 1998, Cell Adhes. Commun 4: 297-305).

30 The stearoyl-CoA desaturase (SCD1) from mouse (SEQ ID No. 39) or man (SEQ ID No. 40), which is regulated by the nuclear factor 1 (NFl) and is involved in the differentiation of preadipocytes to adipocytes (Singh and Ntambi, 1998, Biochim. Biophys. Acta 1398: 148-56).

I 11 The protein syndecan 4 (ryudocan) from mouse (SEQ ID No. 41) or man (SEQ ID No. 42) involved in the focal adhesion of fibroblasts, which is described as a transmembrane adhesion component (Woods and Couchman, 1994, Mol. Biol. Cell., 5: 183-92).

The protein ALF1 from mouse (SEQ ID No. 43) or man (SEQ ID No. 44) and belonging to the class consisting of the E2A basic helix-loop-helix transcription factors, which regulates the growth of mouse fibroblasts (Loveys et al., 1996, Nucleic. Acids Res. 24: 2813-20).

The potentially prenylated protein tyrosine phosphatase (PRL) from mouse (SEQ ID No. 45) or man (SEQ ID No. 46), which is described in connection with signal transduction in the regenerating liver and in muscle growth, in particular of the heart (Zeng et al., 1998, Biochem. Biophys. Res. Commun. 244: 421-7).

Nuclear factor (NF1-B) from mouse (SEQ ID No.

47) or man (SEQ ID No. 48), which is described in 20 connection with alternative splicing and whose function was investigated in oncogenesis in chicken fibroblasts (Schuur et al., 1995, Cell Growth Differ. 6: 219-27).

In addition to the indicated polypeptide sequence of NF1-B of man (SEQ ID No. 48) the slightly differing 25 polypeptide sequence of man (SEQ ID No. 114), that is indicated in the sequence listing as well, can be used.

The cysteine proteinase cathepsin Z from mouse (SEQ ID No. 56) or man (SEQ ID No. 57), for which participation in tumour growth is suspected (Santamaria 30 et al., 1998, J. Biol. Chem. 273: 16818-23).

A connection with skin disorders, for example with disturbed wound healing, was not described or suggested until now for any of these polypeptides or their coding nucleic acids. It was therefore unexpected, that these compounds can be used according to the invention. The 12 accession numbers of the polypeptides used according to the invention are indicated in Table 3.

The object of the invention is furthermore achieved by the use of at least one nucleic acid according to one of SEQ ID No. 49 or SEQ ID No. 50 or variants thereof for the diagnosis and/or prevention and/or treatment, for example for the therapeutic and/or prophylactic treatment, of skin disorders or for the identification of pharmacologically active substances.

The nucleic acids used according to the invention are: The nucleic acid for the so-called steroid receptor coactivator from mouse (SEQ ID No. 49) or man (SEQ ID No. 50), whose mRNA is not translated and is functional as an RNA. The steroid receptor coactivator is described as active only in connection with steroid hormone receptors (steroid receptor coactivator: Lanz et al., 1999, Cell 97: 17-27). A connection with skin disorders was unknown until now.

A connection with skin disorders, for example with disturbed wound healing, was not described or suggested '"'"until now for any of these nucleic acids. It was therefore unexpected that these compounds can be used eeoc 25 according to the invention. The accession numbers of *o the nucleic acids according to the invention and their cDNAs are shown in Table 3.

In the analysis of gene expression during the wound healing process, it was additionally possible to 30 identify genes whose already known and described functions were not connected until now with wound healing, but whose regulation is essential for the wound healing process and which were thus brought into a causal relationship with wound healing for the first time. The polypeptides of these genes do not belong to 13 the targets of therapies known until now in connection with the pathological alteration of wound healing, such that completely novel therapeutic approaches result from this invention.

The object of the invention is therefore additionally achieved by the use of at least one polypeptide or variants thereof according to one of SEQ ID No. 51 to SEQ ID No. 54 and SEQ ID No. 101 to SEQ ID No. 102 or nucleic acid encoding this or variants thereof for the identification of pharmacologically active substances or for diagnosis and/or prevention and/or treatment in wound healing.

The following polypeptides and/or nucleic acids encoding these can be used according to the invention: The SR calcium ATPase (SERCA) of mouse (SEQ ID No. 51) or of man (SEQ ID No. 52), which is described in connection with the muscle growth of the heart (Baker et al., 1998, Nucleic Acids Res., 26: 1092-8). A connection of SERCA with Darier's disease, a skin disease, has furthermore been described (Sakuntabhai et al., 1999, Nat. Genet. 21: 271-7).

The protein calgranulin (MRP8) of mouse (SEQ ID No. 53) or of man (SEQ ID No. 54) expressed in inflammatory dermatosis after lesions of the skin, (Kelly et al., 1989, J. Pathol. 159: 17-21), whose involvement in wound healing was also unknown until now.

The calcium binding protein MRP-14 from mouse (SEQ ID No. 101) or human (SEQ ID No.102) known from DE 30 198 13 839, US 5,776,348 and US 5,614,397 (Odink et al., 1987, Nature 330: 80-82; Lagasse and Weissmann 1992, Blood 79: 1907-1915). The protein forms heterodimers with MRP8 and is upregulated in macrophages in acutely inflamed tissues (Sorg, 1992, Behring Inst. Mitt. 91: 126-137). In addition increased 14 amounts of MRP-14 have been observed in the epidermis of patients with Lichen planus, Lupus erythematosus and Psoriasis vulgaris (Kunz et al., Arch. Dermatol. Res.

284: 386-390). The MRP8/MRP14 heterodimer binds fatty acids, in particular arachidonic acid with high specificity while the monomers show no binding activity (Kerkhoff et al., 1999, J. Biol. Chem., 274: 32672- 32679). In addition to the role in inflammatory processes a function of MRP8 and/or MRP14 in the differentiation processes of keratinocytes during wound healing could be shown for the first time in this study.

A connection with wound healing was not described or suggested until now for any of these polypeptides or these coding nucleic acids. It was therefore unexpected that these polypeptides could be used according to the invention. The accession numbers of the polypeptides according to the invention and their cDNAs are shown in Figure 6.

20 The polypeptides used according to the invention can furthermore be characterized in that they are synthetically prepared. Thus, the entire polypeptide or Sparts thereof can be synthesized, for example, with the aid of the conventional synthesis (Merrifield technique). Parts of the polypeptides described above are particularly suitable to obtain antisera (see Example 10), with whose aid suitable gene expression banks can be searched in order thus to arrive at .further functional variants of the polypeptide used according to the invention.

The term "variants" within the meaning of the present invention also comprises functionally active variants. Functionally active variants has to be understood to mean polypeptides that are regulated as, for example, the polypeptides used according to the present invention during disorders in particular skin 15 disorders, or regenerative processes of the skin, in particular wound healing disorders. The term "regulation" has to be understood to mean, for example, the increase or decrease of the amount of polypeptides or nucleic acids coding for them, wherein this change is affected on, for example, the transcriptional level.

Functional variants include, for example, polypeptides which are encoded by nucleic acids, which are isolated from non-wound-healing-specific tissue, e.g. embryonic tissue, but after expression have the indicated functions in a cell involved in wound healing.

Variants within the meaning of the present invention are also polypeptides which have a sequence homology, in particular a sequence identity of about preferably about 80%, in particular about especially about 95% to the polypeptide having the amino acid sequence according to one of SEQ ID No. 1 to SEQ ID No. 48, SEQ ID No. 51 to SEQ ID No. 58, SEQ ID 20 No. 89 to SEQ ID No. 94, SEQ ID No. 101 to SEQ ID No. 106 and SEQ ID No. 109 to SEQ ID No. 114. Examples of those variants, that can also be functionally .eoooi S" active, are accordingly the corresponding polypeptides which originate from other organisms than man or mouse, preferably from non-human mammals such as, for example, monkeys, pigs and rats. Other examples are polypeptides which are encoded in various individuals or in various organs of organism by different alleles of the gene (see Example 6).

Variants of the polypeptide can also be parts of the polypeptide used according to invention with at least 6 amino acids length, preferably with at least 8 amino acids length, in particular with at least 12 amino acids length. Also included are deletions of the polypeptide used according to the invention, in the range from about 1-60, preferably from about 1-30, in 16 particular from about 1-15, especially from about amino acids. For example, the first amino acid methionine can be absent without the function of the polypeptide being significantly altered.

The term "coding nucleic acid" relates to a DNA sequence which codes for an isolatable bioactive polypeptide used according to the invention or a precursor. The polypeptide can be encoded by a sequence of full length or any part of the coding sequence as long as the specific, for example enzymatic, activity is retained.

It is known that small alterations in the sequence of the nucleic acids used according to the invention can be present, for example, due to the degeneration of the genetic code, or that untranslated sequences can be attached to the 5' and/or 3' end of the nucleic acid without its activity being significantly altered. This invention therefore also comprises so-called "variants" of the nucleic acids described above.

o oo The term "variants" indicates all DNA sequences which are complementary to a DNA sequence, which hybridize with the reference sequence under stringent conditions and that encode a peptide with a similar activity to the polypeptide encoded by the reference 25 sequence.

"Stringent hybridization conditions" are understood as meaning those conditions in which oooeo hybridization takes place at 60 0 C in 2.5 x SSC buffer, followed by a number of washing steps at 37 0 C in a 30 lower buffer concentration, and remains stable.

S"Variants of the nucleic acids can also be parts of the nucleic acids used according to the present invention with at least 8 nucleotides length, preferably with at least 18 nucleotides length, in particular with at least 24 nucleotides length.

17 Preferentially, the nucleic acids used according to the invention are DNA or RNA, preferably a DNA, in particular a double-stranded DNA. The sequence of the nucleic acids can furthermore be characterized in that it has at least one intron and/or one polyA sequence.

The nucleic acids used according to the invention can also be used in the form of their antisense sequence.

For the expression of the gene concerned, in general a double-stranded DNA is preferred, the DNA region coding for the polypeptide being particularly preferred. This region begins with the first start codon (ATG) lying in a Kozak sequence (Kozak, 1987, Nucleic. Acids Res. 15: 8125-48) up to the next stop codon (TAG, TGA or TAA), which lies in the same reading frame to the ATG.

A further use of the nucleic acid sequences used according to the invention is the construction of antisense oligonucleotides (Zheng and Kemeny, 1995, Clin.

Exp. Immunol. 100: 380-2; Nellen and Lichtenstein, S:i" 20 1993, Trends Biochem. Sci. 18: 419-23; Stein, 1992, Leukemia 6: 967-74) and/or ribozymes (Amarzguioui, et al. 1998, Cell. Mol. Life Sci. 54: 1175-202; Vaish, et al., 1998, Nucleic Acids Res. 26: 5237-42; Persidis, 1997, Nat. Biotechnol. 15: 921-2; Couture and 25 Stinchcomb, 1996, Trends Genet. 12: 510-5). Using antisense oligonucleotides, the stability of the nucleic acid described above can be decreased and/or the translation of the nucleic acid described above inhibited. Thus, for example, the expression of the corresponding genes in cells can be decreased both in vivo and in vitro. Oligonulecotides can therefore be suitable as therapeutics. This strategy is suitable, for example, even for skin, epidermal and dermal cells, in particular if the antisense oligonucleotides are complexed with liposomes (Smyth et al., 1997, J.

Invest. Dermatol. 108: 523-6; White et al., 1999, J.

18 Invest. Dermatol. 112: 699-705; White et al., 1999, J.

Invest. Dermatol. 112: 887-92). For use as a probe or as an "antisense" oligonucleotide, a single-stranded DNA or RNA is preferred.

Furthermore, a nucleic acid which has been prepared synthetically can be used for carrying out the invention. Thus, the nucleic acid used according to the invention can be synthesized, for example, chemically with the aid of the DNA sequences described in Figures 4 to 6 and/or with the aid of the protein sequences likewise described in these figures with reference to the genetic code, e.g. according to the phosphotriester method (see, for example, Uhlmann, E. Peyman, A.

(1990) Chemical Reviews, 90, 543-584, No. 4).

As a rule, oligonucleotides are rapidly degraded by endo- or exonucleases, in particular by DNases and RNases occurring in the cell. It is therefore advantageous to modify the nucleic acid in order to stabilize it against degradation, so that a high 20 concentration of the nucleic acid is maintained in the cell over a long period (Beigelman et al., 1995, Nucleic Acids Res. 23: 3989-94; Dudycz, 1995, W09511910; Macadam et al., 1998, W09837240; Reese et al., 1997, W09729116). Typically, such a stabilization 25 can be obtained by the introduction of one or more internucleotide phosphorus groups or by the introduction of one or more non-phosphorus internucleotides.

Suitable modified internucleotides are summarized in Uhlmann and Peymann (1990 Chem. Rev. 90, 544) (see also Beigelman et al., 1995 Nucleic Acids Res. 23: 3989-94; Dudycz, 1995, WO 95/11910; Madadam et al., 1998, WO 98/37240; Reese et al., 1997, WO 97/29116).

Modified internucleotide phosphate radicals and/or nonphosphorus bridges in a nucleic acid which can be employed in one of the uses according to the invention 19 contain, for example, methylphosphonate, phosphorothioate, phosphoramidate, phosphorodithioate, phosphate ester, while non-phosphorus internucleotide analogues, for example, contain siloxane bridges, carbonate bridges, carboxymethyl esters, acetamidate bridges and/or thioether bridges. It is also intended that this modification should improve the shelf life of a pharmaceutical composition which can be employed in one of the uses according to the invention.

In a further embodiment of the invention, the nucleic acids used according to the invention are used for the preparation of a vector, preferably in the form of a shuttle vector, phagemid, cosmid, expression vector or vector having gene therapy activity.

Furthermore, knock-out gene constructs or expression cassettes can be prepared using the nucleic acids described above.

Thus, the nucleic acid used according to the invention can be contained in a vector, preferably in 20 an expression vector or vector having gene therapy activity. Preferably, the vector having gene therapy *e activity contains wound- or skin-specific regulatory S* "sequences which are functionally associated with the nucleic acid described above.

25 The expression vectors can be prokaryotic or eukaryotic expression vectors. Examples of prokaryotic expression vectors are, for expression in E.coli, e.g.

the vectors pGEM or pUC derivatives, examples of eukaryotic expression vectors are for expression in Saccharomyces cerevisiae, e.g. the vectors p426Met25 or Sp426GAL1 (Mumberg et al. (1994) Nucl. Acids Res., 22, 5767-5768), for expression in insect cells, e.g.

Baculovirus vectors such as disclosed in EP-Bl-0 127 839 or EP-B1-0 549 721, and for expression in mammalian cells, e.g. the vectors Rc/CMV and Rc/RSV or vectors, which are all generally obtainable.

20 In general, the expression vectors also contain promoters suitable for the respective host cell, such as, for example, the trp promoter for expression in E.coli (see, for example, EP-B1-0 154 133), the Met GAL 1 or ADH2 promoter for expression in yeasts (Russel et al. (1983), J. Biol. Chem. 258, 2674-2682; Mumberg, supra), the Baculovirus polyhedrin promoter, for expression in insect cells (see, for example, EP-Bl-0 127 839). For expression in mammalian cells, for example, suitable promoters are those which allow a constitutive, regulatable, tissue-specific, soil-cyclespecific or metabolically specific expression in eukaryotic cells. Regulatable elements according to the present invention are promoters, activator sequences, enhancers, silencers and/or repressor sequences.

Examples of suitable regulatable elements which make possible constitutive expression in eukaryotes are promoters which are recognized by the RNA polymerase III or viral promoters, CMV enhancer, CMV promoter 20 (also see Example 13), SV40 promoter or LTR promoters, 9** e.g. from MMTV (mouse mammary tumour virus; Lee et al.

(1981) Nature 214, 228-232) and further viral promoter and activator sequences, derived from, for example, HBV, HCV, HSV, HPV, EBV, HTLV or HIV.

Examples of regulatable elements which make possible inducible expression in eukaryotes are the tetracycline operator in combination with a corresponding repressor (Gossen M. et al. (1994) Curr.

Opin. Biotechnol. 5, 516-20) Preferably, the expression of wound-healingrelevant genes takes place under the control of tissuespecific promoters, where skin-specific promoters such as, for example, the human K10 promoter (Bailleul et al., 1990. Cell 62: 697-708), the human K14 promoter (Vassar et al., 1989, Proc. Natl. Acad. Sci. USA 86: 1563-67) or the bovine cytokeratin IV promoter (Fuchs 21 et al., 1988; The biology of wool and hair (ed.

G.E. Rogers, et pp. 287-309. Chapman and Hall, London/New York) are particularly to be preferred.

Further examples of regulatable elements which make possible tissue-specific expression in eukaryotes are promoters or activator sequences from promoters or enhancers of those genes which code for proteins which are only expressed in certain cell types.

Examples of regulatable elements which make possible cell cycle-specific expression in eukaryotes are promoters of the following genes: cdc25, cyclin A, cyclin E, cdc2, E2F, B-myb or DHFR (Zwicker J. and MOller R. (1997) Trends Genet. 13, 3-6).

Examples of regulatable elements which make possible metabolically specific expression in eukaryotes are promoters which are regulated by hypoxia, by glucose deficiency, by phosphate concentration or by heat shock.

In order to make possible the introduction of 20 nucleic acids used according to the invention and thus the expression of the polypeptide in a eu- or prokaryotic cell by transfection, transformation or infection, the nucleic acid can be present as a plasmid, as part of a viral or non-viral vector.

25 Suitable viral vectors here are particularly: baculoviruses, vaccinia viruses, adenoviruses, adenoassociated viruses and herpesviruses. Suitable nonviral vectors here are particularly: virosomes, liposomes, cationic lipids, or poly-lysine-conjugated 30 DNA.

Examples of vectors having gene therapy activity are virus vectors, for example adenovirus vectors or retroviral vectors (Lindemann et al., 1997, Mol. Med.

3: 466-76; Springer et al., 1998, Mol. Cell. 2: 549- 58). Eukaryotic expression vectors are suitable in 22 isolated form for gene therapy use, as naked DNA can penetrate into skin cells on topical application (Hengge et al., 1996, J. Clin. Invest. 97: 2911-6; Yu et al., 1999, J. Invest. Dermatol. 112: 370-5).

Vectors having gene therapy activity can also be obtained by complexing the nucleic acid used according to the invention with liposomes, since a very high transfection efficiency, in particular of skin cells, can thus be achieved (Alexander and Akhurst, 1995, Hum.

Mol. Genet. 4: 2279-85). In the case of lipofection, small unilamellar vesicles are prepared from cationic lipids by ultrasonic treatment of the liposome suspension. The DNA is bound ionically to the surface of the liposomes, namely in such a ratio that a positive net charge remains and the plasmid DNA is complexed to 100% of the liposomes. In addition to the lipid mixtures DOTMA (1,2-dioleyloxypropyl-3-trimethylammonium bromide) and DPOE (dioleoylphosphatidylethanolamine) employed by Felgner et al. (1987, supra), 20 meanwhile numerous novel lipid formulations were synthesized and tested for their efficiency in the

S.

transfection of various cell lines (Behr, J.P. et al.

(1989), Proc. Natl. Acad. Sci. USA 86, 6982-6986; Felgner, J.H. et al. (1994) J. Biol. Chem. 269, 2550- 2561; Gao, X. Huang, L. (1991), Biochim. Biophys.

Acta 1189, 195-203). Examples of the novel lipid *e formulations are DOTAP N-[1-(2,3-dioleoyloxy)propyl]- N,N,N-trimethylammonium ethyl-sulphate or DOGS (TRANSFECTAM; diocta-decylamidoglycylspermine).

Auxiliaries which increase the transfer of nucleic acids into the cell can be, for example, proteins or peptides which are bound to DNA or synthetic peptide- DNA molecules which make possible the transport of the nucleic acid into the nucleus of the cell (Schwartz et al. (1999) Gene Therapy 6, 282; Brand6n et al. (1999) Nature Biotech. 17, 784). Auxiliaries also include 23 molecules which make possible the release of nucleic acids into the cytoplasm of the cell (Planck et al.

(1994) J. Biol. Chem. 269, 12918; Kichler et al. (1997) Bioconj. Chem. 8, 213) or, for example, liposomes (Uhlmann and Peymann (1990) supra). Another particularly suitable form of gene therapy vectors can be obtained by applying the nucleic acid used according to the invention to gold particles and shooting these into tissue, preferably into the skin, or cells with the aid of the so-called gene gun (Example 13; Wang et al., 1999, J. Invest. Dermatol., 112: 775-81, Tuting et al., 1998, J. Invest. Dermatol. 111: 183-8).

A further form of a vector having gene therapy activity can be prepared by the introduction of "naked" expression vectors into a biocompatible matrix, for example a collagen matrix. This matrix can be introduced into wounds in order to transfect the immigrating cells with the expression vector and to express the polypeptides according to the invention in the cells (Goldstein and Banadio, US 5,962,427).

For gene therapy use of the nucleic acid described above, it is also advantageous if the part of the nucleic acid which codes for the polypeptide contains one or more non-coding sequences including intron 25 sequences, preferably between promoter and the start codon of the polypeptide, and/or a polyA sequence, in S"particular the naturally occurring polyA sequence or an virus polyA sequence, especially at the 3' end of the gene, as a stabilization of the mRNA can be 30 achieved thereby (Jackson, R.J. (1993) Cell 74, 9-14 and Palmiter, R.D. et al. (1991) Proc. Natl. Acad. Sci.

USA 88, 478-482).

Knock-out gene constructs are known to the person skilled in the art, for example, from the US patents 5,625,122; US 5,698,765; US 5,583,278 and US 5,750,825.

24 The present invention further relates to a host cell, in particular a skin cell, which is transformed using a vector according to the invention or a knockout gene construct. Host cells can be either prokaryotic or eukaryotic cells, examples of prokaryotic host cells are E.coli and examples of eukaryotic cells are Saccharomyces cerevisiae or insect cells.

A particularly preferred transformed host cell is a transgenic embryonic non-human stem cell, which is characterized in that it comprises a knock-out gene construct according to the invention or an expression cassette according to the invention. Processes for the transformation of host cells and/or stem cells are well known to the person skilled in the art and include, for example, electroporation or microinjection.

The invention further relates to a transgenic nonhuman mammal whose genome comprises a knock-out gene construct as described above or an expression cassette as described above. Transgenic animals in general show a tissue-specifically increased expression of the nucleic acids and/or polypeptides and can be used for the analysis of wound healing disorders. Thus, for example, an activin A transgenic mouse exhibits 25 improved wound healing (Munz et al., 1999, EMBO J. 18: 5205-15) while a transgenic mouse having a dominantly negative KGF receptor exhibits delayed wound healing (Werner et al., 1994, Science 266: 819-22).

Processes for the preparation of transgenic 30 animals, in particular of the mouse, are likewise known to the person skilled in the art from DE 196 25 049 and US 4,736,866; US 5,625,122; US 5,698,765; US 5,583,278 and US 5,750,825 and include transgenic animals which can be produced, for example, by means of direct injection of expression vectors (see above) into embryos or spermatocytes or by means of the 25 transfection of expression vectors into embryonic stem cells (Polites and Pinkert: DNA Microinjection and Transgenic Animal Production, page 15 to 68 in Pinkert, 1994: Transgenic animal technology: a laboratory handbook, Academic Press, London, UK; Houdebine, 1997, Harwood Academic Publishers, Amsterdam, The Netherlands; Doetschman: Gene Transfer in Embryonic Stem Cells, page 115 to 146 in Pinkert, 1994, supra; Wood: Retrovirus-Mediated Gene Transfer, page 147 to 176 in Pinkert, 1994, supra; Monastersky: Gene Transfer Technology; Alternative Techniques and Applications, page 177 to 220 in Pinkert, 1994, supra).

If nucleic acids used according to the invention are integrated into so-called targeting vectors (Pinkert, 1994, supra), it is possible after transfection of embryonic stem cells and homologous recombination, for example, to generate knock-out mice which, in general, as heterozygous mice, show decreased expression of the nucleic acid, while homozygous mice 20 no longer exhibit expression of the nucleic acid. The animals thus produced can also be used for the analysis of wound healing disorders. Thus, for example, the eNOS (Lee et al., 1999, Am. J. Physiol. 277: H1600-1608), Nf-1 (Atit et al., 1999, J. Invest. Dermatol. 112: 835- 25 42) and osteopontin (Liaw et al., 1998, J. Clin.

Invest. 101: 967-71) knock-out mice exhibit impaired wound healing. Here too, a tissue-specific reduction of the expression of wound healing-relevant genes, for example in skin-specific cells using the Cre-loxP 30 system (stat3 knock-out, Sano et al., EMBO J 1999 18: 4657-68), is particularly to be preferred. Transgenic and knock-out cells or animals produced in this way can also be used for the screening and for the identification of pharmacologically active substances vectors having gene therapy activity.

26 The invention further relates to a process for preparing a polypeptide for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances in a suitable host cell, which is characterized in that a nucleic acid as described above is used.

The polypeptide is prepared, for example, by expression of the nucleic acid described above in a suitable expression system, as already explained above, according to the methods generally known to the person skilled in the art. Suitable host cells are, for example, the E.coli strains DHS, HB101 or BL21, the yeast strain Saccharomyces cerevisiae, the insect cell line Lepidoptera, e.g. from Spodoptera frugiperda, or the animal cells COS, Vero, 293, HaCaT, and HeLa, which are all generally obtainable.

o The invention further relates to a process for preparing a fusion protein for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances in a suitable host cell, in which a nucleic 25 acid as described above is used.

Fusion proteins are prepared here as explained above which contain the polypeptides described above as, the fusion proteins themselves already having the function of a polypeptide as described above or the specific function being functionally active only after cleavage of the fusion portion. Especially included here are fusion proteins having a proportion of about 1-300, preferably about 1-200, in particular about 1- 100, especially about 1-50, foreign amino acids.

Examples of such peptide sequences are prokaryotic peptide sequences, which can be derived, for example, 27 from the galactosidase of E.coli. Furthermore, viral peptide sequences, such as, for example, of the bacteriophage M13 can also be used in order thus to produce fusion proteins for the phage display process known to the person skilled in the art.

Further preferred examples of peptide sequences for fusion proteins are peptides, that facilitate easier detection of the fusion proteins, these are, for example, "Green-Fluorescent-protein" or variants thereof.

For the purification of the proteins described above further polypeptide(s) (tag) can be attached.

Suitable protein tags allow, for example, high-affinity absorption to a matrix, stringent washing with suitable buffers without eluting the complex to a noticeable extent and subsequently targeted elution of the absorbed complex. Examples of the protein tags known to the person skilled in the art are a (His) 6 tag, a Myc tag, a FLAG tag, a haemaglutinin tag, glutathione 20 transferase (GST) tag, intein having an affinity chitin-binding tag or maltose-binding protein (MBP) tag. These protein tags can be situated N- or Cterminally and/or internally.

~The invention further relates to a process for producing an antibody, preferably a polyclonal or monoclonal antibody, for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active 30 substances, in which a polypeptide or functional equivalents thereof or parts thereof having at least 6 amino acids, preferably having at least 8 amino acids, in particular having at least 12 amino acids is used according to the present invention.

28 The process is carried out according to methods generally known to the person skilled in the art by immunizing a mammal, for example a rabbit, with the polypeptide described above or the mentioned parts thereof, if appropriate in the presence of, for example, Freund's adjuvant and/or aluminium hydroxide gels (see, for example, Diamond, B.A. et al. (1981) The New England Journal of Medicine, 1344-1349). The polyclonal antibodies formed in the animal as a result of an immunological reaction can then be easily isolated from the blood according to generally known methods and purified, for example, by means of column chromatography. Monoclonal antibodies can be produced, for example, according to the known method of Winter Milstein (Winter, G. Milstein, C. (1991) Nature, 349, 293-299) The present invention further relates to an antibody for the diagnosis and/or prevention and/or .treatment of disorders, in particular skin disorders, 20 or treatment in wound healing or for the identification of pharmacologically active substances, which is .eoeei Sdirected against a polypeptide described above and reacts specifically with the polypeptides described above, where the abovementioned parts of the eeoc polypeptide are either immunogenic themselves or can be rendered immunogenic by coupling to suitable carriers, such as, for example, bovine serum albumin, or can be increased in their immunogenicity. This antibody is either polyclonal or monoclonal, preferably it is a monoclonal antibody. The term antibody is understood S"according to the present invention as also meaning antibodies or antigen-binding parts thereof prepared by genetic engineering and optionally modified, such as, for example, chimeric antibodies, humanized antibodies, multifunctional antibodies, bi- or oligospecific antibodies, single-stranded antibodies, F(ab) or F(ab) 2 29 fragments (see, for example, EP-B1-0 368 684, US 4,816,567, US 4,816,397, WO 88/01649, WO 93/06213, WO 98/24884) The antibodies according to the invention can be used for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances.

Thus, for example, the local injection of monoclonal antibodies against TGF beta 1 can improve wound healing in the animal model (Ernst et al., 1996, Gut 39: 172-5) The present invention also relates to a process for producing a medicament for the treatment of disorders, in particular skin disorders and/or disorders in wound healing, in which at least one nucleic acid, at least one polypeptide or at least one antibody according to the present invention is combined with suitable additives and auxiliaries.

20 The present invention furthermore relates to a medicament produced by this process for the treatment of disorders, in particular skin disorders and/or **disorders in wound healing, which contains at least one eeo nucleic acid, at least one polypeptide or at least one e e antibody according to the present invention, if appropriate together with suitable additives and auxiliaries. The invention furthermore relates to the use of this medicament for the treatment of disorders, in particular skin disorders and/or disorders in wound 30 healing.

The therapy of the disorders, in particular skin disorders and/or disorders in wound healing, can be carried out in a conventional manner, e.g. by means of dressings, plasters, compresses or gels which contain the medicaments according to the invention. It is thus 30 possible to administer the pharmaceuticals containing the suitable additives or auxiliaries, such as, for example, physiological saline solution, demineralized water, stabilizers, proteinase inhibitors, gel formulations, such as, for example, white petroleum jelly, highly liquid paraffin and/or yellow wax, etc., topically and locally in order to influence wound healing immediately and directly. The administration of the medicaments according to the invention can furthermore also be carried out topically and locally in the area of the wound, if appropriate in the form of liposome complexes or gold particle complexes.

Furthermore, the treatment can be carried out by means of a transdermal therapeutic system (TTS), which makes possible a temporally controlled release of the medicaments according to the invention. The treatment by means of the medicaments according to the invention, however, can also be carried out by means of oral dosage forms, such as, for example, tablets or o e 20 capsules, by means of the mucous membranes, for example *the nose or the oral cavity, or in the form of dispositories implanted under the skin. TTS are known for example, from EP 0 944 398 Al, EP 0 916 336 Al, EP 0 889 723 Al or EP 0 852 493 Al.

The present invention furthermore relates to a process for preparing a diagnostic for the diagnosis of disorders, in particular skin disorders or disorders in wound healing, which is characterized in that at least one nucleic acid, at least one polypeptide or at least 30 one antibody according to the present invention is used, if appropriate together with suitable additives and auxiliaries.

For example, it is possible according to the present invention to prepare a diagnostic based on the polymerase chain reaction (Examples 5, 8 and 9 PCR diagnostic, e.g. according to EP 0 200 362) or an RNase 31 protection assay, such as shown in detail in Example 4, with the aid of a nucleic acid described above. These tests are based on the specific hybridization of the nucleic acids described above with the complementary counter strand, usually of the corresponding mRNA. The nucleic acid useable according to the invention can in this case also be modified, such as described, for example, in EP 0 063 879. Preferably a DNA fragment as described above is labeled according to generally known methods by means of suitable reagents, e.g.

radioactively with a-P 32 -dCTP or non-radioactively with biotin or digoxigenin, and incubated with isolated RNA, which has preferably been bound beforehand to suitable membranes of, for example, cellulose or nylon. With the same amount of investigated RNA from each tissue sample, the amount of mRNA which was specifically labeled by the probe can thus be determined and compared to the amount of mRNA from healthy tissue.

Alternatively, the determination of mRNA can also be e. 20 carried out in tissue sections with the aid of in situ hybridization (see, for example, Werner et al., 1992, Proc. Natl. Acad. Sci. USA 89: 6896-6900) With the aid of the diagnostic according to the invention, a tissue sample can thus also be 25 specifically measured in vitro for the strength of expression of the corresponding gene in order to be able to safely diagnose a possible wound healing disorder or dermatological disorders (Examples 4, 5, 8, 9 and 10). Such a process is particularly suitable for the early prognosis of disorders. This makes possible commencement of preventive therapy and the analysis of predispositions. Thus the expression of the gene spi2 is already decreased in the unwounded state in intact skin which exhibited wound healing disorders after wounding. The expression of the gene spi2 therefore 32 makes possible a prediction of the wound healing disorder even in the intact tissue.

The present invention furthermore relates to a diagnostic for the diagnosis of disorders, in particular skin disorders or disorders in wound healing, which comprises at least one nucleic acid, at least one polypeptide or at least one antibody according to the invention, if appropriate together with suitable additives and auxiliaries.

A further diagnostic according to the invention contains the polypeptide used according to the invention or the immunogenic parts thereof described in greater detail above. The polypeptide or the parts thereof, which are preferably bound to a solid phase, e.g. of nitrocellulose or nylon, can be brought into contact in vitro, for example, with the body fluid to be investigated, e.g. wound secretion, in order thus to be able to react, for example, with autoimmune **antibodies. The antibody-peptide complex can then be 20 detected, for example, with the aid of labeled antihuman IgG or antihuman IgM antibodies. The labeling involves, for example, an enzyme, such as peroxidase, which catalyses a color reaction. The presence and the amount of autoimmune antibody present can thus be 25 detected easily and rapidly by means of the color reaction.

Another diagnostic contains the antibodies according to the invention themselves. With the aid of these antibodies, it is possible, for example, to easily and rapidly investigate a tissue sample as to whether the concerned polypeptide is present in an increased amount in order to thereby obtain an indication of a possible wound healing disorder. In this case, the antibodies according to the invention are labeled, for example, with an enzyme, as already described above. The specific antibody-peptide complex 33 can thereby be detected easily and also rapidly by means of an enzymatic colour reaction (see examples 11 and 12).

A further diagnostic according to the invention comprises a probe, preferably a DNA probe, and/or primer. This opens up a further possibility of obtaining the nucleic acids useable according to the invention, for example by isolation from a suitable gene bank, for example from a wound-specific gene bank, with the aid of a suitable probe (see, for example, J.

Sambrook et al., 1989, Molecular Cloning. A Laboratory Manual 2 nd edn., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY Chapter 8 page 8.1 to 8.81, Chapter 9 page 9.47 to 9.58 and Chapter 10 page 10.1 to 10.67).

Suitable probes are, for example, DNA or RNA fragments having a length of about 100-1000 nucleotides, preferably having a length of about 200- 500 nucleotides, in particular having a length of about 300-400 nucleotides, whose sequence can be derived from the polypeptide sequences according to SEQ ID No. 1 to SEQ ID No. 48, SEQ ID No. 51 to SEQ ID No. 58, SEQ ID No. 89 to SEQ ID No. 94, SEQ ID No. 101 to SEQ ID No.

106 and SEQ ID No. 109 to SEQ ID No. 114 of the sequence protocol, the nucleic acid sequences according 25 to SEQ ID No. 49 to SEQ ID No. 50 of the sequence protocol and/or with the aid of the cDNA sequences of eee*e the database entries indicated in Figures 4 to 6 (see also Example 4 and Alternatively, it is possible with the aid of the 30 derived nucleic acid sequences to synthesize oligonucleotides which are suitable as primers for a polymerase chain reaction. Using this, the nucleic acid according to the invention or parts of this can be amplified and isolated from cDNA, for example woundspecific cDNA (Examples 5 and Suitable primers are, for example, DNA fragments having a length of about 34 100 nucleotides, preferably having a length of about to 50 nucleotides, in particular having a length of nucleotides, whose sequence can be derived from the polypeptides according to SEQ ID No. 1 to SEQ ID No. 48, SEQ ID No. 51 to SEQ ID No. 58, SEQ ID No. 89 to SEQ ID No. 94, SEQ ID No. 101 to SEQ ID No. 106 and SEQ ID No. 109 to SEQ ID No. 114 of the sequence protocol, the nucleic acid sequences according to SEQ ID No. 49 to SEQ ID No. 50 of the sequence protocol and/or with the aid of the cDNA sequences of the database entries indicated in Figures 4 to 6 (Example 4).

The invention furthermore relates to a process for preparing a test for the discovery of functional interactors in connection with disorders, in particular skin disorders or treatment in wound healing, characterized in that at least one nucleic acid, at least one polypeptide or at least one antibody according to the present invention, if appropriate together with suitable additives and auxiliaries, is used for preparing the test.

ooooo: The term "functional interactors" in the sense of the present invention is understood as meaning all those molecules, compounds and/or compositions and coo• substance mixtures which can interact under suitable conditions with the nucleic acids, polypeptides or S"antibodies as described above, if appropriate together Swith suitable additives and auxiliaries. Possible interactors are simple chemical organic or inorganic 30 molecules or compounds, but can also include peptides, proteins or complexes thereof. On account of their interaction, the functional interactors can influence the function(s) of the nucleic acids, polypeptides or antibodies in vivo or in vitro or alternatively only bind to the nucleic acids, polypeptides or antibodies 35 as described above or enter into other interactions of covalent or non-covalent manner with them.

The invention furthermore comprises a test produced according to the invention for the identification of functional interactors in connection with disorders, in particular skin disorders or treatment in wound healing, which comprises at least one nucleic acid, at least one polypeptide or at least one antibody according to the present invention, if appropriate together with suitable additives and auxiliaries.

A suitable system can be produced, for example, by the stable transformation of epidermal or dermal cells with expression vectors which contain selectable marker genes and the nucleic acids described above. In this process, the expression of the nucleic acids described above is altered in the cells such that it corresponds to the pathologically disturbed expression in vivo.

ago Anti-sense oligonucleotides which contain the nucleic S 20 acid sequence useable according to the invention can also be employed for this purpose. It is therefore of particular advantage for these systems to know the expression behavior of the genes in disturbed regenerative processes, such as disclosed in this 25 application. Often, the pathological behavior of the cells in vitro can thus be imitated and substances can S•be sought which reproduce the normal behavior of the S"cells and which have a therapeutic potential.

Suitable cells for these test systems are, for 30 example, HaCaT cells, which are generally obtainable, and the expression vector pCMV4 (Anderson et al., 1989, J. Biol. Chem. 264: 8222-9). The nucleic acid useable according to the invention can in this case be integrated into the expression vectors both in the sense and in the anti-sense orientation, such that the functional concentration of mRNA of the corresponding 36 genes in the cells is either increased, or is decreased by hybridization with the antisense RNA. After the transformation and selection of stable transformers, the cells in culture in general show an altered proliferation, migration and/or differentiation behavior in comparison with control cells. This behavior in vitro is often correlated with the function of the corresponding genes in regenerative processes in the body (Yu et al., 1997, Arch. Dermatol. Res. 289: 352-9; Mils et al., 1997, Oncogene 14: 15555-61; Charvat et al., 1998, Exp Dermatol 7: 184-90; Mythily et al., 1999, J. Gen. Virol. 80: 1707-13; Werner, 1998, Cytokine Growth Factor Rev. 9: 153-65) and can be detected using tests which are simple and rapid to carry out, such that test systems for pharmacologically active substances based thereon can be constructed.

Thus, the proliferation behavior of cells can be detected very rapidly by, for example, the incorporation of labeled nucleotides into the DNA of 20 the cells (see, for example, Fries and Mitsuhashi, 1995, J. Clin. Lab. Anal. 9: 89-95; Perros and Weightman, 1991, Cell Prolif. 24: 517-23; Savino and Dardenne, 1985, J. Immunol. Methods 85: 221-6), by staining the cells with specific stains (Schulz et al., 1994, J. Immunol. Methods 167: 1-13) or by means of immunological processes (Frahm et al., 1998, J.

Immunol. Methods 211: 43-50). The migration can be detected simply by the migration index test (Charvat et al., supra) and comparable test systems (Benestad et 30 al., 1987, Cell Tissue Kinet. 20: 109-19, Junger et al., 1993, J. Immunol. Methods 160: 73-9) Suitable differentiation markers are, for example, keratin 6, and 14 and also loricrin and involucrin (Rosenthal et al., 1992, J. Invest. Dermatol. 98: 343-50), whose expression can be easily detected, for example, by means of generally obtainable antibodies.

37 Another suitable test system is based on the identification of functional interactions using the socalled two-hybrid system (Fields and Sternglanz, 1994, Trends in Genetics, 10, 286-292; Colas and Brent, 1998 TIBTECH, 16, 355-363). In this test, cells are transformed using expression vectors which express fusion proteins from the polypeptide useable according to the invention and a DNA binding domain of a transcription factor such as, for example, Gal4 or LexA. The transformed cells additionally contain a reporter gene, whose promoter contains binding sites for the corresponding DNA binding domains. By transformation of a further expression vector which expresses a second fusion protein from a known or unknown polypeptide having an activation domain, for example of Gal4 or herpesvirus VPI6, the expression of the reporter gene can be greatly increased if the second fusion protein interacts functionally with the polypeptide useable according to the invention. This co -20 increase in expression can be utilized in order to identify novel interactors, for example by preparing a cDNA library from regenerating tissue for the construction of the second fusion protein. Moreover, this test system can be utilized for the screening of substances which inhibit an interaction between the polypeptide useable according to the invention and a functional interactor. Such substances decrease the expression of the reporter gene in cells which express fusion proteins of the polypeptide useable according to 30 the invention and of the interactor (Vidal and Endoh, 1999, Trends in Biotechnology; 17: 374-81). Novel active compounds which can be employed for the therapy of disorders of regenerative processes can thus be rapidly identified.

Functional interactors of the polypeptides used according to the invention can also be nucleic acids 38 which are isolated by means of selection processes, such as, for example, SELEX (see Jayasena, 1999, Clin.

Chem. 45: 1628-50; Klug and Famulok, 1994, M. Mol.

Biol. Rep. 20: 97-107; Toole et al., 1996, US 5582981).

In the SELEX process, typically those molecules which bind to a polypeptide with high affinity (aptamers) are isolated by repeated amplification and selection from a large pool of different, single-stranded RNA molecules.

Aptamers can also be synthesized and selected in their enantiomorphic form, for example as the Lribonucleotide (Nolte et al., 1996, Nat. Biotechnol.

14: 1116-9; Klussmann et al., 1996, Nat. Biotechnol.

14: 1112-5). Thus isolated forms have the advantage that they are not degraded by naturally occurring ribonucleases and therefore have greater stability.

The invention further relates to a process for preparing an array immobilized on a support material for analysis in connection with disorders, in particular skin disorders or disorders in wound 20 healing, in which at least one nucleic acid, at least g one polypeptide and/or at least one antibody as described above is used for preparation.

Processes for preparing such arrays are known, for example, from WO 89/10977, WO 90/15070, WO 95/35505 and 25 US 5,744,305 by means of spotting, printing or solidphase chemistry in connection with photolabile protective groups.

The invention further relates to an array immobilized on a support material for analysis in 30 connection with disorders, in particular skin disorders or disorders in wound healing, which comprises at least one nucleic acid, at least one polypeptide and/or at least one antibody as described above.

A preferred embodiment of the process for preparing an array immobilized on a support material 39 according to the invention is a process for preparing DNA-chips and/or protein-chips for analysis in connection with disorders, in particular skin disorders or disorders in wound healing, in which at least one nucleic acid, at least one polypeptide and/or at least one antibody as described above is used for preparation.

Processes for preparing such DNA-chips and/or protein-chips are known, for example, from WO 89/10977, WO 90/15070, WO 95/35505 and US 5,744,305 by means of spotting, printing or solid phase chemistry in connection with photolabile protective groups.

Accordingly a preferred subject matter of the invention comprises a DNA chip and/or protein chip for analysis in connection with disorders, in particular skin disorders or disorders in wound healing, which comprises at least one nucleic acid and/or at least one polypeptide and/or at least one antibody according to the present invention. DNA chips are known, for 20 example, from US 5,837,832.

The present invention also relates to a medicament for the indication and therapy, which contains a nucleic acid useable according to the invention or a polypeptide useable according to the invention and, if appropriate, suitable additives and auxiliaries and a process for preparing such a medicament for the treatment of dermatological disorders, in particular of wound healing disorders, in which a nucleic acid useable according to the invention or a polypeptide 30 useable according to the invention is formulated with a pharmaceutically acceptable carrier.

For gene therapy use in man, a medicament is especially suitable which contains the nucleic acid useable according to the invention in naked form or in the form of one of the vectors having gene therapy 40 activity described above or in a form complexed with liposomes or gold particles. The pharmaceutical vehicle is, for example, a physiological buffer solution, preferably having a pH of about 6.0-8.0, preferably of about 6.8-7.8, in particular of about 7.4, and/or an osmolarity of about 200-400 milliosmol/litre, preferably of about 290-310 milliosmol/litre. In addition, the pharmaceutical vehicle can contain suitable stabilizers, such as, for example, nuclease inhibitors, preferably complexing agents such as EDTA and/or other auxiliaries known to the person skilled in the art.

The administration of the nucleic acid described above, if appropriate in the form of the virus vectors described above in greater detail or as liposome complexes or gold particle complex usually takes place topically and locally in the area of the wound. It is also possible to administer the polypeptide itself with suitable additives or auxiliaries, such as, for example, physiological saline solution, demineralized water, stabilizers, proteinase inhibitors, gel formulations, such as, for example, white petroleum jelly, highly liquid paraffin and/or yellow wax, etc., in order to influence the wound healing immediately and 25 directly.

The nucleic acids of the polypeptides useable Saccording to the invention were isolated from cDNA libraries which were prepared from intact and wounded skin. In the course of this, the cDNAs were selected 30 which had different abundancies in well-healing wounds in comparison with poorly healing wounds (Example 1).

This took place, for example, with the aid of subtractive hybridization (Diatchenko et al., 1996, Proc. Natl. Acad. Sci. USA 93: 6025-30) and/or with the comparative counting out of clones in cDNA libraries by means of sequencing ("ESTs", Adams et al., 1992, Nature 41 355, 632-4; Adams et al., 1991, Science 252, 1651-6) The cDNAs counted out in this way are derived from genes which are expressed either more strongly or more weakly in wound healing disorders than in normally proceeding wound healing.

Generally, the analysis of differentially expressed genes in tissues is afflicted with distinctly more errors in the form of false-positive clones than in the analysis of cell culture systems. This problem can not be circumvented by the use of defined cell culture systems, as suitable cell systems are not available due to the high complexity of the wound healing process and existing simple cell culture systems do not adequately mimick the tissue. This problem is especially prominent in the skin, which consists of a variety of different cell types.

Furthermore, the process of wound healing is a highly complicated process, which comprises temporal and spatial changes of cellular processes like 20 proliferation and differentiation of these various cell types. Due to these problems, the success of the oeooo screening depended critically on the selection of the experimental parameters. By targeted choice of parameters a novel screening- and verification strategy was used. The point in time for taking biopsies is critical for the success of the screening: impaired wound healing and skin disorders are often caused by disturbed cell proliferation and cell differentiation.

These processes are initiated at day 1 after wounding, which is why the analysis of the molecular processes *prior to this point in time would allow little insight into those processes, that are essential to normally progressing wound healing. However, during the progress of wound healing the composition of cell types in the wound strongly changes after day 1 after wounding. This can result in the measurement of differential 42 expression of a specific gene in a wound, which is not caused by the changed expression in the cells, but is only caused by the altered cell composition. This corroborates, that the selection of the point in time when biopsies are taken is decisive for the success of the screening.

Moreover, there are enormous variabilities in the wound condition at the time of a possible biopsy of the patient on initial contact with the physician. An animal model was therefore used for the identification of the above described nucleic acids. BALB/c mice were wounded and wound biopsies were taken at various points in time. This process has the advantage that the boundary conditions such as genetic background, nature of the wound, time of the biopsy etc. can be exactly controlled and thus only allow a reproducible analysis of gene expression. Even under the defined mouse conditions, further methodological problems result such as redundancy of the analysed clones and 20 underrepresentation of weakly expressed genes, which complicate the identification of relevant genes. In addition, we observed an overrepresentation of genes, which are differentially expressed during the process of wound healing, but which are not suited for the use S. 25 in wound healing or for skin disorders. These genes comprise, for example, genes encoding proteins of the basic metabolism, e.g. glycolysis, citrate cycle, gluconeogenesis and the respiratory chain, but also genes encoding ribosomal proteins, e.g. L41 and In the present analysis of gene expression, during the wound healing process, in addition to genes whose function was completely unknown until now, genes were also identified which until now were unconnected with wound healing disorders. Novel variants of some of the known genes were furthermore identified with sequences 43 which significantly differ from the sequences published and/or patented until now.

Of the part of the identified genes not connected with wound healing disorders until now, it was known until now that they have a function in proliferation (NF1-B: Schuur et al., 1995, Cell Growth Differ. 6: 219-27; potentially prenylated protein tyrosine phosphatase: Zeng et al., 1998, 244: 421-7; mas oncogene: van 't Veer et al., 1988, Oncogene Res. 3: 247-54; CBP: Blobel et al., 1998, Proc. Natl. Acad.

Sci. USA 95: 2061-6; BTG1: Rouault et al., 1992, EMBO J. 11: 1663-70; Acylamino acid-releasing enzyme: Schoenberger et al., 1986, J. Clin. Chem. Clin.

Biochem. 24: 375-8; ALFl: Loveys et al., 1996, Nucleic.

Acids Res. 24: 2813-20, p68 RNA helicase: Ford et al., 1988, Nature 332: 736-8, Nup98: Kasper et al., 1999, Mol. Cell. Biol. 19: 764-76; ribonuclease L inhibitor: Benoit et al., 1998, Gene 209: 149-56; cathepsin Z: Santamaria et al., 1998, J. Biol. Chem. 273: 16818-23) 20 cell cycle control (Checkpoint suppressor 1: Pat et al., 1997, Mol. Cell. Biol 17: 3037-46), cell migration (Ryoducan: Woods and Couchman, 1994, Mol. Biol. Cell 1183-92), differentiation (mKAP13: Aoki et al., 1998, J. Invest. Dermatol. 111: 804-9; pmg-2: Kuhn et al., 25 1999, Mech. Dev 86: 193-196, calnexin: Olsen et al., 1995, Electrophoresis 16: 2241-8, JEM-1: Tong et al., 1998, Leukemia 12: 1733-40; CD9: Jones et al., 1996, Cell Adhes. Commun. 4: 297-305; rab2: Ayala et al., 1990, Neuron 4: 797-805; stearoyl-COA desaturase: Singh 30 and Ntambi, 1998, Biochim. Biophys. Acta 1398: 148-56; cardiac ankyrin repeat protein: Zou et al., 1997, Development 124: 793-804) and/or apoptosis (MA-3: Shibahara et al., 1995, Gene 166: 297-301). However, these genes were not connected with wound healing until now (Table 4).

44 In addition to the known polypeptides of man (Bisbal et al., 1995, J. Biol. Chem. 270: 13308-17) and mouse (De Coignac et al., 1998, Gene 209: 149-56) ribonuclease L inhibitor and mouse p68 RNA helicase (Lemaire and Heinlein, 1993, Life Sci. 52: 917-26), closely related polypeptides having a significantly differing sequence were identified. From the known mouse mKAPl3/Pmgl polypeptide (Aoki et al., 1998, J.

Invest. Dermatol. 111, 804-9), the sequence of the corresponding polypeptide of man was identified for the first time (Example 7) (SEQ ID No. 55). In addition to this polypeptide from man 6 further homologues of mKAP13 were identified that were not known until now (SEQ ID No. 89 to SEQ ID No. 94). Furthermore SEQ ID No. 109 depicts an additional variant of the mas oncogene of mouse, that was not known until now (Metzger et al., 1995, FEBS Lett.357: 27-32).

Furthermore, in addition to the known Jem-1 of man i. (Tong et al., 1998, Leukemia 12: 1733-1740) a further 20 variant from man (SEQ ID No. 110) not known until now, as well as two variants from mouse (SEQ ID No. 112 and SEQ ID No. 111) that were not known until now could be identified. In addition to the already known sequences of MCARP from mouse (Zhou et al., 1997, Development,

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25 124: 793-804) and NF-1B(GP:BAA92677) from man closely related polypeptides with differing sequence were S...identified (SEQ ID No. 113 and SEQ ID No. 114) Furthermore, in addition to the polypeptides HSPC028 and KIAAO614 described from man (Table 2) the 30 corresponding sequences from mouse were identified for the first time (SEQ ID No. 107 SEQ ID No. 108).

The polypeptides of these genes do not belong to the targets known until now of therapies of wound healing disorders, such that completely novel therapeutic approaches result from this invention. Of the remaining identified genes, still no relevant 45 functional description exists (Table Moreover, it was possible to find a gene whose mRNA is not translated and is functional as an RNA (SEQ ID No. 49 to SEQ ID No. 50; steroid receptor coactivator: Lanz et al., 1999, Cell 97: 17-27).

After the primary identification of the genes, it is necessary to confirm the wound healing-specific expression by a further method. This was carried out with the aid of so-called reverse Northern blots, RNase protection assays or TaqMan assays. Using these methods, the amount of mRNA in tissue extracts from various wound healing states of 10 weeks old control mice and/or 1 year old mice and/or of 4 weeks old (=young) mice and/or mice with diabetes (db/db mouse) was determined. For example, the wound-specific expression of the clones in a subtractive cDNA library was thus determined with the aid of a reverse Northern blot (Example It was seen that about 20% of all clones in the libraries showed different signals with hybridization probes from wound cDNA in comparison with probes from intact skin (Figure After the g identification of the clones, these were partially :eooeo sequenced, redundant clones sorted out, and the sequence matched with sequence databases with the aim 25 of identifying full-length sequences of the mouse genes and the human genes (Example The sequencing and redundancy analysis of the positive clones showed that more than 75% of the clones were present a number of times and thus only about 5% of all starting clones 30 were able to be further used. A minority of these eo o wound-specific genes in turn exhibited decreased expression in poorly healing wounds. Of these, it was possible in about 50% to confirm the differential expression in the RNase protection assay, "Real-time RT-PCR" or "TaqMan assay" (Examples 4 and It was thus seen that the gene spi2 used as a marker gene was 46 expressed about 10 times more strongly in wound tissue in comparison with intact skin. It was also shown that the expression of the gene in poorly healing wounds of dexamethasone-treated and of old animals was about 2 times weaker than in normal well-healing wounds of control animals (Table 1).

For the testing or generation of full-length cDNA sequences of the nucleic acids useable according to the invention, full-length clones were generated with the aid of colony hybridization (Sambrook et al., 1989, Molecular cloning: A Laboratory Manual, Cold Spring Harbor, Cold Spring Harbor Laboratory Press, New York, Chapter 8-10) and/or PCR-based methods ("RACE", Frohman et al., 1988, Proc. Natl. Acad. Sci. USA 85: 898-9002, Chenchik et al., 1996, in A Laboratory Guide to RNA: Isolation, Analysis, and Synthesis, Ed. Kreig, Wiley- Liss, pages 272-321; "LDPCR", Barnes, 1994, Proc. Natl.

Acad. Sci. USA 91: 2216-20) both for the mouse genes and for the human genes and the sequence of these clones was determined (Example 6).

Mice are exceptionally well suited to serve as a model system for wound healing processes. To confirm that the homologous human genes, that were identified in the mouse as genes relevant to wound healing, are differentially expressed in human wound tissue, intact skin and wound tissue from man and from mouse were oeeeo investigated in parallel by means of "TaqMan analysis".

In addition it was possible to obtain detailed information, in which region of the skin a wound healing specific regulated expression takes place, through in situ hybridization or immunolocalization of the nucleic acids or polypeptides used according to the invention in intact skin and wound tissue. This provides information about the function of the wound relevant gene in the wound healing process as well as about the importance of differential expression in 47 disturbed wound healing processes or skin disorders. In addition, the relevance and the therapeutic potential of the genes relevant for wound healing could be confirmed by the in vivo application of the gene in an animal model.

The invention will now be further illustrated below with the aid of the figures and examples, without the invention being restricted hereto.

Priority application DE 199 55 349.1 filed November 17, 1999, US 60/172,511 filed December 17 and DE 100 30 149.5 filed June 20, 2000 including the specification, drawings, claims, sequence listing and abstract, is hereby incorporated by reference. All publications cited herein, are incorporated in their entireties by reference.

Description of the tables, figures and sequences:

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S

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Table i: Table 2: Tabular arrangement of the altered expression of various genes relevant to wound healing in different wound healing stages.

Tabular survey of the polypeptide sequences having unknown biological function identified in the analysis of gene expression during the wound-healing process and their cDNAs and accession numbers.

Tabular survey of the polypeptide sequences having already known and described functions identified in the analysis of gene expression during the wound-healing process and their cDNAs and accession numbers.

Tabular survey of the polypeptide sequences having already known and described functions additionally identified in the analysis of Table 3: Table 4: 48 Table 5: Table 6: 9.

9 9 9 9..

9

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gene expression during the wound-healing process and their cDNAs and accession numbers.

Quantitative RTPCR of spi2. The number of cycles until reaching the fluorescence threshold (Ct) for three independent measurements in each case and the mean value (Ct mean), the difference in the Ct values of GAPDH and spi2 (ACt), the abundance of spi2 calculated therefrom relative to GAPDH and the relative induction of spi2 relative to the intact skin of control animals is presented.

Tabular survey of the amounts of mRNA of wound relevant genes in different wound healing stages of the mice as determined by means of "TaqMan assay".

Tabular survey of the amount of mRNA of wound relevant genes in human day 1- and day wounds determined by means of "TaqMan assay".

Tabular survey of the amount of woundrelevant mRNA in intact skin of ulcer patients, at the edge of a wound of ulcer patients and at the ground of a wound of ulcer patients as determined by means of "TaqMan Assay".

Autoradiogram of hybridizations of membranes with an identical pattern of applied cDNA fragments using four different probes. The cDNA fragments were all derived from a woundspecific, subtractive cDNA library which was enriched for those cDNAs which were expressed in the wound tissue more strongly in comparison with intact skin. All probes were Table 7: Table 8: Figure 1: 49 Figure 2: 0 0 *0 0 0e 0 0 0 prepared from cDNAs which originated from subtractive hybridizations. A: wound-specific probe (subtraction wound versus intact skin), B: skin-specific probe (subtraction intact skin versus wound), C: probe specific for well-healing wound (subtraction wound control animals versus wound dexamethasone-treated animals), D: probe specific for poorly healing wounds (subtraction wound dexamethasone-treated animals versus wound control animals).

Part of the cDNA sequence of the marker gene spi2 (SEQ ID No. 61). The sequence is the consensus sequence of two sequencings of clones which were contained in the woundspecific, subtractive cDNA library. Vector and primer sequences of the cDNA synthesis were removed, such that only the sequences of the insert for the consensus sequence were taken into account. The quality of the sequence analysis error) allows only the identification of the full-length cDNA, but does not allow an exact determination of the sequence of the inserts. The position of the recognition site of the restriction endonuclease HindIII, which served for the linearization of the plasmid in the preparation of the probe for the RNase protection assay, is underlined.

Full-length sequence of the spi2-cDNA (SEQ ID No. 62, EMBL database entry MMSPI201, accession No. M64086) The sequence of the nucleic acids contained in the wound-specific cDNA library is underlined (compare Figure 3, complementary sequence). The coding region (bold) of the cDNA extends from the start codon (ATG) in position 61 as far as the stop Figure 3: 50 codon (TGA) in position 1317. The position of the primers for the quantitative RTPCR (Example 5) in the coding region is underlined.

Figure 4: Partial sequence of the mouse cDNA of GAPDH (SEQ ID No. 63), as a reference sequence, used in the RNase protection assay.

Figure 5: RNase protection assay of spi2 with RNA of various wound healing states. Radio-labelled probes of GAPDH intact probe) and spi2 intact probe) were hybridized with total RNA, obtained from intact skin 5 and 7) or from wounds 6 and 8) of control mice (3 and of dexamethasone-treated mice and 6) or of old mice (7 and 8) and separated by gel electrophoresis after RNase treatment.

In each lane, the signal intensities of the 20 Spi2 signals were standardized with the ~signals of the GAPDH probe. The relative intensities with respect to intact skin of control animals are lane 3: 1.0; lane 4: 13.28; lane 5: 0.84; lane 6: 7.72; lane 7: 25 0.54; lane 8: 5.2.

Figure 6: Correction of the sequence of spi2 (SEQ ID No. 64). The primers of the PCR are shown in bold; differences from the published database 30 sequence are underlined.

Figure 7: Comparison of the determined amino acid sequence of spi2 (spi2-Consensus.pro) with the published amino acid sequence of the database entry (JH0494.pro).

51 Figure 8: Sequence of the human homologue of mKAP1/Pmg- 1. The Primer of the PCR are underlined.

SEQ ID No. 1 to SEQ ID No. 58 and SEQ ID No. 89 to SEQ ID No. 89 to SEQ ID No. 124 show the polypeptide or cDNA sequences useable according to the invention from man or mouse.

SEQ ID No. 59 to SEQ ID No. 64 show polypeptide and cDNA sequences of the marker genes spi2 and GADPH.

SEQ ID No. 65 to SEQ ID No. 84 and SEQ ID No. 125 and SEQ ID No. 128 show DNA sequences of oligonucleotides which were used for the experiments of the present invention.

SEQ ID No. 85 to SEQ ID No. 88 show amino acid sequences of oligopeptides, which were used for the experiments of the present invention.

20 Examples Example 1: Preparation of cDNA libraries by means of subtractive hybridization Total RNA was isolated from intact skin and from wound tissue (wounding on the back 1. day before tissue sampling by scissor cut) of Balb/c mice by standard methods (Chomczynski and Sacchi, 1987, Anal. Biochem.

162: 156-159, Chomczynski and Mackey, 1995, Anal.

Biochem. 225: 163-164). The RNAs were then transcribed into cDNA with the aid of a reverse transcriptase. The cDNA synthesis was carried out using the "SMART PCR cDNA synthesis kit" from Clontech Laboratories GmbH, Heidelberg, according to the directions of the 52 corresponding manual. In order to identify those cDNAs which occurred with differing frequency in the two cDNA pools, a subtractive hybridization (Diatchenko et al., 1996, Proc. Natl. Acad. Sci. USA 93: 6025-30) was carried out. This was effected using the "PCR select cDNA subtraction kit" from Clontech Laboratories GmbH, Heidelberg, according to the directions of the corresponding manual, the removal of excess oligonucleotides after the cDNA synthesis being carried out by means of agarose gel electrophoresis. The resulting cDNA fragments were integrated into the vector pT-Adv (Clontech Laboratories GmbH) by means of T/A cloning and transformed in E.coli (SURE electroporation-competent cells, Stratagene) by means of electroporation. Two cDNA libraries were set up, where one was enriched for cDNA fragments which are expressed more strongly in the wound tissue in comparison with intact skin ("wound-specific cDNA library"), while the other was enriched in cDNA :i 20 fragments which are more strongly expressed in intact skin in comparison with wound tissue ("skin-specific cDNA library").

Example 2: Identification of wound healing-regulated 25 cDNA fragments In order to identify those clones of the two cDNA libraries in Example 1 which contained cDNA fragments relevant to wound healing, the expression of the corresponding cDNAs was analysed in the "reverse 30 Northern blot" in intact and wounded skin and also in well-healing and poorly healing wounds. Here, the cDNA fragments are immobilized on membranes in the form of arrays of many different cDNAs, and hybridized with a complex mixture of radio-labelled cDNA (Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, Cold Spring Harbor Laboratory Press, New 53 York, Chapter 9 page 9.47 to 9.58 and Chapter 10 page 10.38 to 10.50; Anderson and Young: Quantitative filter hybridisation; in: Nucleic Acids Hybridisation, A Practical Approach, 1985, Eds. Hames and Higgins, IRL Press Ltd.; Oxford, Chapter 4, page 73 to 112).

In order to prepare suitable membranes for the analysis, 1536 clones were isolated from each library and the cDNA insertions were amplified by means of polymerase chain reaction. 2 gl each of suspension culture of the clones were lysed at 960C for 1 minute in 40 pl of TE buffer (10 mM Tris-HC1, 1 mM EDTA, pH and a 20 pl PCR reaction ("Advantage cDNA polymerase mix kit" from Clontech) was inoculated with 1 pg of lysate. The amplification was carried out in 35 PCR cycles (1 min 96 0 C followed by 35 cycles of 2-stage PCR: 960C/30" and 680C/3') with universal primers (TCGAGCGGCCGCCCGGGCAGGT (SEQ ID No. 65) and AGCGTGGTCGCGGCCGAGGT (SEQ ID No. which are used in the "PCR-select cDNA subtraction kit" for the 20 obtainment of the cDNA fragments and thus include all cDNA insertions. 5 pl of PCR reaction were treated with gl of buffer (1.16 M NaCi, 20 mM Tris, pH 0.001% Bromophenol Blue) in 384-well microtitre plates and punched out onto Qiabrane membranes (Qiagen, Hilden) in 20 repetitions with the Nunc 384 pin replicator using the Nunc replicator system (Nunc GmbH Co. KG, Wiesbaden). The membranes were incubated with 0.4 M NaOH for 30 minutes for denaturation of the DNA and neutralized for 3 minutes with 1 M Tris-HC1, pH 7.5. The DNA was then immobilized by UV irradiation (120 mJ/cm 2 followed by baking for 30 min at 800C.

For the preparation of suitable hybridization probes, RNA was isolated from intact and wounded skin (see above) and also from well-healing and poorly healing wound tissue. In order to obtain tissue from mice having poorly healing wounds, BALB/c mice were 54 treated before wounding with dexamethasone (injection of 0.5 mg of dexamethasone in isotonic saline solution per kg of body weight twice per day for 5 days) or old mice (12 months) were wounded. The RNA from wound tissue of these animals and also from controls was isolated as described above and cDNA was in each case synthesized. Two subtractive hybridizations (cDNA from dexamethasone-treated animals versus cDNA from control animals and conversely) were then carried out as described above. This took place as described above using the "PCR select cDNA subtraction kit". These subtracted cDNAs and also the subtractive cDNAs described above (intact skin versus wound and conversely) were treated with the restriction endonuclease RsaI and purified by means of agarose gel electrophoresis (Sambrook et al., supra, Chapter 6, page 6.1 to 6.35), in order to separate the cDNA synthesis and amplification primers (see "PCR-select cDNA subtraction kit" manual, Clontech). The cDNAs were 20 then radio-labelled using the "random hexamer priming" method (Feinberg and Vogelstein, 1983, Anal. Biochem.

132: 6-13) in order to prepare hybridization probes.

The membrane was preincubated in 25 ml of hybridization solution for 30 min at 650C (25 mM sodium 25 phosphate, pH 7.5, 125 mM NaCl, 7% SDS). The hybridization probe was denatured at 1000C for 10 min, then cooled on ice, about 100 CPM per ml were added to the hybridization solution and the hybridization was carried out in a hybridization oven for 16 hours at 30 65 0 C. The membrane was then washed twice with the hybridization solution without probe at 65 0 C for min. The membrane was then washed at 65 0 C a number of times for 10 min in each case in wash solution (2.5 mM sodium phosphate, pH 7.5, 12.5 mM NaC1, 0.7% SDS) until it was no longer possible to detect any activity in the solution poured off. The radioactive signals 55 were analysed using a phosphoimager (BioRad, Quantity One®) (Figure Those cDNAs were then selected which produced different signal intensities with the various probes. Plasmid DNA preparations were prepared from the corresponding clones according to standard methods (Sambrook et al., supra) and the DNA sequence of the inserts was analysed. Figure 1 shows a survey of the expression patterns of various genes which it was possible to determine by this method.

Example 3: Analysis of cDNA sequences relevant to wound healing The cDNA sequence of the inserts from Example 2 was analysed for redundancy using the program SeqMan 4.01 from DNAStar Inc. (GATC GmbH, Constance, Germany) and non-redundant sequences were compared with the program BLAST 2.0 (Altschul et al., Nucleic Acids Res.

3389-402) with the present EMBL (Stoesser et al., 1999, Nucleic Acids Res., 27: 18-24), TREMBL (Bairoch 0..0 20 and Apweiler, 1997, Nucleic Acids Res. 25: 31-26) and .PIR (George et al., 1996, Nucleic Acids Res. 24: 17-20) and/or GenBank (Benson et al., 1999, Nucleic. Acids *Res. 27: 12-7) database. It emerged here that some cDNA sequences relevant to wound healing originate from 25 known genes which until now, however, were still not connected with regenerative processes.

It was thus possible to identify the spi2 gene as a gene relevant to wound healing. Figure 2 shows the starting sequence which was present twice in the woundspecific cDNA library (see above), Figure 3 the fulllength sequence of spi2 from the EMBL database (entry MMSPI201, accession No. M64086 (SEQ ID No. 60), which agrees with the starting sequence with high significance (BLAST score 883). A comparison of the two sequences shows that the starting sequence contains 56 the 3' end of the spi2 cDNA (underlined sequence in Figure The Spi2 spi2-cDNA codes for the protein "alpha-l-antichymotrypsin-like protein EB22/4" (PIR: JH0494), whose functional variant in man is "alphalantichymotrypsin" (database entries: protein: PIR: E55627, cDNA: EMBL: K01500 (SEQ ID No. The functional variants of the protein in mouse and man have about 60% sequence homology. Corresponding analyses were carried out with all other determined cDNA fragments and a list of those database entries found, that have a significant diagnostic and therapeutic potential was generated (Tables 2 to 4).

Example 4: Verification of the expression pattern of cDNAs relevant to wound healing by means of "RNase protection assays" The differential expression of the genes was verified with the aid of the "RNase protection assay".

The test was carried out as described in the literature o* 20 (Sambrook et al., supra Chapter 7, page 7.71 to 7.78; Werner et al., 1992; Growth Factors and Receptors: A Practical Approach 175-197, Werner, 1998, Proc. Natl.

SAcad. Sci. USA 89: 6896-6900). Counter-strand RNA of the isolated clones which was transcribed in vitro and 25 radio-labelled was employed as a hybridization probe. A

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counter-strand RNA probe of the murine GAPDH-cDNA (length of the transcript without vector sequence: 120 base pairs, Figure cloned into pBluescript II KS (Stratagene) with the aid of the restriction 30 endonucleases XbaI and HindII, served as an internal control. This plasmid was linearized with XhoI before transcription. The plasmids of the cloned cDNA fragments of the identified cDNAs were likewise linearized with restriction endonucleases before transcription. Thus the spi2 clone, for example, was linearized with HindIII (length of the transcript 57 without vector sequence: 322 base pairs, Figure The transcriptions were carried out with T7 polymerase (Roche Diagnostics, Mannheim) in the presence of 32 p-UTP (Amersham, Brunswick) according to the of the manufacturer. After a DNase digestion (Boehringer, 40U/batch), the unincorporated nucleotides were removed with the aid of column chromatography (Pharmacia, Microspin Combi-Pack S200) according to the details of the manufacturer and the probes were purified by gel electrophoresis and elution (Sambrook et al., supra, Chapter 6, page 6.36 to 6.48) For the hybridization reaction, about 105 CPM each of the labelled transcripts were employed. For this, 20 gg of total RNA were precipitated with appropriate amounts of transcript (specific sample spi2 and internal control GAPDH), taken up in 30 Al of hybridization buffer deionized formamide, 400 mM NaCI, 40 mM Pipes pH 4.6, 1 mM EDTA) and hybridized overnight at 420C. An RNase T1 digestion (Boehringer, 200 U/batch) was then carried !i~i 20 out. Af ter inactivation of the RNase by proteinase K digestion (Boehringer, 44 gg/batch) and phenol extraction, the samples were precipitated with isopropanol according to standard methods (Sambrook et al., supra). The samples were then separated by gel electrophoresis on a denaturing 5% acrylamide gel (6M urea)., The gel was dried and the radioactive signals were analysed (Figure 5) using a phosphoimager (BioRad, :Quantity One@).

Example 5: Verification of the expression pattern of :cDNAs relevant to wound healing by means of real-time quantitative RTPCR A further verification of the differential expression of the nucleic acids according to the invention was carried out by means of a real-time RTPCR in the ABI Prism 7700 sequence detection system (PE 58 Applied Biosystems). The apparatus was equipped with the ABI Prism 7200/7700 SDS software version 1.6.3 (1998). The detection of PCR products was carried out during the amplification of the cDNA with the aid of the stain SYBR Green 1, whose fluorescence is greatly increased by binding to double-stranded DNA (Karlsen et al. 1995, J. Virol. Methods. 55: 153-6; Wittwer et al., 1997, BioTechniques 22: 130-8, Morrison et al., 1998, BioTechniques 24: 954-62). The basis for the quantification is the PCR cycle (threshold cycle, CT value) which is achieved when the fluorescence signal exceeds a defined threshold. The analysis is carried out by means of the AA-CTCT method (User Bulletin #2, Relative Quantitation of Gene Expression, PE Applied Biosystems, 1997). The abundances of the cDNAs were determined relative to an endogenous reference (GAPDH).

The results are shown in Table Normally healing day 1-wounds and intact skin was obtained from 10 weeks old BALB/c mice treated with 20 isotonic saline solution by scissors cut as described above. To obtain tissue from mice with poorly healing wounds BALB/c mice were treated prior to wounding with dexamethasone (injection of 0.5 mg of dexamethosone in isotonic saline solution per kg of body weight twice 25 per day for 5 days).

Total RNA was obtained from skin and wound tissue as described above and 1 4g of total RNA was subjected to reverse transcription in a thermocycler (GeneAmp PCR system 9700, PE) using the TaqMan reverse transcription 30 reagent kit (PE) according to the recommendations of the manufacturer (SYBR Green PCR and RT-PCR Reagents Protocol, PE Applied Biosystems, 1998). The primers for the amplification of the Spi2 cDNA (spi2 primer 1: CTGTCCTCTGCTTCCCAGATG (SEQ ID No. 67), spi2 primer 2: TCCAGTTGTGTCCCATTGTCA (SEQ ID 59 No. 68) and the reference (GAPDH primer 1: ATCAACGGGAAGCCCATCA (SEQ ID No. 69), GAPDH primer 2: GACATACTCAGCACCGGCCT (SEQ ID No. 70)) were selected with the aid of the nucleic acid useable according to the invention and the known sequence of GAPDH using the Primer Express software for Macintosh PC Version (PE Applied Biosystems, P/N 402089, 1998). For the PCR, the SYBR Green PCR Core Reagents Kit (4304886, PE Applied Biosystems) was used. The concentration of the primers in the PCR was initially optimized in the range from 50 nM to 600 nM and the specificity of the PCR was tested by analysis of the length of the amplified products in an agarose gel electrophoresis. The efficiency of the PCR system was then determined by means of a dilution series (User Bulletin Relative Quantitation of Gene Expression, PE Applied Biosystems, 1997). It emerged here that for both cDNAs the efficiency of the amplification was 100%, i.e. at each 1:2 dilution of the cDNA one more cycle was needed in 20 order to exceed the fluorescence threshold value.

*e For the quantification, each batch of cDNA was amplified from 10 ng of reverse-transcribed total RNA in a total volume of 25 pl. The running conditions for the PCR corresponded to the details of the manufacturer (PE Applied Biosystems, SYBR Green PCR and RT-PCR Reagents Protocol, 1998). The CT values were analysed and the abundance of spi2 was calculated. It was also I: possible with the second assay to confirm the induction of spi2 in well-healing wounds, the reduction of the induction in poorly healing wounds of dexamethasonetreated animals and the reduction of the expression in intact skin of dexamethasone-treated animals. The slight differences in the absolute values are to be attributed to the different test systems.

60 Example 6: Verification of the sequence of the cDNA of spi2 In order to verify the cDNA sequence of spi2, oligonucleotides were synthesized with the aid of the database sequence (primer 1: ACTGCAGAACACAGAAGATGG- CTTTCATTG (SEQ ID No. 71), primer 2: CCGGGAAGAAG- CGTCAACACTTGGGGAGTT (SEQ ID No. Using these primers, starting from mouse wound cDNA (see above) the coding region of the cDNA of spi2 (Figure 3) was amplified with the aid of the advantage cDNA PCR kit.

The PCR reaction was set up according to the details of the manufacturer and the amplification was carried out for 40 cycles (30" 940C, 30" 640C, 1.5' 72 0 the denaturation time in the first cycle being extended to 1.5 minutes and the synthesis time in the last cycle to minutes. The PCR product (1309 bp) was purified by agarose gel electrophoresis (Sambrook et al., supra) and cloned into the vector pCR2 with the aid of the pCR2.1TOPO cloning kit (Invitrogen) according to the 20 details of the manufacturer. The sequence of 3 independent clones was analyzed using standard methods and the consensus sequence was determined (Figure 6) with the aid of the program SeqMan2 (see above). It is seen here that the cDNA sequence determined here in the wound tissue differs slightly from the published sequence (Inglis et al., 1991, Gene 106: 213-20), as well as the coded proteins of both sequences (Figure Both polypeptides have comparative degrees of homology of 60% to the human sequence, such that it can be assumed therefrom that the polypeptides are functional variants of the gene. Reasons for the difference could be based on the different starting material for the cDNA synthesis (wound tissue versus chondrocyte cell line) or on different alleles of the gene in the donor.

61 Example 7: Cloning of the human homologue to mKAP13 Using the published protein sequence of mKAP13 (Aoki et al., 1998, J. Invest. Dermatol. 111, 804-9), the human EST database GenBank dbest (Benson et al., supra) was searched for homologous sequences with the aid of the BLAST program (Altschil et al., supra). Four sequence entries were found (W76571, W72002, AA055832 and AA055833) which had similarities to the mouse mKAP13 and/or to the ESTs found. From the four sequences, the consensus sequence was determined with the aid of the program SeqMan and PCR primers constructed (AACTCAGCTGAACTCACATCTCCCGTCAAC (SEQ ID No. 73) and GTCTGAAAGAACTAGCCTGTCCAGCCAGTA (SEQ ID No. Using these primers, as described above (see Example 6) the human homologue of mKAP13 was amplified, cloned and sequenced (Figure 8) with the aid of the PCR from cDNA which was obtained from intact human skin (see Example It emerged here that owing to the generally known poor quality of the EST sequences, the 20 actual sequence differed considerably from the sequence predicted by the EST assemblage such that the selection of the primers was very critical for the success of the cloning.

Example 8: Analysis of the expression pattern of cDNAs relevant to wound healing at different wound healing stages of the mouse by means of "TaqMan analysis" The regulation of the expression of cDNAs relevant to wound healing in different wound healing stages of mouse was carried out by means of "TaqMan analysis" in S the Gene-Amp 5700 of Applied Biosystems. Normally healing day 1-wounds and intact skin of 10 weeks old BALB/c mice treated with isotonic saline solution was obtained by scissors cut as described above. To obtain tissue of mice with poorly healing wounds, BALB/c mice 62 were treated prior to use with dexamethasone (injection of 0.5 mg of dexamethosone in isotonic saline solution per kg of body weight twice per day for 5 days). Intact skin of mice that were treated with dexamethasone as described above was used as control. To obtain tissue of young and old mice untreated day 1-wounds and intact skin of 4 weeks old and 12 months old BALB/c mice was used. Wound tissue and intact skin of mice with diabetes (db/db mouse) was obtained by isolating untreated day 1-wounds and intact skin of 10 weeks old C57B/Ks-db/db/Ola mice by scissors cut. C57B/Ks wildtype mice were used as control animals. From the latter animals similarly intact skin as well as untreated day 1-wounds were obtained.

The isolation of RNA was carried out by homogenizing of the biopsies in RNAclean buffer (AGS, Heidelberg) that was supplemented with 2-mercapto ethanol at 1/100 of the total volume using a disperser.

Subsequently the RNA was extracted by twofold 20 phenolization by means of water saturated acidic phenol in the presence of l-bromo-3-chloro-propane.

Subsequently an isopropanol and ethanol precipitation was carried out and the RNA was washed with ethanol. Thereafter a DNase I digestion of the RNA was 25 carried out. For this 20 jg RNA (add to 50 .l with DEPC-treated water) with 5.7 pl transcription buffer (Roche), 1 p1 RNase inhibitor (Roche; 40 U/pl) and 1 p1 DNase I (Roche; 10 U/gl) was incubated for 20 minutes at 370C. Then 1 il DNase I was added again and was 30 further incubated for 20 minutes at 37 0 C. Subsequently S' the RNA was treated with phenol, precipitated with ethanol and washed. All steps indicated above were carried out with solutions or liquids treated with DEPC (Diethylpyrocarbonat) as long these did not contain reactive amino groups. Thereafter cDNA was produced from the extracted RNA. This was carried out in the 63 presence of 1 x TaqMan RT-buffer (Perkin Elmer), 5.5 mM MgC1 2 (Perkin Elmer), 500 pM dNTPs each (Perkin Elmer), gM random hexamere (Perkin Elmer), 1.25 U/gl multiScribe Reverse Transcriptase (50 U/p1 Perkin Elmer), 0.4 U/gl RNase inhibitor (20 U/pl, Perkin Elmer), 20 p1 RNA (50 ng/gl) and DEPC-treated water (added to 100 pl volume) After addition of RNA and thorough mixing the solution was distributed to two 0.2 ml reaction vessels (50 pl each) and the reverse transcription was carried out in a temperature cycler min at 25 0 C; 30 min at 48 0 C and 5 min at 950C). The subsequent quantification of cDNA was carried out by means of quantitative PCR using the SYBR Green PCR master mixes (Perkin Elmer), wherein for each of the cDNA species to be determined a triple determination was carried out (with target primers and GAPDH primers each time). A base solution for each triplet contained within 57 gl total volume 37.5 p1 2 x SYBR Master Mix, 0.75 pl AmpErase UNG (1 U/pl) and 18.75 pl DEPC treated 20 water. For each triplicate determination 1,5 l forward and reverse primer were added in a previously optimized concentration ratio to 57 l base solution. 60 pl of each of the base solution/primer mix was mixed with l cDNA solution (2 ng/gl) and distributed into 3 wells. A base solution with primers for the determination of GAPDH (SEQ ID No. 69 and SEQ ID No.

was produced in parallel, mixed with further 15 Ml of the same cDNA solution and distributed into 3 wells.

S

In addition in order to produce a standard curve for the GAPDH-PCR, different cDNA solutions were generated by serial dilutions (4 ng/gl; 2 ng/Ml; 1 ng/gl; ng/gl and 0.25 ng/gl). 15 Ml of each cDNA solution was mixed with 60 ul base solution/primer mix for determination of GAPDH and distributed into 3 wells.

Similarly a standard curve for the PCR of the target gene was generated; in this process the same dilutions, that were also used for the GAPDH standard curve, were 64 employed. A PCR reaction without cDNA served as a control. In each case 15 pl DEPC water were added to p1 base solution/primer mix of target and GAPDH, respectively, mixed and distributed into 3 wells in each case. The amplification of the reaction set-ups were carried out in a GeneAmp 5700 (2 min at 50°C; min at 95 0 C, followed by 3 cycles with 15 sec at 960C and 2 min at 60 0 C, afterwards 37 cycles. with 15 s at 0 C and 1 min at 600C). The evaluation was carried out by determining a relative abundance of each target gene in relation to the GAPDH reference. For this a standard curve was generated initially by plotting the CT-values of the dilution series against the logarithm of the cDNA amount in the PCR set up (in ng of translated RNA) and the slope(s) of the rectilinear was determined. The efficiency of the PCR then results as follows: E 1/s The relative abundance of the cDNA species investigated in relation to GAPDH equals: X (1+EGAPDH)CT(GAPDH)/ (1+Ey) CT(Y). Afterwards the values were 20 standardized by equating the amount of cDNA from intact skin of 10 weeks old BALB/c control animals or the intact skin of C57B/Ks control animals with one. The *i relative change of expression in different wound healing stages is put together in Table 6.

Thus it could be shown by using, for example, suitable primers (p68-primer 1: CCTTATCTCTGTGCTTTCG- GGAA) (SEQ ID No. 83; p68-primer 2: CGACCTGAACCTCTG- TCTTCG (SEQ ID No. that significantly less p68 30 helicase mRNA were present in wounds of control animals in comparison to intact skin. Furthermore a significant decrease of expression was also observed in wounds of old and young mice. On the other hand the amount of p68 helicase mRNA in poorly healing wounds of animals treated with dexamethasone was strongly increased. In addition an increase in expression in comparison to 65 intact skin was also detected in wounds of diabetic mice while, in wounds of control animals a decrease of expression was detected. This exemplifies that p68 helicase is differentially expressed during wound healing. In addition this experiment shows that an increase in p68 helicase expression is accompanied by impaired wound healing, and that preferentially a decrease in p68 helicase expression and/or in protein activity is essential for the normal progression of wound healing.

Example 9: Detection of differential expression of genes relevant to wound healing by means of "TaqMan assay" Mice have proven to be a suitable model system for investigating wound healing in man. However, it should be reconfirmed whether the expression pattern specific to wound healing of the nucleic acids useable according to the invention, that was observed in the mouse, could 0oo* 20 also be shown in man. For that purpose skin samples

S.

were taken from healthy trial participants of untreated intact skin, of day 1-wounds or of day 5-wounds by 9.

means of 4 mm and 6 mm punch, respectively. Of each group (intact skin, day 1-wound, day 5-wound) biopsies 25 of 14 trial participants were pooled each time. In addition punch biopsies were taken at the same time from patients with chronic venous ulcers (Ulcera cruris venosum) from intact skin as well as from ground of wound and edge of wound. For each group (intact skin, 30 edge of wound, ground of wound) biopsies of six trial participants were pooled each time. RNA was isolated from all biopsies as described in Example 8, then DNase I digested and thereafter transcribed into cDNA. The quantification of cDNAs relevant to wound healing was similarly carried out as described in Example 8. The results of the experiments are compiled in Table 7. For 66 the analysis of the p68 helicase the primers for amplification (hGAPDH-primerl: CATGGGTGTGAACCATGAGAAG (SEQ ID No. 75); hGAPDH-primer2: CTAAGCAGTTGGTGGTGCAGG (SEQ ID No. 76); hp 68-primerl: GAGGCCATTTCCAGCGACT (SEQ ID No. 77); hp 68-primer2: GAATAACCCGACATGGCGTC (SEQ ID No. 78)) were based on the known sequences of human GAPDH (GenBank: M17851) and human p68 helicase (Embl: X15729). cDNA from reverse transcribed total-RNA in a total volume of pl was amplified for each reaction set-up for quantification. The PCR was carried out according to the instruction of the manufacturer (PE applied Biosystems, SYBR Green PCR and RT-PCR Reagents Protocol, 1998). The CT-values were analyzed and therefrom the abundance of hp68 helicase mRNA relative to GAPDH mRNA was calculated. It could be shown that the amount of hp68 helicase mRNA in human day 1-wounds was reduced in comparison to intact skin by approximately 60% (Table This correlates with the 20 regulation of the expression of the murine p68 helicase homologue in normally healing wounds of 10 weeks old control mice as well as in wounds of young and old BALB/c mice in comparison to intact skin, respectively (Table In this experiment a 30%-70% reduced expression was observed in day 1-wounds.

In human day 5-wounds an increase of the amount of hp 68 helicase mRNA to 60% of the value for intact skin was observed indicating that the regulation of expression is essential in a very early phase of wound healing. The analysis of normally healing day *of 10 weeks old BALB/c mice showed that the amount of murine p68 helicase mRNA increased in the murine cell system to 67% of the value in intact skin.

Consequently, the kinetic of expression of p68 helicase is also comparable in normal healing wounds both in mouse and man. Therefore, it could be shown in this 67 experiments that the genes identified in the mouse system to be relevant to wound healing were also differentially expressed in men. This corroborates the results of the experiments of Example 8, that showed that p68 helicase is essential for wound healing.

Furthermore it was shown, that in an ulcer, which represents a disturbed wound healing process, no decrease of p68 helicase expression as in normally progressing wound healing is detectable, but rather a slight increase of expression is observable. This is particularly evident at the ground of a wound. This shows that the regulation of expression not only plays an essential role for wound healing in man but furthermore is essential for the normal progression of wound healing. A disturbed expression, preferentially an increased expression of p68 helicase, can lead to severe wound healing disorders.

Example 10: Localization of genes relevant to wound 20 healing in intact human skin and in wounds by means of in situ hybridization To obtain further information on the importance of 0 genes that were identified to be relevant to wound healing mRNA was detected in sections of human wounds 25 and intact skin by means of radioactive or nono0o. radioactive in situ hybridization. The success of in situ hybridization critically depends on a variety of eoe.oi parameters like, for example, the abundance of the mRNA in the tissue, an optimal hybridization temperature or 30 the stringency of the washing steps subsequent to hybridization. The selection of a suitable probe sequence is also essential. For the success of such an experiment elaborate optimization steps are necessary.

In spite of the experimental hurdles it was possible to further substantiate the relevance of MRP-8, MRP-14 and 68 p68 helicase for wounds, that was already shown in Example 8, by means of in situ hybridization.

For the experiment biopsies were taken from intact skin as well as from normally healing day 5-wounds of healthy patients as described in Example 9. Tissue sections were fixed in 4% paraformaldehyd, treated with proteinase K (1 gg/ml isotonic saline solution) for minutes at 37 0 C, and again with paraformaldehyd and finally with acetanhydrid (0.5 ml in 0.1 M triethanolamine, pH The localization of the mRNA of human MRP-8 and MRP-14 was carried out by means of non-radioactive in situ hybridization. For this a partial human MRP-8 cDNA fragment was amplified by means of PCR. The primers used therein contained in addition to a section homologous to MRP-8 an RNA-polymerase promoter for the production of riboprobes (the antisense primer used (T7-MRP-8): TAATACGACTCACTATAGGGCCCACGCCCATCTTTATCACCAG (SEQ ID No. 79); the sense primer used (T3-MRP-8): 20 AATTAACCCTCACTAAAGGGGGAATTTCCATGCCGTCTACAGG (SEQ ID No.

80). The amplified cDNA fragment was cloned into the PCR 2.1 TOPO vector (Invitrogen) and thereafter verified by sequencing. The production of the antisense riboprobe and the sense control was done using the DIG 25 RNA labeling mixes (Roche) and the respective RNA polymerase according to the instruction of the manufacturer. The subsequent in situ hybridization was carried out as described by Komminoth et al. (1992, Histochemistry 98: 217-228).

30 In comparison to intact skin a strong induction of mRNA expression in the suprabasal cell layers of the hyperproliferative epithelium was detected in human day by means of the antisense probe, while no staining was detected with the sense probe. This is in agreement with the result of the quantitative analysis 69 of the amount of murine Mrp8 mRNA by means of "TaqMan's analysis", in which a marked upregulation was detected in day 1-wounds (Table 6) and also in day 5-wounds. In addition to the verification of the upregulation of gene expression the localization in hyperproliferative epithelium emphasizes that the gene plays an important role in a central process of wound healing. Therefore, it was possible to corroborate the relevance for wounds in man for MRP-8, that was identified in the mouse system.

The localization of MRP-14 was carried out analogous to the localization of MRP-8, wherein Sp6- MRP-14 primer (ATTTAGGTGACACTATAGAATAC CCC GAG GCC TGG CTT ATG GT; SEQ No. 125) was used as antisense primer and T3-MRP-14 primer (AATTAACCCTCACTAAAGGGG GTG GCT CCT CGG CTT TGA CA; SEQ No. 126) as control sense primer.

The localisation in intact skin and in day 5-wounds was done as described for MRP-8.

It was shown that MRP-14 mRNA is also strongly 20 expressed in the suprabasal cell layer of the hyperproliferating epithelium while no staining was oo. detected with the sense probe. This is in agreement with the result of the quantitative analysis of the amount of murine Mrp-14 mRNA by means of "TaqMan 25 analysis" in which a marked upregulation was detected in day 1-wounds (Table 6) and also in day Thus, it was possible to corroborate in this experiment the relevance of mrp-14 for wounds in man, that was identified in the mouse system. Moreover, this experiment proves that both monomers of the MRP-14/MRP- 8 heterodimer are wound regulated in a similar way. The expression of MRP-14/MRP-8 in suprabasal keratinocytes of the hyperproliferative epithelium shows in addition that the dimer is not only involved in inflammatory processes, as suspected until now, but also has an essential function in proliferation and/or 70 differentiation of keratinocytes during the progress of wound healing.

The localization of p68 helicase in human skin and wound biopsies was carried out by radioactive in situ hybridization. To that end, paraformaldehyd fixed sections of probes of interact skin and day were embedded into paraffin. The production of the hybridization probe was based on the in vitro transcription of a partial cDNA fragment of human p68 helicase in the presence of a- 35 S-UTP. The production of the PCR-product was carried out with primers having attached thereto the promoter sequences for transcription in sense and antisense direction (T3-p68primer: AATTAACCCTCACTAAAGGGGGCAACATTACTTCCATATTGC (antisense primer with T3-promoter; SEQ No. 81), T7p68-primer: TAATACGACTCACTATAGGGCGAGACAGGGAAAACTATGAC (sense control primer with T7-promoter; SEQ No. 82).

35S-UTP and 5 mM ATP, GTP and CTP each, as well as either 25 U T3 or T7 RNA polymerase (Roche), 1 gg PCR- 20 product, 10 mM dithiothreitol, 40 U RNAse inhibitor (Roche) and 1X TB-buffer (Roche) were used for in vitro transcription.

The human tissue sections (see above) were treated with proteinase K on glass slides and acetylated S 25 subsequently. Thereafter, the sections were covered with 30 tl hybridization solution and incubated for h at 60 °C in a chamber in which humid Whatman papers S"soaked with 50% formamid/4 x SSC were layered. Then the sections were incubated with 0.7 x 10 6 cpm radioactively 30 labeled riboprobe in 30 ul hybridization solution for 16 h at 60 0 C. Subsequently, the sections were washed under stringent conditions, incubated with RNAseA and dehydrated with ethanol. The sections were then overlaid with photo emulsion (Kodak IBO 1433) and stored under exclusion of light and oxygen for 2-6 weeks and thereafter developed according to the 71 manufacturers instruction by means of developer and fixative (Kodak IBO 1433).

It was shown that p68 helicase is expressed in the basal cell layer of the epithelium in intact skin, while no hybridization was detectable with the sense control riboprobe. A marked decrease in expression in the basal cell layer of the epithelium was observed in human day 5-wounds. This is an agreement with a result of the "TaqMan analysis" of human intact skin and human day 5-wounds (Example 9, Table 7) and the "TaqMan analysis" of murine tissue samples (Example 8; Table Furthermore, the localization in the strongly proliferating basal cell layer of the epithelium corroborates, that the differential expression of p68 helicase plays an important role during wound healing.

The experiment further reaffirms the result of Example 8, that showed that the regulation of p68 helicase expression, preferentially the inhibition of expression was essential for wound healing.

Example 11: Verification of differential expression of polypeptides relevant to wound healing To confirm the essential function of the polypeptides, that were identified in the mouse system to be relevant to wound healing, by a further method tissue section of human intact skin and human normally healing wounds were investigated by means of immunostaining. The success of immunostaining critically depends, as already for in situ 30 hybridization (Example 10), on the experimental conditions. In case of immunostaining, for example, the pretreatment of the tissue sections, the affinity of the antibody and the detection method are critical for the success. In spite of the variety of experimental problems expression specific to wounds could be 72 verified for MBNL and Rab2 and CBP (Example 8) by means of immunostaining.

Localization of human MBNL was carried out with a polyclonal rabbit antibody of (Eurogenetec)directed against the peptides ArgGluPheGlnArgGlyThrCysSer- ArgProAspThrGluCys (SEQ ID No. 85; Eurogentec) and ArgGluTyrGlnArgGlyAsnCysAsnArgGlyGluAsnAspCysArg (SEQ ID No. 86; Eurogentec). Native cryo section of intact skin and day 5-wounds of healthy patients were generated by cutting of biopsies in a refrigerated microtom at -20 0 C. The sections were fixed in aceton for 10 min. The incubation with the specific antiserum was carried out at room temperature in a humid chamber.

To that end the sections were incubated with 100 pl diluted serum (1:200 in PBS, 1 BSA). A peroxidase coupled anti-rabbit antibody from goat (Dianova) was used as secondary antibody, that was employed in a 1:1000 dilution (in PBS, 1% BSA). The sections were covered with 100 l of the secondary antibody solution 20 and incubated for 1 h in the humid chamber.

Subsequently, the glass slides were rinsed three times with PBS and the detection reaction was carried out. To S* that end the sections were incubated in staining solution for 10 minutes (freshly prepared from 10 ml AEC-solution (5 mg/ml 3-amino-9-ethylcarbazol in dimethylformamid); 200 ml 50 mM sodium acetat, pH 5.2; gi H 2 0 2 and briefly rinsed with PBS. Counterstaining was carried out with Mayer's Hematoxylin solution (Sigma) for 5 minutes at room temperature. After rinsing with tap water the sections were incubated for 1 minute in "Scott's Tab Water Substitute" (Sigma), again rinsed with tab water and mounted with Immu-Mount (Shandon).

The MBNL protein is strongly expressed in the basal cell layer of intact skin. In comparison the supra basal cell layers show significantly weaker 73 expression. An even distribution of the protein is found throughout all cell layers of the epidermis in the hyperproliferative epithelium of a wound (at day after wounding) and in the epidermis in the vicinity of the wound. A stronger concentration of the protein in the basal cell layer is not detectable in this case.

The experiment clearly shows that the expression of the MBNL gene, that is relevant for wounds is not only temporally but also spatially differentially regulated, which implies an interplay between different cell types. This example clearly shows that due to the complexity of the wound healing process that, for example, comprises a temporal and spatial change of the cell types involved, great difficulties can occur during the identification of cDNAs relevant for wounds.

This further corroborates, that the ability to identify MBNL to be relevant for wounds was surprising and that the correct design of the screen critically contributed to the identification of wound relevant genes useable according to the invention.

*eeo *"Immunolocalisation of both Rab2 as well as CBP in intact human skin and human day 5-wounds were carried S•out on native cryo sections as described above. The immunostaining reaction was based on the Vectastain Universal Elite ABC Kit (Vector Laboratories, Inc., #PK-6200). To this end the sections were covered with eele blocking solution (horse serum in PBS) and incubated at room temperature for 20 min in a humid chamber. After this, the solution was sucked off. Then the sections were covered with 100 Al of the polyclonal rabbit anti- Rab2 antibody (Santa Cruz, #sc-307; dilution: 1:200 in •PBS/1% BSA) or the polyclonal rabbit anti-CBP antibody (Upstate Biotechnology, 06-294; dilution: 1:1500 in PBS/I% BSA). The incubation time was 30 minutes in a humid chamber. Thereafter, the glass slides were washed three times with PBS and subsequently incubated for 74 minutes with 100 pl secondary antibody (peroxidase coupled horse anti-abbit and anti-mouse antibody; Vector Laboratories, Inc.; #BA-1400). The object lights were again rinsed 3 times with PBS and subsequently covered with 100 pl Vectastain Elite ABC Reagent (Vector Laboratories, Inc.) each for 30 minutes. Then the glass slides were rinsed with PBS and the staining steps (peroxidase-substrate-staining and hematoxylin counterstaining) was carried out as described in the previous section.

Immunostaining with the anti-Rab2 antibody showed a strong induction of protein expression in human day in the supra basal cell layer of the hyperproliferative epithelium. This is seemingly in contradiction with the results of the "TaqMan analysis" in the murine system, that showed a slight decrease of the amount of mRNA in day 1-wounds (Table 6) A more accurate analysis of the kinetics of the expression in murine wounds, however, showed that a steady increase 20 of the amount of mRNA could be detected by means of "TaqMan analysis" starting at day 3 after wounding, which resulted at day 5 in a doubling and at day 7 in quadrupling of the rab2 mRNA relative to the amount at day 3. This again correlates with the observed increase of protein expression in human day 5-wounds. This data clearly shows, as already has been the case for the MBNL expression (see the preceding section), that the complexity of the wound healing process, in this case the complexity of the kinetics of expression, significantly impedes the identification of genes relevant to wounds. Therefore, the essential function of Rab2 could be confirmed by immunostaining.

Immunostaining with the anti-CBP-antibody showed that the "CREB binding protein" (CBP) was expressed in intact skin primarily in basal cells of the epithelium.

At day 5 after wounding significantly fewer cells that 75 expressed this protein could be found in the hyperproliferative epithelium. This is in agreement with the observation by means of "TaqMan analysis" that the amount of CBP mRNA in wounds of 10 weeks old control animals as well as in day 1-wounds of young or old mice is significantly lesser than in intact skin (Table This wound specific regulation could also be confirmed in human day 5-wounds by means of "TaqMan analysis". Therefore, it was possible again to corroborate the central function of the gene useable according to the invention in wound healing.

Example 12: Analysis of differential protein expression of p68 helicase in intact skin, in normally healing wounds and in ulcer of man by means of immunostaining.

It was possible to show that the mRNA of the p68 helicase is differentially regulated in wound healing both in man as well as in mouse (Example 8 and 9).

Thereby it could be proven that p68 helicase is 20 essential for wound healing (Example A further experiment that serves to substantiate the importance of p68 helicase is the immunolocalization of p 68 helicase in punch biopsies of intact human skin, of human day 5-wounds of healthy patients and punch 25 biopsies of human venous skin ulcers (Ulcera cruris venosum).

9 This was carried out with a polyclonal rabbit antibody (Eurogenetec), that was directed against the peptide CysAspGluLeuThrArgLysMetArgArgAspGlyTrpProAla (SEQ ID No. 87; Eurogentec) and AsnThrPheArg- AspArgGluAsnTyrAspArgGlyTyrSerSerCys (SEQ ID No. 88; Eurogentec). The native cryo sections of the tissue samples were generated by cutting the biopsies in a refrigerated microtom at -20 0 C. Subsequently, the 76 sections were fixed with aceton. The incubation with the specific antiserum was carried out at room temperature in a humid chamber for 1 hour. To that end the sections were incubated with 100 il diluted serum (1:200 in PBS, 1% BSA). A peroxidase coupled antirabbit antibody from goat (Dianova) that was employed in a 1:1000 dilution (in PBS, 1% BSA) was used as secondary antibody. The section were covered with 100 gl of the secondary antibody solution and incubated in the humid chamber for 1 hour. Afterwards the glass slides were washed three times with PBS and the detection reaction was carried out. To this end the sections were incubated for 10 minutes in staining solution (freshly prepared from 10 ml AEC-solution mg/ml 3-amino-9-ethylcarbazol in dimethylformaned); 200 ml 50 mM sodium acetat, pH 5.2; 30 ml H202) and briefly washed with PBS. Counterstaining was carried out with Mayer's hematoxylin solution (Sigma) for 5 minutes at room temperature. After rinsing with tap water the 20 sections were incubated for one minute in "Scott's tap water substitute" (Sigma), again rinsed with tap water and mounted with Immu-mount (Shandon).

The evaluation of the immunostaining showed that p68 helicase is stronger expressed in the basal keratinocytes than in the suprabasal cell layers in intact skin. On the other hand the protein is markedly less strong expressed in normally healing day in the area of the edge of the wound, whereby a spatial 30 protein gradient is generated. However, in ulcer with delayed wound healing this gradient formation and decrease of expression towards the edge of the wound does not take place. This confirms that p68 helicase is differentially expressed during the progress of wound healing and that the exact regulation is essential for normally progressing wound healing. Therefore, it could 77 be exemplary confirmed that the misregulation of p68 helicase, that is relevant to wounds, leads to wound healing disorders in man and that p68 helicase is suitable as a therapeutic target: wound healing disorders can be treated by the modulation, preferentially by the inhibition of p68 helicase activity.

Example 13: Detection of the relevance for wound healing of MRP-8 by means of in vivo application of the gene to rabbit wounds To verify that MRP-8 plays an essential role for the process of normally progressing wound healing the influence of MRP-8 on wound healing was studied in male white New Zealand rabbits in vivo. Wound healing was determined based on the amount of collagen in granulation tissue, wherein a decreased amount of collagen in relation to a normal healing wound indicates an impaired wound healing. Towards this end 20 an expression plasmid pMHintMRP8 was generated that contained the coding sequence of MRP-8. Initially a suitable expression vector pMHint was generated starting from pMH (Roche) by introducing Intron II of the insulin gene from rat between the CMV promoter and 25 the multiple cloning site using the HindIII restriction site. Then using the multiple cloning site the MRP-8 cDNA was cloned into pMHint. For this the coding region of MRP-8 cDNA was amplified by means of PCR (MRP8primer 1. GAG AGA GGT ACC ATG CCG TCT GAA CTG GAG (SEQ 30 ID No. 127) and MRP8 primer 2: GAG AGA GAC ACG TGC TAC TCC TTG TGG CTG TCT TTG (SEQ ID No. 128)), afterwards cut with KpnI and PnlI ligated with the expression vector pMHint that had been cut with KpnI and PnlI and thereby obtaining the expression plasmid pMHintMRP8.

78 For the analysis of the influence of MRP-8 on wound healing two rabbits were used, that were anesthetized with xylazin and ketamin (13 or 87 mg/kg and treated with a depilatory. Afterwards an adrenalin solution (2 xylocain and adrenalin, 1: 100000, ASTRA) was injected intradermally to achieve vasoconstriction and to separate the skin from the ear cartilage underneath. Four 8 mm large wounds were placed at the inner side of the ear by means of punching. Each wound was bombarded by means of the Helios Gene Gun (BIORAD) either with pMHintMRP8 or as a control with pMHint, in which the luciferase gene had been cloned, at a pressure of 500 psi, wherein 0.5 jg expression plasmid, that had been immobilized on gold particles (BIORAD) were employed per shot. Subsequently the wounds were covered with semi-occlusive bandage. At day 10 after wounding the animals were sacrificed, wound biopsies were removed and granulation tissue was analyzed. The tissue was homogenized in 1 N NH 4 0H and 20 examined for the amount of collagen by means of HPLC. A total collagen content of 195 mg/g tissue was measured in the control, while in tissue, that had been bombarded with pMHintMRP8, a 74% lower amount of collagen was determined. This clearly shows that an increased amount of MRP-8 in wound tissue leads to an impaired wound healing, if the amount of the binding partner MRP-14 is not effected. This shows, that the MRP8 homodimer has a negative effect on wound healing.

0 Since conditions, which inhibit the formation of a homodimer, positively influence the wound healing process, the expression and/or acitivity of MRP-8 has to be modulated, preferentially to be inhibited: e.g.

the formation of MRP8 homodimers can be inhibited by the use of MRP-8-antisense-oligonucleotides. Also, the use of an anti-MRP-8 antibody or of a functional interactor for the sequestration of the MRP-8 monomers 79 would have this effect. In addition, the MRP-8/MRP-14 heterodimer can be used as a therapeutically active substance, which would result in an increase in amount of heterodimer relative to the amount of the homodimer which has a negative effect on the wound healing process. The administration can be carried out e.g.

through recombinantly produced proteins or through gene therapeutic expression plasmids.

*o **oooo oo* o oo*** *ooo **oo* *ooo *o*oe °oo o *ooo Page(s) 50 SS are claims pages they appear after the, sequence listing Table 1 Differentially expressed Genes KIAA0494 rnas oncogene basic-leucine zipper nuclear factor JEM-l checkpoint suppressor Ribonuclease L inhibitor (Mu-

RLI)

p68 RNA Helikase inKAPl3 ping-i ping- 2 MA-3 (apoptosis-related gene) BTGl helix-loop-helix transcription factor potentially prenylated protein tyrosine phosphatase Marker gene spi2 proteinase inhibitor (spi2/eb4) Intact skin Control animals 2, 38E-03 1, 44E-05 7, 33E-04 1, 98E-01 1, 07E-02 1, 29E-01 5, 04E+00 8, 60E-02 1, 02E-03 1, 43E-05 1, 14E-05 Wound Control animals 1, 15E-03 2, OOE-02 2, 08E-03 1, 39E-01 3, 13E-02 2, 39E-01 2, 98E+00 7, 43E-02 2, 02E-03 1, 23E-05 2, 40E-05 Intact skin Dexainetha sone 2, 20E-03 2, 61E-05 4, 20E-04 9, 44E-02 7, 70E-03 5, 86E-02 1,51E+00 1, 29E-02 3, 51E-04 2, 60E-06 7, 15E-06 Wound Dexamethasone 2, 71E-03 1,68E-02 1,05E-03 6,56E-02 3, 61E-02 8,39E-02 2, 88E-01 1,74E-03 4,42E-04 3, 87E-06 1,88E-05 9,31E-03 1,85E-02 5, 60E-03 1, 49E-02 3,59E-02 1,80E-01 3, 21E-02 9, 67E-02 0 0 Table 2 No. NAME 1. MBNL

PROTEIN-

MOUSE*

SEQ ID. No. PROTEIN-MAN* SEQ ID. cDNA-MOUSE* cDNA.MAN* No.

I GB: AF231 110 EMBL: Y1 3829 GB: AAF72159 103 GB: CAA74155 trEMBL: 043311 2. MBNL Variante 3. Wolf-Hirschhom syndrome candidate 2 pir: G3860189 2 trEMBL: Q9Z1V9 4. KIAA0494 pir: G3860187 3 trEMBL: 095392 GB: BAA32328 4 EMBLAF101435 EMBL: AFi01 434

EMBLGB:

AB007963 SEQ ID Nr. 108 EMBL: ABO1 4514 KIAA0614 6. KIAA0521 7. KIAA0261 SEQ ID Nr. 106 106 GB: BAA31 589 GB: BAA25447 GB: BAA1 3391 EMBL: A1301 1093 EMBL: 087450 pir: PIR-database EMBL: EIBL-database GB: GeneBank nucleic acids GP: GeneBank polypeptides SP: SwissProt

NAME

KIAA0585 HSPCO28 calnexin

CBP

mas OncogenelMRG mas Oncogene (this work) acylamino acid-releasing enzyme basic-leucine zipper nuclear factor (JEM-1) basic-leucine zipper nuclear factor (JEM-1) (this work) basic-leucine zipper nuclear factor (JEM-1) tthis work) cardiac ankyrin repeat protein MCARP cardiac ankyrin repeat protein MCARP (this work) checkpoint suppressor rab2, GTP-binding protein, ras related Nup98-Nup96 precursor

PROTEIN-

MOUSE*

SEQ ID Nr. 105 pir: B54354 GB: AAA21014 GB: AAB28651 pir: S51001 SP: P30554 Table 3 SEQ ID. No. PROTEIN-MAN* GB: BAA25511 105 GB: AAD39844 1 0 pir: 153260 SP: P27824 12 GB: AAC51331 SEQ ID. Nr 5 6 11 13 15 cDNA-MOUSE* SEQ ID Nr. 107 EMBL: L18888 GB: S66385 GB: X67735 120 14 109 SP: P35410 pir: JC4655 SP: P13798 trEMBL: 015298 cDNA-MAN* GB: AB01 1157 GB: AF083246 EMBL: M94859 EMBL: U47741 GB: S78653 EMBL: 038441 EMBL: U79751 121 GB: X83703 GB: U68723 EMBL: X1 2953 EMBL: AF071 076 GB: AAC03533 GB: CAA64684 GB: CAA58676 GB: AAB58252 pir: B34323 SP: P08886 trEMBL: Q9Y6J5 122 123 GB: AF041 847 124 EMBL: X95403 Table 3 continued 23. Ribonuklease L inhibitor (Mu-RLI) 24. Ribonuclease L inhibitor (Mu-RLI) (this work) p68 RNA Helicase 26. p68 RNA Helicase (this work) 27. mKAP13/pmg-1 28. pmg-2 29. PMG-1/PMG-2-homologe (this work) PMG-1/PMG-2-homologe (this work) 31. PMG-1/PMG-2-homologe (this work) 32. PMG-1/PMG-2-homologe (this work) 33. PMG-1/PMG-2-homologe (this work) 34. PMG-1/PMG-2-homologe (this work) MA-3 (apoptosis-related gene) 36. MA-3 (apoptosis-related gene; variant) 37. BTG1 trEMBL: 088793 24 pir: JC6555 26 pir: 148385 28 SP: 061656 30 trEMBL: 008640 31 GB: AAD47277 32 pir: A57017 trEMBL: 013181 pir: JC1087 SP: P17844 EMBL: U90446 EMBL: X76388 SEQ ID Nr. 117 EMBL: X65627 SE0IDNr. 119 EMBIL: D85925 EMBL: AF1 62800 SEQ ID Nr. 118 EMBL: X15729 Figur 7 96 97 98 99 100 EMBIL: U83908 SEQ ID Nr. 116 EMBL: X61123 EMBIL: M38690 EMBIL: AF097514 pir: JC4523 33 trEMBL: 061823 GB: AAA37327 35 pir: JC5193 trEMBL: 099834 pir: S20947 GB: CAA43435 pir: A40402 SP: P21926 trEMBL: 09Y695 EMBL: D50465 38. 00D9 antigen pir: 149589 GB: AAA37405 pir: A36507 SP: P13011 EMBL: Li16846 EMBL: L08115 EMBL: M26270 39. stearoyi-CoA desaturase Table 3 continued 36. MA-3 (apoptosis-related gene; variant) 37. BTG 1 38. CD9 antigen 39. stearoyl-CoA desaturase ryudocan core protein 41. helix-loop-helix transcription factor ALFi 42. potentially prenylated protein tyrosine phosphatase 43 NFi-B3 protein N Fl-B protein (Variant) 44 steroid receptor RNA activator cathepsin Z GB: AAA37327 35 pir: 149589 37 GB: AAA37405 pir: A36507 39 SP: P13011 pir: JC5613 41 SP 035988 SP: 061286 43 trEMBL: 070274 45 pir: B36596 47 trEMBL: 002780 pir: S20947 GB: CAA43435 pir: A40402 SP: P21926 trEMBL: 09Y695 pir: JC1 457 SP: P31431 pir: A42121 SP: 099081 trembl: 012974 GP BAA92677 EMBIL: Li16846 EMBIL: L08115 EMBL: M26270 EMBIL: D89571 EMBIL: M97635 EMBL: AF035644 EMBIL: D90173 SEQ ID Nr. 116 EMBIL: X61 123 EMBL: M38690 EMBL: AF097514 EMBL: D1 3292 EMBL: M80627 EMBIL: U14603 GB AB037860 SEQ ID NR. 49 EMBL: AJ242663 SEQ ID Nr. EMBL: AF092038 EMBL: AF032906 GP: 0AB44494 56 GP: AAC39839 pir: PIR-database EMBL: EMBL- database trembi: translated EMBL- database GB: GeneBank nucleic acids GP: GeneBank polypeptides SP: SwissProt Table 4 No. NAME 46. SR calcium ATPase

PROTEIN-MOUSE*

trEMBL: 062268 pir: 156163 SP: P27005 SP: P31725 SEQ ID. No. PROTEIN.MAN' 51 SP: 014983 53 SP: P051 09 mli SP: P06702 SEQ ID. Nr CDNA-MOUSE* CDNA-MAN* 52 EMBL: X67140 EMBL: U96781 54 EMBL: 857123 GB: X06234 1029 GB: AB02341 8 GB: X99886 47. Intracellular calcium-binding protein (MRP8) 48. MRP-14 pir: PIR-database EMEL: EMEL- database GB: GeneBank nucleic acids GP: GeneBank polypeptides trentbl: translated EMBL- database SP: SwissProt Table 1~ I Spi 2

CT

Average

GAPDH

CT

Average

ACT

Abundance induction intact skin 24,7 24,95 20,21 20,15 0,04 1,00 3 4,80 Control 25,0 20,21 animals 9 25,0 20,04 3 Wound 21,6 21,64 18,98 19,17 0,18 5,02 2,47 Control 21,5 19,27 animals 4 21,7 19,25 2 Intact skin 25,1 25,06 19,95 20,10 0,03 0,89 8 4,96 Dexamethaso 24,8 20,24 ne 9 25,1 20,11 1 Wound 22,9 22,95 19,59 19,57 0,10 2,67 0 3,38 Dexamethaso 22,9 19,49 ne 3 23,0 19,62 1 ACT CT(GAPDH) CT (Spi2) Abundance 2

(ACT)

Table 6 Differentially expressed Genes Intact Wound Intact Wound Skin Control Skin Dexametha Control animals Dexametha sane animals sane KIAA0494 1,00 0, 67 1,03 1,39 mas Oncogene 1,00 0,22 0,37 0,46 basic-leucine zipper nuclear 1,00 0,45 0,58 0,45 factor JEM-l checkpoint suppressor 1,00 0,42 0,88 0,69 Ribonuclease L inhibitor (Mu- 1,00 0,37 0,72 2,90 RLI) p68 RNA Helicase 1,00 0,67 0,74 2,22 mKAPl3 ping-i 1,00 0,36 0,27 0,64 pmg-2 1,00 0,45 0,39 0,91 MA-3 (apoptosis-related gene) 1,00 0,11 0,58 0,16 BTG1 1,00 0,53 0,57 2,50 helix-loop-helix transcription 1,00 0,34 0,78 0,48 factor potentially prenylated protein 1,00 0,56 0,36 1,91 tyrosine phosphatase MBNL 1,00 0,47 0,70 1,73 Acylamino acid releasing 1,00 1,12 0,72 1,41 enzyme_____ KIAA0585 1,00 0,35 0,39 1,12 H-SPCO28 1,00 0,16 0,36 1,07 Rab2 1,00 0,65 0,96 0,66 Nup98-Nup96 Precursor 1,00 1,66 1,76 1,80 MRP-8 1,00 68,10 0,38 190,7 MRP-14 1,00 205,60 0,77 875,96 NFl-B 1,00 0,61 1,43 0,79 CBP 1,00 0,72 1,45 0,92 KIAA0261 1,00 0,38 0,57 1,70 MCARP 1,00 29,81 1,62 56,17 Calnexin 1,00 1,18 0,88 1,67 Steroid Receptor Coactivator 1,00 1,27 8,16 2,72 Wolf-Hirschhorn-Syndrom 1,00 0,98 1,31 0,95 Candidate 2 Cathepsin Z 1,00 1,26 0,83 0,58 SR Calcium ATPase 1,00 0,71 1,90 0,29 CD9 1,00 0,84 1,19 1,41 Acyl-CoA Desaturase 2 1,00 0,46 0,47 0,41 Ryodocan Core Protein 1,00 1,16 0,87 2,24 KIAA0614 1,00 0, 66 1,14 0,25 KIAA0521 1,00 0,23 0,63 0,01 Table 6 continued Differentially expressed Genes Intact Wound Intact Wound Skin young young Skin old old Animals Animals Animals Animals KIAA0494 01,23 0,36 0,41 0,32 basic-leucine zipper nuclear 2,00 0,29 0,61 0,29 factor JEM-1 checkpoint suppressor 1,58 0,42 0,85 0,27 Ribonuclease L inhibitor (Mu- 2,97 1,03 0,73 0,68

RLI)

p68 RNA Helicase 0,98 0,22 0,61 0,30 mKAP13 pmg-1 5,27 0,001 2,09 0,41 pmg-2 5,11 0,0005 0,67 0,20 MA-3 (apoptosis-related gene) 1,57 0,20 0,61 0,18 BTG1 1,86 0,75 0,82 0,64 helix-loop-helix transcription 1,61 0,35 0,67 0,33 factor potentially prenylated protein 0,95 0,26 0,49 0,32 tyrosine phosphatase MBNL 0,36 0,32 0,38 0,25 Acylamino acid releasing enzyme 1,79 0,92 1,60 0,59 KIAA0585 1,52 0,34 1,05 0,55 HSPC028 0,90 0,46 0,38 0,29 Rab2 1,98 0,98 1,21 0,48 Nup98-Nup96 Precursor 2,63 1,33 0,83 1,37 MRP-8 0,85 30,00 1,21 37,24 MRP-14 0,86 100,42 2,30 128,69 NFl-B 1,19 0,81 1,24 0,36 CBP 1,45 0,79 0,78 0,46 KIAA0261 0,65 0,18 0,30 0,15 MCARP 0,30 5,58 0,004 64,11 Calnexin 2,46 0,79 1,08 0,83 Steroid Receptor Coactivator 1,90 0,81 0,98 0,52 Wolf-Hirschhorn-Syndrom 1,50 1,12 1,17 0,58 Cantidate 2 Cathepsin Z 1,00 0,80 0,58 0,31 SR Calcium ATPase 0,29 0,65 1,30 1,36 CD9 1,55 0,90 1,14 0,59 Acyl-CoA Desaturase 2 0,49 0,32 0,77 0,48 Ryodocan Core Protein 0,91 0,70 1,04 0,66 KIAA0614 0,97 0,13 0,71 0,26 KIAA0521 0,48 0,44 0,56 0,33 Table 6 continued Differentially expressed Genes Intact Wound Intact Wound Skin Diabetes Skin Diabetes Diabetes- -Control Diabetes Mice Control animals Mice animals KIAA0494 1,00 0,41 0,95 0,36 Ribonuclease L inhibitor (Mu- 1,00 0,60 1,22 1,06 RLI)__ p68 RNA Helicase 1,00 0,83 1,48 1,69 mKAP13 ping-i 1,00 0,13 0,61 0,09 pmg-2 1,00 0,10 0,45 0,19 MA-3 (apoptosis-related gene) 1,00 0,16 0,99 0,24 BTG1 1,00 1,72 1,79 3,39 helix-loop-helix transcription 1,00 0,58 1,63 0,81 potentially prenylated protein 1,00 0,35 1,19 0,87 tyrosine phosphatase MBNL 1,00 0,20 0,76 0,24 Acylainino acid releasing 1,00 0,56 1,47 0,67 KIAA0585 1,00 0,75 0,61 0,99 Rab2 1,00 0,43 2,16 0,13 Nup98-Nup96 Precursor 1,00 1,36 1,41 1,19 MRP-8 1,00 47,21 5,26 40,94 MRP-14 1,00 105,44 0,79 127,29 NFl-B 1,00 0,39 1,42 0,34 CBP 1,00 1,05 0,93 0,63 KIAA0261 1,00 0,32 0,77 0,62 MCARP 1,00 171,54 13,18 515,81 Acyl-CoA Desaturase 2 1,00 1,10 2,80 0,83 Ryodocan Core Protein 1,00 1,28 1,27 1,86 KIAA0614 1,00 0,69 1, 31 0,59 KIAA0521 1,00 0,42 1,50 1 0,61 Table 7 Differentially expressed Patient Patient Patient Genes pool 1 pool 1 pool 1 Intact Skin Day 1-Wound Day p68 Helicase 1,00 0,32 0,59 Ribonuclease L Inhibitor 1,00 0,17 0,54 MRP-8 1,00 6,40 38,13 potentially prenylated 1,00 0,29 0,86 protein tyrosine phosphatase MA-3 Variant (SEQ ID Nr. 1,00 0, 17 0, 46 58) MA-3 (apoptosis-related 1,00 0,20 0,44 gene) human Checkpoint 1,00 0,34 0,41 Suppressor HSPCO28 1,00 0,35 0,36 helix-loop-helix 1,00 0,45 0,45 transcription factor KIAA0261 1,00 0,21 0,52 basic-leucine zipper 1,00 0,13 0,36 nuclear factor (JEM-l) KIAA0494 1,00 0, 29 0,42 MNBL 1,00 0,43 0,46 Acylamino acid releasing 1,00 0,98 0,76 enzyme KIAA0585 1,00 0,53 0,54 9 9 9 9&9* 9 999999 9 9*9* Table 8 Differentially Intact Skin Edge of the Ground of expressed Gene Ulcer Patients wound the wound Ulcer Ulcer Patients Patients p68 Helicase 1,00 1, 09 1, 44 RNAse L Inhibitor 1,00 0,20 0,26 MRP8 1,00 70,7 8,9 potentiell prenylierte 1,00 0,31 0,55 Tyrosin Phosphatase MA-3 Variante (SEQ ID 1,00 0,16 0,18 Nr. 58) MA-3 (apoptosis- 1,00 0,20 0,24 related gene) Checkpoint Suppressor 1,00 0,39 0,45 Helix-Loop-Helix 1,00 0,46 0,65 transcription factor KIAA0261 1,00 0,61 0,96 basic-leucine zipper 1,00 0,59 0,56 nuclear factor KIAA0494 1,00 0,17 0,25 MNBL 1,00 0,24 0,35 Acylamino acid 1,00 1,35 1,36 releasing enzyme KIAA0585 1,00 3,23 2,72 n.e en.

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C C SEQUENCE LISTING <110> Switch Biotech AG <120> Use of polypeptides or nucleic acids encoding these for the diagnosis or treatment of skin disorders, and their use for the identification of pharmacologically active substances <130> S29829AU <140> <141> <150> DE 199 55 349.1 <151> 1999-11-17 <150> US 60/172,511 <151> 1999-12-17 <150> DE 100 30 149.5 <151> 2000-06-20 <160> 128 <170> Patentln Ver. 2.1 <210> 1 <211> 388 <212> PRT <213> Homo sapiens <400> 1 Met Ala Val Ser Val Thr Pro lie Arg Asp Thr Lys Trp Leu Thr Leu 1 5 10 Glu Val Cys Arg Glu Phe Gin Arg Gly Thr Cys Ser Arg Pro Asp Thr 25 Glu Cys Lys Phe Ala His Pro Ser Lys Ser Cys Gin Val Glu Asn Gly 35 40 Arg Val Ile Ala Cys Phe Asp Ser Leu Lys Gly Arg Cys Ser Arg Glu 55 Asn Cys Lys Tyr Leu His Pro Pro Pro His Leu Lys Thr Gin Leu Glu 70 75 lie Asn Gly Arg Asn Asn Leu lie Gin Gin Lys Asn Met Ala Met Leu 85 90 SAla Gin Gin Met Gin Leu Ala Asn Ala Met Met Pro Gly Ala Pro Leu 100 105 110 Gin Pro Val Pro Met Phe Ser Val Ala Pro Ser Leu Ala Thr Asn Ala 115 120 125 Ser Ala Ala Ala Phe Asn Pro Tyr Leu Gly Pro Val Ser Pro Ser Leu 130 135 140 Val Pro Ala Glu lie Leu Pro Thr Ala Pro Met Leu Val Thr Gly Asn 145 150 155 160 Pro Gly Val Pro Val Pro Ala Ala Ala Ala Ala Ala Ala Gin Lys Leu 165 170 175 Met Arg Thr Asp Arg Leu Glu Val Cys Arg Glu Tyr Gin Arg Gly Asn 180 185 190 Cys Asn Arg Gly Glu Asn Asp Cys Arg Phe Ala His Pro Ala Asp Ser 195 200 205 Thr Met lie Asp Thr Asn Asp Asn Thr Val Thr Val Cys Met Asp Tyr 210 215 220 lie Lys Gly Arg Cys Ser Arg Glu Lys Cys Lys Tyr Phe His Pro Pro 225 230 235 240 Ala His Leu Gin Ala Lys lie Lys Ala Ala Gin Tyr Gin Val Asn Gin 245 250 255 Ala Ala Ala Ala Gin Ala Ala Ala Thr Ala Ala Ala Met Thr Gin Ser 260 265 270 Ala Val Lys Ser Leu Lys Arg Pro Leu Glu Ala Thr Phe Asp Leu Gly 275 280 285 lie Pro Gin Ala Val Leu Pro Pro Leu Pro Lys Arg Pro Ala Leu Glu 290 295 300 Lys Thr Asn Gly Ala Thr Ala Val Phe Asn Thr Gly lie Phe Gin Tyr 305 310 315 320 Gin Gin Ala Leu Ala Asn Met Gin Leu Gin Gin His Thr Ala Phe Leu 325 330 335 Pro Pro Val Pro Met Val His Gly Ala Thr Pro Ala Thr Val Ser Ala 340 345 350 00 ~Ala Thr Thr Ser Ala Thr Ser Val Pro Phe Ala Ala Thr Ala Thr Ala 355 360 365 Asn Gin lie Pro lie lie Ser Ala Glu His Leu Thr Ser His Lys Tyr 370 375 380

O

Val Thr Gin Met 385 <210>2 <211> 521 <212> PRT <213> Mus musculus <400> 2 Asp Thr Gly Leu Trp Leu His Asn Lys Leu Gly Ala Thr Asp Glu Leu 1 5 10 Trp Ala Pro Pro Ser lie Ala Ser Leu Leu Thr Ala Ala Val lie Asp 25 Asn lie Arg Leu Cys Phe His Arg Leu Ser Ser Ala Val Lys Leu Lys 40 Leu Leu Leu Gly Thr Leu His Leu Pro Arg Arg Thr Val Asp Glu Met 55 Asn Ala Ala Leu Met Asp lie lie Gin Leu Ala Thr Leu Asp Ser Asp 70 75 Pro Trp Val Leu Met Val Ala Asp lie Leu Lys Ser Phe Pro Asp Thr 90 Gly Ser Leu Asn Leu Asp Leu Glu Glu Gin Asn. Pro Asn Val Gin Glu 100 105 110 lie Leu Gly Glu Leu Arg Glu Lys Val Ser Glu Cys Glu Ala Ser Ala 115 120 125 Met Leu Pro Leu Glu Cys Gin Tyr Leu Asn Lys Asn Ala Leu Thr Thr 130 135 140 Leu Ala Gly Pro Leu Thr Pro Pro Val Lys His Phe Gin Leu Lys Arg 145 150 155 160 Lys Pro Lys Ser Ala Thr Leu Arg Ala Glu Leu Leu Gin lie Ser Thr 165 170 175 Glu Thr Ala Gin Gin Leu Lys Arg Ser Ala Gly Val Pro Phe His Ala 180 185 190 Lys Gly Arg Gly Leu Leu Arg Lys Met Asp Thr Thr Thr Pro Leu Lys 195 200 205 Gly lie Pro Lys Gin Ala Pro Phe Arg Ser Pro Thr Thr Pro Ser Val 210 215 220 Phe Ser Pro Ser Gly Asn Arg Thr Pro lie Pro Pro Ser Arg Thr Pro 225 230 235 240 Leu Gin Lys Glu Arg Gly Val Lys Leu Leu Asp lie Ser Glu Leu Asn 245 250 255 Thr Val Gly Ala Gly Arg Glu Ala Lys Arg Arg Arg Lys Thr Leu Asp 260 265 270 Thr Glu Val Val Glu Lys Pro Thr Lys Glu Glu Thr Val Val Glu Asn 275 280 285 Ala Thr Pro Asp Tyr Ala Ala Gly Leu Val Ser Thr Gin Lys Leu Gly 290 295 300 Ser Leu Asn Ser Glu Pro Thr Leu Pro Ser Thr Ser Tyr Leu Pro Ser 305 310 315 320 Thr Pro Ser Val Val Pro Ala Ser Ser Tyr lie Pro Ser Ser Glu Thr 325 330 335 Pro Pro Ala Thr Pro Ser Arg Glu Ala Ser Arg Pro Pro Glu Glu Pro 340 345 350 Ser Ala Pro Ser Pro Thr Leu Pro Thr Gin Phe Lys Gin Arg Ala Pro 355 360 365 Met Tyr Asn Ser Gly Val Ser Pro Ala Thr Pro Ala Ala Pro Thr Ser 370 375 380 Pro Arg Thr His Thr Thr Pro Pro Ala Val Thr Pro Thr Ala Gin Thr 385 390 395 400 Pro Pro Val Ala Met Val Ala Pro Gin Thr Gin Ala Pro Ala Pro Val 405 410 415 Gin Gin Gin Pro Lys Lys Asn Leu Ser Phe Thr Arg Glu Gin Met Phe 420 425 430 Ala Ala Gin Glu Met Phe Lys Thr Ala Asn Lys Val Thr Arg Pro Glu 435 440 445 Lys Ala Leu lie Leu Gly Phe Met Ala Gly Ser Arg Glu Asn Pro Cys 450 455 460 Pro Glu Gin Gly Asp Val lie Gin lie Lys Leu Ser Glu His Thr Glu 465 470 475 480 Asp Leu Pro Lys Ala Asp Gly Gin Gly Ser Thr Thr Met Leu Val Asp 485 490 495 Thr Val Phe Glu Met Asn Tyr Ala Thr Gly Gin Trp Thr Arg Phe Lys 500 505 510 Lys Tyr Lys Pro Met Thr Asn Val Ser 515 520 <210>3 <211> 525 <212> PRT <213> Homo sapiens <300> <301> Wright, T. J.

<302> Comparative analysis of a novel gene from the Wolf-Hirschhorn/Pitt-Rogers-Danks syndrome critical region <303> Genomics <304> 1999 <305> 59 <306> 203-212 <308> PIR G3860187 <309> 1998-10-26 <313> 1 TO 525 <400> 3 Met Arg Glu Ser Asp Thr Gly Leu Trp Leu His Asn Lys Leu Gly Ala 1 5 10 Thr Asp Glu Leu Trp Ala Pro Pro Ser lie Ala Ser Leu Leu Thr Ala 25 Ala Val lie Asp Asn lie Arg Leu Cys Phe His Gly Leu Ser Ser Ala 40 Val Lys Leu Lys Leu Leu Leu Gly Thr Leu His Leu Pro Arg Arg Thr 55 Val Asp Glu Met Lys Gly Ala Leu Met Glu lie lie Gin Leu Ala Ser 70 75 Leu Asp Ser Asp Pro Trp Val Leu Met Val Ala Asp lie Leu Lys Ser 90 Phe Pro Asp Thr Gly Ser Leu Asn Leu Glu Leu Glu Glu Gin Asn Pro 100 105 110 Asn Val Gin Asp lie Leu Gly Glu Leu Arg Glu Lys Val Gly Glu Cys 115 120 125 Glu Ala Ser Ala Met Leu Pro Leu Glu Cys Gin Tyr Leu Asn Lys Asn 130 135 140 Ala Leu Thr Thr Leu Ala Gly Pro Leu Thr Pro Pro Val Lys His Phe 145 150 155 160 Gin Leu Lys Arg Lys Pro Lys Ser Ala Thr Leu Arg Ala Glu Leu Leu 165 170 175 Gin Lys Ser Thr Glu Thr Ala Gin Gin Leu Lys Arg Ser Ala Gly Val 180 185 190 Pro Phe His Ala Lys Gly Arg Gly Leu Leu Arg Lys Met Asp Thr Thr 195 200 205 Thr Pro Leu Lys Gly lie Pro Lys Gin Ala Pro Phe Arg Ser Pro Thr 210 215 220 Ala Pro Ser Val Phe Ser Pro Thr Gly Asn Arg Thr Pro lie Pro Pro 225 230 235 240 Ser Arg Thr Leu Leu Arg Lys Glu Arg Gly Val Lys Leu Leu Asp lie 245 250 255 Ser Glu Leu Asp Met Val Gly Ala Gly Arg Glu Ala Lys Arg Arg Arg 260 265 270 Lys Thr Leu Asp Ala Glu Val Val Glu Lys Pro Ala Lys Glu Glu Thr 275 280 285 Val Val Glu Asn Ala Thr Pro Asp Tyr Ala Ala Gly Leu Val Ser Thr 290 295 300 Gin Lys Leu Gly Ser Leu Asn Asn Glu Pro Ala Leu Pro Ser Thr Ser 305 310 315 320 Tyr Leu Pro Ser Thr Pro Ser Val Val Pro Ala Ser Ser Tyr lie Pro 325 330 335 Ser Ser Glu Thr Pro Pro Ala Pro Ser Ser Arg Glu Ala Ser Arg Pro 340 345 350 Pro Glu Glu Pro Ser Ala Pro Ser Pro Thr Leu Pro Ala Gin Phe Lys 355 360 365 Gin Arg Ala Pro Met Tyr Asn Ser Gly Leu Ser Pro Ala Thr Pro Thr 370 375 380 Pro Ala Ala Pro Thr Ser Pro Leu Thr Pro Thr Thr Pro Pro Ala Val 385 390 395 400 Ala Pro Thr Thr Gin Thr Pro Pro Val Ala Met Val Ala Pro Gin Thr 405 410 415 Gin Ala Pro Ala Gin Gin Gin Pro Lys Lys Asn Leu Ser Leu Thr Arg 420 425 430 Glu Gin Met Phe Ala Ala Gin Glu Met Phe Lys Thr Ala Asn Lys Val 435 440 445 Thr Arg Pro Glu Lys Ala Leu lie Leu Gly Phe Met Ala Gly Ser Arg 450 455 460 Glu Asn Pro Cys Gin Glu Gin Gly Asp Val lie Gin lie Lys Leu Ser 465 470 475 480 Glu His Thr Glu Asp Leu Pro Lys Ala Asp Gly Gin Gly Ser Thr Thr 485 490 495 Met Leu Val Asp Thr Val Phe Glu Met Asn Tyr Ala Thr Gly Gin Trp 500 505 510 Thr Arg Phe Lys Lys Tyr Lys Pro Met Thr Asn Val Ser 515 520 525 .<210> 4 <211> 495 <212> PRT <213> Homo sapiens <400> 4 Met Lys Lys Arg Lys Glu Leu Asn Ala Leu lie Gly Leu Ala Gly Asp 1 5 10 Ser Arg Arg Lys Lys Pro Lys Lys Gly Pro Ser Ser His Arg Leu Leu 20 25 Arg Thr Glu Pro Pro Asp Ser Asp Ser Glu Ser Ser Ser Glu Glu Glu 35 40 Glu Glu Phe Gly Val Val Gly Asn Arg Ser Arg Phe Ala Lys Gly Asp 55 Tyr Leu Arg Cys Cys Lys lie Cys Tyr Pro Leu Cys Gly Phe Val lie 70 75 Leu Ala Ala Cys Val Val Ala Cys Val Gly Leu Val Trp Met Gin Val 90 Ala Leu Lys Glu Asp Leu Asp Ala Leu Lys Glu Lys Phe Arg Thr Met 100 105 110 Glu Ser Asn Gin Lys Ser Ser Phe Gin Glu lie Pro Lys Leu Asn Glu 115 120 125 Glu Leu Leu Ser Lys Gin Lys Gin Leu Glu Lys lie Glu Ser Gly Glu 130 135 140 Met Gly Leu Asn Lys Val Trp lie Asn lie Thr Glu Met Asn Lys Gin 145 150 155 160 lie Ser Leu Leu Thr Ser Ala Val Asn His Leu Lys Ala Asn Val Lys 165 170 175 Ser Ala Ala Asp Leu lie Ser Leu Pro Thr Thr Val Glu Gly Leu Gin 180 185 190 Lys Ser Val Ala Ser lie Gly Asn Thr Leu Asn Ser Val His Leu Ala 195 200 205 Val Glu Ala Leu Gin Lys Thr Val Asp Glu His Lys Lys Thr Met Glu 210 215 220 Leu Leu Gin Ser Asp Met Asn Gin His Phe Leu Lys Glu Thr Pro Gly 225 230 235 240 Ser Asn Gin lie lie Pro Ser Pro Ser Ala Thr Ser Glu Leu Asp Asn 245 250 255 Lys Thr His Ser Glu Asn Leu Lys Gin Asp lie Leu Tyr Leu His Asn S260 265 270 Ser Leu Glu Glu Val Asn Ser Ala Leu Val Gly Tyr Gin Arg Gin Asn 275 280 285 Asp Leu Lys Leu Glu Gly Met Asn Glu Thr Val Ser Asn Leu Thr Gin 290 295 300 Arg Val Asn Leu lie Glu Ser Asp Val Val Ala Met Ser Lys Val Glu 305 310 315 320 Lys Lys Ala Asn Leu Ser Phe Ser Met Met Gly Asp Arg Ser Ala Thr 325 330 335 Leu Lys Arg Gin Ser Leu Asp Gin Val Thr Asn Arg Thr Asp Thr Val 340 345 350 Lys lie Gin Ser lie Lys Lys Glu Asp Ser Ser Asn Ser Gin Val Ser 355 360 365 Lys Leu Arg Glu Lys Leu Gin Leu lie Ser Ala Leu Thr Asn Lys Pro 370 375 380 Glu Ser Asn Arg Pro Pro Glu Thr Ala Asp Glu Glu Gin Val Glu Ser 385 390 395 400 Phe Thr Ser Lys Pro Ser Ala Leu Pro Lys Phe Ser Gin Phe Leu Gly 405 410 415 Asp Pro Val Glu Lys Ala Ala Gin Leu Arg Pro lie Ser Leu Pro Gly 420 425 430 Val Ser Ser Thr Glu Asp Leu Gin Asp Leu Phe Arg Lys Thr Gly Gin 435 440 445 Asp Val Asp Gly Lys Leu Thr Tyr Gin Glu lie Trp Thr Ser Leu Gly 450 455 460 Ser Ala Met Pro Glu Pro Glu Ser Leu Arg Ala Phe Asp Ser Asp Gly 465 470 475 480 Asp Gly Arg Tyr Ser Phe Leu Glu Leu Arg Val Ala Leu Gly lie 485 490 495 <210> <211>416 <212> PRT <213> Homo sapiens <400> Arg Arg Met Asn His Lys Ser Lys Lys Arg lie Arg Glu Ala Lys Arg 1 5 10 Ser Ala Arg Pro Glu Leu Lys Asp Ser Leu Asp Trp Thr Arg His Asn 25 Tyr Tyr Glu Ser Phe Ser Leu Ser Pro Ala Ala Val Ala Asp Asn Val 35 40 Glu Arg Ala Asp Ala Leu Gin Leu Ser Val Glu Glu Phe Val Glu Arg 50 55 Tyr Glu Arg Pro Tyr Lys Pro Val Val Leu Leu Asn Ala Gin Glu Gly 70 75 Trp Ser Ala Gin Glu Lys Trp Thr Leu Glu Arg Leu Lys Arg Lys Tyr 85 90 Arg Asn Gin Lys Phe Lys Cys Gly Glu Asp Asn Asp Gly Tyr Ser Val 100 105 110 o Lys Met Lys Met Lys Tyr Tyr lie Glu Tyr Met Glu Ser Thr Arg Asp 115 120 125 Asp Ser Pro Leu Tyr lie Phe Asp Ser Ser Tyr Gly Glu His Pro Lys 130 135 140 Arg Arg Lys Leu Leu Glu Asp Tyr Lys Val Pro Lys Phe Phe Thr Asp 145 150 155 160 Asp Leu Phe Gin Tyr Ala Gly Glu Lys Arg Arg Pro Pro Tyr Arg Trp 165 170 175 Phe Val Met Gly Pro Pro Arg Ser Gly Thr Gly lie His lie Asp Pro 180 185 190 Leu Gly Thr Ser Ala Trp Asn Ala Leu Val Gin Gly His Lys Arg Trp 195 200 205 Cys Leu Phe Pro Thr Ser Thr Pro Arg Glu Leu lie Lys Val Thr Arg 210 215 220 Asp Glu Gly Gly Asn Gin Gin Asp Glu Ala lie Thr Trp Phe Asn Val 225 230 235 240 lie Tyr Pro Arg Thr Gin Leu Pro Thr Trp Pro Pro Glu Phe Lys Pro 245 250 255 Leu Glu lie Leu Gin Lys Pro Gly Glu Thr Val Phe Val Pro Gly Gly 260 265 270 Trp Trp His Val Val Leu Asn Leu Asp Thr Thr lie Ala lie Thr Gin 275 280 285 Asn Phe Ala Ser Ser Thr Asn Phe Pro Val Val Trp His Lys Thr Val 290 295 300 Arg Gly Arg Pro Lys Leu Ser Arg Lys Trp Tyr Arg lie Leu Lys Gin 305 310 315 320 Glu His Pro Glu Leu Ala Val Leu Ala Asp Ser Val Asp Leu Gin Glu 325 330 335 Ser Thr Gly lie Ala Ser Asp Ser Ser Ser Asp Ser Ser Ser Ser Ser 340 345 350 Ser Ser Ser Ser Ser Asp Ser Asp Ser Glu Cys Glu Ser Gly Ser Glu 355 360 365 Gly Asp Gly Thr Val His Arg Arg Lys Lys Arg Arg Thr Cys Ser Met 370 375 380 Val Gly Asn Gly Asp Thr Thr Ser Gin Asp Asp Cys Val Ser Lys Glu 385 390 395 400 Arg Ser Ser Ser Arg lie Arg Asp Thr Cys Gly Gly Arg Ala His Pro 405 410 415 <210> 6 <211>419 <212> PRT <213> Homo sapiens <300> <301> Zhang, Q.

<302> Human HSPC028 gene, complete cds <400> 6 Met Asn Lys His Gin Lys Pro Val Leu Thr Gly Gin Arg Phe Lys Thr 1 5 10 Arg Lys Arg Asp Glu Lys Glu Lys Phe Glu Pro Thr Val Phe Arg Asp 25 Thr Leu Val Gin Gly Leu Asn Glu Ala Gly Asp Asp Leu Glu Ala Val 40 Ala Lys Phe Leu Asp Ser Thr Gly Ser Arg Leu Asp Tyr Arg Arg Tyr 55 Ala Asp Thr Leu Phe Asp lie Leu Val Ala Gly Ser Met Leu Ala Pro 70 75 Gly Gly Thr Arg lie Asp Asp Gly Asp Lys Thr Lys Met Thr Asn His 90 Cys Val Phe Ser Ala Asn Glu Asp His Glu Thr lie Arg Asn Tyr Ala 100 105 110 Gin Val Phe Asn Lys Leu lie Arg Arg Tyr Lys Tyr Leu Glu Lys Ala 115 120 125 Phe Glu Asp Glu Met Lys Lys Leu Leu Leu Phe Leu Lys Ala Phe Ser 130 135 140 Glu Thr Glu Gin Thr Lys Leu Ala Met Leu Ser Gly lie Leu Leu Gly 145 150 155 160 Asn Gly Thr Leu Pro Ala Thr lie Leu Thr Ser Leu Phe Thr Asp Ser 165 170 175 o Leu Val Lys Glu Gly lie Ala Ala Ser Phe Ala Val Lys Leu Phe Lys 180 185 190 Ala Trp Met Ala Glu Lys Asp Ala Asn Ser Val Thr Ser Ser Leu Arg 195 200 205 Lys Ala Asn Leu Asp Lys Arg Leu Leu Glu Leu Phe Pro Val Asn Arg 210 215 220 Gin Ser Val Asp His Phe Ala Lys Tyr Phe Thr Asp Ala Gly Leu Lys 225 230 235 240 Glu Leu Ser Asp Phe Leu Arg Val Gin Gin Ser Leu Gly Thr Arg Lys 245 250 255 Glu Leu Gin Lys Glu Leu Gin Glu Arg Leu Ser Gin Glu Cys Pro lie 260 265 270 Lys Glu Val Val Leu Tyr Val Lys Glu Glu Met Lys Arg Asn Asp Leu 275 280 285 Pro Glu Thr Ala Val lie Gly Leu Leu Trp Thr Cys lie Met Asn Ala 290 295 300 Val Glu Trp Asn Lys Lys Glu Glu Leu Val Ala Glu Gin Ala Leu Lys 305 310 315 320 His Leu Lys Gin Tyr Ala Pro Leu Leu Ala Val Phe Ser Ser Gin Gly 325 330 335 Gin Ser Glu Leu lie Leu Leu Gin Lys Val Gin Glu Tyr Cys Tyr Asp 340 345 350 Asn lie His Phe Met Lys Ala Phe Gin Lys lie Val Val Leu Phe Tyr 355 360 365 Lys Ala Asp Val Leu Ser Glu Glu Ala lie Leu Lys Trp Tyr Lys Glu 370 375 380 Ala His Val Ala Lys Gly Lys Ser Val Phe Leu Asp Gin Met Lys Lys 385 390 395 400 Phe Val Glu Trp Leu Gin Asn Ala Glu Glu Glu Ser Glu Ser Glu Gly 405 410 415 Glu Glu Asn <210> 7 <211> 1630 <212> PRT <213> Homo sapiens <400> 7 Lys Thr Phe Gly Leu His Gly Val Val Leu Asp Val Asp Ser Val Asn 1 5 10 Glu Leu Val Gin Val Glu Thr Tyr Leu Arg Ser Glu Gly Val Leu Val 20 25 o. Arg Tyr Trp Tyr Pro lie Asp Met Leu Glu Arg Pro Pro Ala Gly Tyr S35 40 Arg Arg Thr Ala Thr Asn Gly Leu Val Thr Leu Asp Asn Thr Asn Leu 55 Gin lie His Arg Glu Leu Leu Arg Cys Glu Ala Ala Leu Ala Arg Leu 70 75 Tyr Cys Arg Met Ala Leu Leu Asn lie Phe Ala Pro Lys Leu Pro His 90 Leu Phe Thr Arg Leu Phe His lie Pro Ala lie Arg Asp lie Thr Leu 100 105 110 Glu His Leu Gin Leu Leu Ser Asn Gin Leu Leu Ala Pro Pro Leu Pro S115 120 125 Asp Gly Thr lie Ser Ser Ser Ser lie Leu Leu Ala Gin Ser Leu Gin 130 135 140 His Cys lie His Ser Gin Asn Cys Ser Ala Thr Asp Leu Phe Tyr Gin 145 150 155 160 Gly Asn Ser Gin Thr Val Arg Glu Trp Leu Asn Val Ala lie Thr Arg 165 170 175 Thr Leu His Gin Gly Glu Glu Ser Leu Leu Glu Leu Thr Lys Gin lie 180 185 190 Cys Ser Phe Leu Gin Thr Ala Pro Glu Gin Phe Pro Ser Glu Glu Phe 195 200 205 Pro lie Ser Glu Ser Lys Val Asn Met Asp Val Asn Phe Pro Gly Ala 210 215 220 Ala Phe Val Val Val Ser Cys Lys Glu Ser Gin Ser Gly Phe Arg Lys 225 230 235 240 Asp Ser Ser Leu Tyr Lys Ala Pro Trp Ala Arg Val Leu Val Tyr Gly 245 250 255 Leu Gly His Lys Val Lys Arg Asn Gly Gin Leu Asn Leu lie Glu Ala 260 265 270 Ala Cys Tyr Pro Arg Asp Ala Ser Pro Ala Asn Thr Gly Leu Ala Pro 275 280 285 Pro Pro Thr Ala Asp Gin Tyr Pro Ser Val Val Leu Ser Thr Asp Arg 290 295 300 Val His lie Lys Leu Gly Val Ser Pro Pro Pro Gly Ala Val Leu Val 305 310 315 320 Leu His Ser Leu Pro Leu Glu Phe Pro Leu Ala Met Ala Phe Ala Glu 325 330 335 Gin Leu Leu Ser Trp Lys Ser Glu Asp Ser Glu Gly Lys Ser Glu Asp 340 345 350 Glu Pro Asp Thr lie Pro Thr Ser Val Leu Leu Gin Val Val Glu Leu 355 360 365 Leu Gly Asn Phe Leu Trp Thr Thr Asp Met Ala Ala Cys Val Lys Glu 370 375 380 o Leu Val Phe His Leu Leu Ala Glu Leu Leu Arg Thr Val His Thr Leu 385 390 395 400 Glu Gin Arg Arg His Pro Ala Gly Leu Ser Ser Ser lie Ala Leu Gin .405 410 415 Leu Asn Pro Cys Leu Ala Met Leu Met Ala Leu Gin Ser Glu Leu His 420 425 430 Lys Leu Tyr Asp Glu Glu Thr Gin Asn Trp Val Ser Gly Gly Ala Cys 435 440 445 Gly Gly Ser Gly Gly Ala Ala Ala Gly Asp Gin Gly Arg Phe Ser Thr 450 455 460 Tyr Phe His Ala Leu Met Glu Gly Cys Leu Ala Val Ala Glu Val Thr 465 470 475 480 Leu Pro Thr Asn Met Ser Val Thr Ala Ser Gly Val Thr Ser Ala Thr 485 490 495 Ala Pro Asn Leu Ser Asp Ser Ser Ser Ser Ser Ser Ser Ser Pro Gly 500 505 510 Gin Thr Pro Gin Ser Pro Ser Leu Leu Ser Lys Arg Lys Lys Val Lys 515 520 525 Met Lys Arg Glu Lys Ala Ser Ser Ser Gly Lys Arg Gin Ser Ser Arg 530 535 540 Thr Val Asp Ser Asp Pro Thr Val Leu Ser lie Gly Gly Ser Lys Pro 545 550 555 560 Glu Asp Met Leu Trp Phe His Arg Ala Leu Thr Leu Leu lie lie Leu 565 570 575 Arg His Leu Thr Arg Lys Asp Pro Gin Gly Leu Gly Val Thr Ser Asp 580 585 590 Ala lie Ala Asp Ala Cys Gin Ala Leu Val Gly Pro Thr Ala His Ser 595 600 605 Arg Leu Leu Val lie Ser Gly lie Pro Thr His Leu Asp Glu Gly Val 610 615 620 Val Arg Gly Ala lie Arg Lys Ala Cys Asn Ala His Gly Gly Val Phe 625 630 635 640 Lys Asp Glu lie Tyr lie Pro Leu Gin Glu Glu Asp Thr Lys Lys Pro 645 650 655 Lys Asp Lys Ala Glu Gly Gly Asp Gly Lys Val Glu Pro Glu Lys Thr 660 665 670 Leu Ala Phe Pro Gly Thr Asp Ser Met Glu Val Ser Thr Ser Ser Ser 675 680 685 Leu Thr Pro Ala Met Ser lie Ser Ala Ser Ala Ser Thr Ser Gin Ala 690 695 700 Ser lie Cys Ser Ser Gin Gly lie Ser Gin Thr Val Ser Asp Leu Ser 705 710 715 720 Val Asp Pro Leu Pro Ala Gly Leu Glu Leu Pro lie Pro Pro Gly Leu 725 730 735 Leu Glu Pro His Ala Val Ser Ser Gin Glu Ser Leu Asp lie Ser Leu 740 745 750 Cys Ser Thr Gly Ser Leu Gly Ser Leu Gly Ser Leu Gly Glu Pro Leu 755 760 765 Asp Asn Ala Glu Thr Ala Ser Val Ser Asp Met Gly Ser Met Tyr Thr 770 775 780 Val Thr Ser Leu Asp Asn Gin Pro Leu Ala Ala Arg Pro lie Lys Gly 785 790 795 800 Phe Ala Val Val Glu lie Arg Ser Arg Ala Lys lie Glu Lys lie Arg 805 810 815 Ala Ser Leu Phe Asn Asn Asn Asp Leu lie Gly Leu Ser Ser Leu Asp 820 825 830 Gly Glu Asp Glu Leu Met Glu Met Ser Thr Glu Glu lie Leu Thr Val 835 840 845 Ser Val Val Asn Gin Ser Leu Phe Asp Thr Gin Gly Ser Pro Gly Leu 850 855 860 Glu Asp Tyr Phe Asn Asp Lys Ser lie Lys Gly Glu Lys Leu Val Pro 865 870 875 880 Gly Ala Arg Glu Val Leu Thr Glu lie Phe Lys Ser Cys Ala His Ser 885 890 895 Glu Gin Thr Leu Ser Leu Thr Pro Ala Lys Pro lie Arg Val Ser Asp 900 905 910 lie Tyr Leu Ser Lys Glu Gin lie Asn Ser Gin Thr Pro Gly Asn Leu 915 920 925 Leu His Leu Phe Phe Thr Asn Val Arg Pro Pro Lys Lys Val Leu Glu 930 935 940 Asp Gin Leu Thr Gin lie Leu Arg Lys Tyr Gly Val Pro Lys Pro Lys 945 950 955 960 Phe Asp Lys Ser Lys Tyr Ser Lys Ala Gly Lys Glu Gin His Pro Val 965 970 975 Lys Val Val Ser Thr Lys Arg Pro lie Thr Lys Pro Pro Ala Lys Asp 980 985 990 Lys Ala Val Leu Asn Ser Val Ser Arg Thr Ala Leu Ser Glu Lys Lys 995 1000 1005 Pro Thr Val Lys Pro Lys Ser Pro Glu Lys Ser Lys Pro Asp Glu Lys 1010 1015 1020 Asp Pro Glu Lys Ser Pro Thr Lys Lys Gin Glu Val Pro Glu Glu Lys 1025 1030 1035 1040 Tyr Leu Thr Leu Glu Gly Phe His Lys Phe Val lie Asp Arg Ala Arg 1045 1050 1055 Gin Asp lie Arg Ser Val Trp Arg Ala lie Leu Ser Cys Gly Tyr Asp 1060 1065 1070 Leu His Phe Glu Arg Cys Ala Cys lie Asp Val Arg His Ala Gin Lys S" 1075 1080 1085 Ala Ser Arg Lys Trp Thr Leu Glu Met Asp Val Ala Leu Val Gin Tyr 1090 1095 1100 lie Asn Gin Leu Cys Arg His Leu Ala lie Thr Pro Ala Arg Leu His 1105 1110 1115 1120 Pro His Glu Val Tyr Leu Asp Pro Ala Asp Ala Ala Asp Pro Arg Val 1125 1130 1135 Ala Cys Leu Leu Asn Val Pro lie Glu Ser Leu Arg Leu Arg Phe Ala 1140 1145 1150 Leu Leu Gin Ser Leu Asn Thr Thr Leu Glu Thr Phe Phe Leu Pro Leu 1155 1160 1165 Val Glu Leu Arg Gin Thr Pro Met Tyr Thr His Ser lie Ala Ala Leu 1170 1175 1180 Leu Lys Glu Ala Lys Gly Leu lie Phe Tyr Asp Thr Lys Val Thr Val 1185 1190 1195 1200 Met Asn Arg Val Leu Asn Ala Thr Val Gin Arg Thr Ala Asp His Ala 1205 1210 1215 Ala Pro Glu lie Thr Leu Asp Pro Leu Glu lie Val Gly Gly Glu lie 1220 1225 1230 Arg Ala Ser Glu Asn Ser Tyr Phe Cys Gin Ala Ala Arg Gin Leu Ala 1235 1240 1245 Ser Val Pro Ser Ser Gin Leu Cys Val Lys Leu Ala Ser Gly Gly Asp 1250 1255 1260 Pro Thr Tyr Ala Phe Asn lie Arg Phe Thr Gly Glu Glu Val His Gly 1265 1270 1275 1280 Thr Ser Gly Ser Phe Arg His Phe Leu Trp Gin Val Cys Lys Glu Leu 1285 1290 1295 Gin Ser Ser Ser Leu Ser Leu Leu Leu Leu Cys Pro Ser Ser Ala Val 1300 1305 1310 Asn Lys Asn Lys Gly Lys Tyr lie Leu Thr Pro Ser Pro lie Thr Tyr 1315 1320 1325 Gly Glu Glu Gin Leu Leu His Phe Leu Gly Gin Leu Leu Gly lie Ala 1330 1335 1340 lie Arg Ala Asp Val Pro Leu Pro Leu Asp Leu Leu Pro Ser Phe Trp 1345 1350 1355 1360 Lys Thr Leu Val Gly Glu Pro Leu Asp Pro Glu Gin Asp Leu Gin Glu 1365 1370 1375 Ala Asp lie Leu Thr Tyr Asn Tyr Val Lys Lys Phe Glu Ser lie Asn 1380 1385 1390 Asp Glu Thr Glu Leu Glu Ala Leu Cys Ala Glu lie Ala Ser Gin His 1395 1400 1405 Leu Ala Thr Glu Ser Pro Asp Ser Pro Asn Lys Pro Cys Cys Arg Phe 1410 1415 1420 Thr Tyr Leu Thr Met Thr Gly Glu Glu Val Glu Leu Cys Ser Arg Gly 1425 1430 1435 1440 Arg His lie Leu Val Ala Trp Glu Asn Lys Asp lie Tyr Ala Ala Ala 1445 1450 1455 lie Arg Ser Leu Arg Leu Arg Glu Leu Gin Asn Val Glu Cys Val Thr 1460 1465 1470 Ala Val Arg Ala Gly Leu Gly Ser lie lie Pro Leu Gin Leu Leu Thr 1475 1480 1485 Met Leu Ser Pro Leu Glu Met Glu Leu Arg Thr Cys Gly Leu Pro Tyr 1490 1495 1500 lie Asn Leu Glu Phe Leu Lys Ala His Thr Met Tyr Gin Val Gly Leu 1505 1510 1515 1520 Met Glu Thr Asp Gin His lie Glu Phe Phe Trp Gly Ala Leu Glu Met 1525 1530 1535 Phe Thr Gin Glu Glu Leu Cys Lys Phe lie Lys Phe Ala Cys Asn Gin 1540 1545 1550 Glu Arg lie Pro Phe Thr Cys Pro Cys Lys Asp Gly Gly Pro Asp Thr 1555 1560 1565 Ala His Val Pro Pro Tyr Pro Met Lys lie Ala Pro Pro Asp Gly Thr 1570 1575 1580 Ala Gly Ser Pro Asp Ser Arg Tyr lie Arg Val Glu Thr Cys Met Phe 1585 1590 1595 1600 Met lie Lys Leu Pro Gin Tyr Ser Ser Leu Glu lie Met Leu Glu Lys 1605 1610 1615 Leu Arg Cys Ala lie His Tyr Arg Glu Asp Pro Leu Ser Gly 1620 1625 1630 0 <210> 8 <211> 1050 <212> PRT <213> Homo sapiens <400> 8 Trp Arg Arg Ala Ala Cys Gly Arg Ser Gly Arg Ala Ser Leu Lys Glu 1 5 10 l His Pro Arg Gly Thr Leu Leu Ser Asp Gly Ser Pro Ala Leu Ser Arg 20 25 Asn Val Gly Met Thr Val Ser Gin Lys Gly Gly Pro Gin Pro Thr Pro 40 Ser Pro Ala Gly Pro Gly Thr Gin Leu Gly Pro lie Thr Gly Glu Met 55 Asp Glu Ala Asp Ser Ala Phe Leu Lys Phe Lys Gin Thr Ala Asp Asp 70 75 Ser Leu Ser Leu Thr Ser Pro Asn Thr Glu Ser lie Phe Val Glu Asp 90 Pro Tyr Thr Ala Ser Leu Arg Ser Glu lie Glu Ser Asp Gly His Glu 100 105 110 Phe Glu Ala Glu Ser Trp Ser Leu Ala Val Asp Ala Ala Tyr Ala Lys 115 120 125 Lys Gin Lys Arg Glu Val Val Lys Arg Gin Asp Val Leu Tyr Glu Leu 130 135 140 Met Gin Thr Glu Val His His Val Arg Thr Leu Lys lie Met Leu Lys 145 150 155 160 Val Tyr Ser Arg Ala Leu Gin Glu Glu Leu Gin Phe Ser Ser Lys Ala 165 170 175 lie Gly Arg Leu Phe Pro Cys Ala Asp Asp Leu Leu Glu Thr His Ser 180 185 190 His Phe Leu Ala Arg Leu Lys Glu Arg Arg Gin Glu Ser Leu Glu Glu 195 200 205 Gly Ser Asp Arg Asn Tyr Val lie Gin Lys lie Gly Asp Leu Leu Val 210 215 220 Gin Gin Phe Ser Gly Glu Asn Gly Glu Arg Met Lys Glu Lys Tyr Gly 225 230 235 240 Val Phe Cys Ser Gly His Asn Glu Ala Val Ser His Tyr Lys Leu Leu 245 250 255 Leu Gin Gin Asn Lys Lys Phe Gin Asn Leu lie Lys Lys lie Gly Asn 260 265 270 Phe Ser lie Val Arg Arg Leu Gly Val Gin Glu Cys lie Leu Leu Val 275 280 285 Thr Gin Arg lie Thr Lys Tyr Pro Val Leu Val Glu Arg lie lie Gin 290 295 300 Asn Thr Glu Ala Gly Thr Glu Asp Tyr Glu Asp Leu Thr Gin Ala Leu 305 310 315 320 S* Asn Leu lie Lys Asp lie lie Ser Gin Val Asp Ala Lys Val Ser Glu 325 330 335 Cys Glu Lys Gly Gin Arg Leu Arg Glu lie Ala Gly Lys Met Asp Leu 340 345 350 Lys Ser Ser Ser Lys Leu Lys Asn Gly Leu Thr Phe Arg Lys Glu Asp 355 360 365 Met Leu Gin Arg Gin Leu His Leu Glu Gly Met Leu Cys Trp Lys Thr 370 375 380 Thr Ser Gly Arg Leu Lys Asp lie Leu Ala lie Leu Leu Thr Asp Val 385 390 395 400 Leu Leu Leu Leu Gin Glu Lys Asp Gin Lys Tyr Val Phe Ala Ser Val 405 410 415 Asp Ser Lys Pro Pro Val lie Ser Leu Gin Lys Leu lie Val Arg Glu 420 425 430 Val Ala Asn Glu Glu Lys Ala Met Phe Leu lie Ser Ala Ser Leu Gin 435 440 445 Gly Pro Glu Met Tyr Glu lie Tyr Thr Ser Ser Lys Glu Asp Arg Asn 450 455 460 Ala Trp Met Ala His lie Gin Arg Ala Val Glu Ser Cys Pro Asp Glu 465 470 475 480 Glu Glu Gly Pro Phe Ser Leu Pro Glu Glu Glu Arg Lys Val Val Glu 485 490 495 Ala Arg Ala Thr Arg Leu Arg Asp Phe Gin Glu Arg Leu Ser Met Lys 500 505 510 Asp Gin Leu lie Ala Gin Ser Leu Leu Glu Lys Gin Gin lie Tyr Leu 515 520 525 Glu Met Ala Glu Met Gly Gly Leu Glu Asp Leu Pro Gin Pro Arg Gly 530 535 540 Leu Phe Arg Gly Gly Asp Pro Ser Glu Thr Leu Gin Gly Glu Leu lie 545 550 555 560 Leu Lys Ser Ala Met Ser Glu lie Glu Gly lie Gin Ser Leu lie Cys *565 570 575 Arg Arg Leu Gly Ser Ala Asn Gly Gin Ala Glu Asp Gly Gly Ser Ser 580 585 590 Thr Gly Pro Pro Arg Arg Ala Glu Thr Phe Ala Gly Tyr Asp Cys Thr 595 600 605 Asn Ser Pro Thr Lys Asn Gly Ser Phe Lys Lys Lys Val Ser Ser Thr 610 615 620 Asp Pro Arg Pro Arg Asp Trp Arg Gly Pro Pro Asn Ser Pro Asp Leu 625 630 635 640 Lys Leu Ser Asp Ser Asp lie Pro Gly Ser Ser Glu Glu Ser Pro Gin 645 650 655 Val Val Glu Ala Pro Gly Thr Glu Ser Asp Pro Arg Leu Pro Thr Val 660 665 670 Leu Glu Ser Glu Leu Val Gin Arg lie Gin Thr Leu Ser Gin Leu Leu 675 680 685 Leu Asn Leu Gin Ala Val lie Ala His Gin Asp Ser Tyr Val Glu Thr 690 695 700 Gin Arg Ala Ala lie Gin Glu Arg Glu Lys Gin Phe Arg Leu Gin Ser 705 710 715 720 Thr Arg Gly Asn Leu Leu Leu Glu Gin Glu Arg Gin Arg Asn Phe Glu 725 730 735 Lys Gin Arg Glu Glu Arg Ala Ala Leu Glu Lys Leu Gin Ser Gin Leu 740 745 750 Arg His Glu Gin Gin Arg Trp Glu Arg Glu Arg Gin Trp Gin His Gin 755 760 765 Glu Leu Glu Arg Ala Gly Ala Arg Leu Gin Glu Arg Glu Gly Glu Ala 770 775 780 Arg Gin Leu Arg Glu Arg Leu Glu Gin Glu Arg Ala Glu Leu Glu Arg 785 790 795 800 Gin Arg Gin Ala Tyr Gin His Asp Leu Glu Arg Leu Arg Glu Ala Gin 805 810 815 Arg Ala Val Glu Arg Glu Arg Glu Arg Leu Glu Leu Leu Arg Arg Leu 820 825 830 Lys Lys Gin Asn Thr Ala Pro Gly Ala Leu Pro Pro Asp Thr Leu Ala 835 840 845 Glu Ala Gin Pro Pro Ser His Pro Pro Ser Phe Asn Gly Glu Gly Leu 850 855 860 Glu Gly Pro Arg Val Ser Met Leu Pro Ser Gly Val Gly Pro Glu Tyr 865 870 875 880 Ala Glu Arg Pro Glu Val Ala Arg Arg Asp Ser Ala Pro Thr Glu Ser 885 890 895 Arg Leu Ala Lys Ser Asp Val Pro lie Gin Leu Leu Ser Ala Thr Asn 900 905 910 Gin Phe Gin Arg Gin Ala Ala Val Gin Gin Gin lie Pro Thr Lys Leu 915 920 925 Ala Ala Ser Thr Lys Gly Gly Lys Asp Lys Gly Gly Lys Ser Arg Gly 930 935 940 Ser Gin Arg Trp Glu Ser Ser Ala Ser Phe Asp Leu Lys Gin Gin Leu 945 950 955 960 Leu Leu Asn Lys Leu Met Gly Lys Asp Glu Ser Thr Ser Arg Asn Arg 965 970 975 Arg Ser Leu Ser Pro lie Leu Pro Gly Arg His Ser Pro Ala Pro Pro 980 985 990 Pro Asp Pro Gly Phe Pro Ala Pro Ser Pro Pro Pro Ala Asp Ser Pro 995 1000 1005 Ser Glu Gly Phe Ser Leu Lys Ala Gly Gly Thr Ala Leu Leu Pro Gly 1010 1015 1020 Pro Pro Ala Pro Ser Pro Leu Pro Ala Thr Pro Leu Ser Ala Lys Glu 1025 1030 1035 1040 Asp Ala Ser Lys Glu Asp Val lie Phe Phe 1045 1050 <210> 9 <211> 1287 <212> PRT <213> Homo sapiens <400> 9 Lys Glu Val Gly Ala Gly Ser Ala Asn Gly Val Glu Met Val Gin Gly 1 5 10 Pro Val Gin Thr Pro Ala Leu Thr lie His Arg Arg Lys Arg Arg Arg 25 Ser Cys Pro Pro Asn Arg Ala Ser Tyr Leu Pro Lys Ala Glu Ser Leu 40 Ala Ser Leu Gly Ser His Leu Pro Ala Leu Leu Ser Arg Ala Arg Val 55 Pro Arg Pro Pro Ala Gly Arg Arg Glu Arg Glu Arg Arg Arg Arg Pro 70 75 Val Ala Lys Ala Pro Ala Arg Leu Arg Gly Glu Tyr Glu Thr Gly Val 90 Lys Met Thr Ser Arg Phe Gly Lys Thr Tyr Ser Arg Lys Gly Gly Asn 100 105 110 Gly Ser Ser Lys Phe Asp Glu Val Phe Ser Asn Lys Arg Thr Thr Leu 115 120 125 Ser Thr Lys Trp Gly Glu Thr Thr Phe Met Ala Lys Leu Gly Gin Lys 130 135 140 Arg Pro Asn Phe Lys Pro Asp lie Gin Glu lie Pro Lys Lys Pro Lys 145 150 155 160 Val Glu Glu Glu Ser Thr Gly Asp Pro Phe Gly Phe Asp Ser Asp Asp 165 170 175 Glu Ser Leu Pro Val Ser Ser Lys Asn Leu Ala Gin Val Lys Cys Ser 180 185 190 Ser Tyr Ser Glu Ser Ser Glu Ala Ala Gin Leu Glu Glu Val Thr Ser 195 200 205 Val Leu Glu Ala Asn Ser Lys lie Ser His Val Val Val Glu Asp Thr 210 215 220 Val Val Ser Asp Lys Cys Phe Pro Leu Glu Asp Thr Leu Leu Gly Lys 225 230 235 240 Glu Lys Ser Thr Asn Arg lie Val Glu Asp Asp Ala Ser lie Ser Ser 245 250 255 Cys Asn Lys Leu lie Thr Ser Asp Lys Val Glu Asn Phe His Glu Glu 260 265 270 His Glu Lys Asn Ser His His lie His Lys Asn Ala Asp Asp Ser Thr 275 280 285 Lys Lys Pro Asn Ala Glu Thr Thr Val Ala Ser Glu lie Lys Glu Thr 290 295 300 Asn Asp Thr Trp Asn Ser Gin Phe Gly Lys Arg Pro Glu Ser Pro Ser 305 310 315 320 Glu lie Ser Pro lie Lys Gly Ser Val Arg Thr Gly Leu Phe Glu Trp 325 330 335 Asp Asn Asp Phe Glu Asp lie Arg Ser Glu Asp Cys lie Leu Ser Leu 340 345 350 Asp Ser Asp Pro Leu Leu Glu Met Lys Asp Asp Asp Phe Lys Asn Arg 355 360 365 Leu Glu Asn Leu Asn Glu Ala lie Glu Glu Asp lie Val Gin Ser Val 370 375 380 Leu Arg Pro Thr Asn Cys Arg Thr Tyr Cys Arg Ala Asn Lys Thr Lys 385 390 395 400 Ser Ser Gin Gly Ala Ser Asn Phe Asp Lys Leu Met Asp Gly Thr Ser 405 410 415 Gin Ala Leu Ala Lys Ala Asn Ser Glu Ser Ser Lys Asp Gly Leu Asn 420 425 430 Gin Ala Lys Lys Gly Gly Val Ser Cys Gly Thr Ser Phe Arg Gly Thr 435 440 445 Val Gly Arg Thr Arg Asp Tyr Thr Val Leu His Pro Ser Cys Leu Ser 450 455 460 o Val Cys Asn Val Thr lie Gin Asp Thr Met Glu Arg Ser Met Asp Glu S...465 470 475 480 Phe Thr Ala Ser Thr Pro Ala Asp Leu Gly Glu Ala Gly Arg Leu Arg 485 490 495 Lys Lys Ala Asp lie Ala Thr Ser Lys Thr Thr Thr Arg Phe Arg Pro 500 505 510 SSer Asn Thr Lys Ser Lys Lys Asp Val Lys Leu Glu Phe Phe Gly Phe 515 520 525 Glu Asp His Glu Thr Gly Gly Asp Glu Gly Gly Ser Gly Ser Ser Asn 530 535 540 Tyr Lys lie Lys Tyr Phe Gly Phe Asp Asp Leu Ser Glu Ser Glu Asp 545 550 555 560 Asp Glu Asp Asp Asp Cys Gin Val Glu Arg Lys Thr Ser Lys Lys Arg 565 570 575 Thr Lys Thr Ala Pro Ser Pro Ser Leu Gin Pro Pro Pro Glu Ser Asn 580 585 590 Asp Asn Ser Gin Asp Ser Gin Ser Gly Thr Asn Asn Ala Glu Asn Leu 595 600 605 Asp Phe Thr Glu Asp Leu Pro Gly Val Pro Glu Ser Val Lys Lys Pro 610 615 620 lie Asn Lys Gin Gly Asp Lys Ser Lys Glu Asn Thr Arg Lys lie Phe 625 630 635 640 Ser Gly Pro Lys Arg Ser Pro Thr Lys Ala Val Tyr Asn Ala Arg His 645 650 655 Trp Asn His Pro Asp Ser Glu Glu Leu Pro Gly Pro Pro Val Val Lys 660 665 670 Pro Gin Ser Val Thr Val Arg Leu Ser Ser Lys Glu Pro Asn Gin Lys 675 680 685 Asp Asp Gly Val Phe Lys Ala Pro Ala Pro Pro Ser Lys Val lie Lys 690 695 700 Thr Val Thr lie Pro Thr Gin Pro Tyr Gin Asp lie Val Thr Ala Leu 705 710 715 720 Lys Cys Arg Arg Glu Asp Lys Glu Leu Tyr Thr Val Val Gin His Val 725 730 735 Lys His Phe Asn Asp Val Val Glu Phe Gly Glu Asn Gin Glu Phe Thr 740 745 750 Asp Asp lie Glu Tyr Leu Leu Ser Gly Leu Lys Ser Thr Gin Pro Leu 755 760 765 Asn Thr Arg Cys Leu Ser Val lie Ser Leu Ala Thr Lys Cys Ala Met 770 775 780 Pro Ser Phe Arg Met His Leu Arg Ala His Gly Met Val Ala Met Val 785 790 795 800 Phe Lys Thr Leu Asp Asp Ser Gin His His Gin Asn Leu Ser Leu Cys 805 810 815 Thr Ala Ala Leu Met Tyr lie Leu Ser Arg Asp Arg Leu Asn Met Asp 820 825 830 Leu Asp Arg Ala Ser Leu Asp Leu Met lie Arg Leu Leu Glu Leu Glu 835 840 845 Gin Asp Ala Ser Ser Ala Lys Leu Leu Asn Glu Lys Asp Met Asn Lys 850 855 860 lie Lys Glu Lys lie Arg Arg Leu Cys Glu Thr Val His Asn Lys His 865 870 875 880 Leu Asp Leu Glu Asn lie Thr Thr Gly His Leu Ala Met Glu Thr Leu 885 890 895 Leu Ser Leu Thr Ser Lys Arg Ala Gly Asp Trp Phe Lys Glu Glu Leu 900 905 910 Arg Leu Leu Gly Gly Leu Asp His lie Val Asp Lys Val Lys Glu Cys 915 920 925 Val Asp His Leu Ser Arg Asp Glu Asp Glu Glu Lys Leu Val Ala Ser 930 935 940 Leu Trp Gly Ala Glu Arg Cys Leu Arg Val Leu Glu Ser Val Thr Val 945 950 955 960 His Asn Pro Glu Asn Gin Ser Tyr Leu lie Ala Tyr Lys Asp Ser Gin 965 970 975 Leu lie Val Ser Ser Ala Lys Ala Leu Gin His Cys Glu Glu Leu lie 980 985 990 Gin Gin Tyr Asn Arg Ala Glu Asp Ser lie Cys Leu Ala Asp Ser Lys 995 1000 1005 Pro Leu Pro His Gin Asn Val Thr Asn His Val Gly Lys Ala Val Glu 1010 1015 1020 Asp Cys Met Arg Ala lie lie Gly Val Leu Leu Asn Leu Thr Asn Asp 1025 1030 1035 1040 Asn Glu Trp Gly Ser Thr Lys Thr Gly Glu Gin Asp Gly Leu lie Gly 1045 1050 1055 Thr Ala Leu Asn Cys Val Leu Gin Val Pro Lys Tyr Leu Pro Gin Glu 1060 1065 1070 Gin Arg Phe Asp lie Arg Val Leu Gly Leu Gly Leu Leu lie Asn Leu 1075 1080 1085 Val Glu Tyr Ser Ala Arg Asn Arg His Cys Leu Val Asn Met Glu Thr 1090 1095 1100 Ser Cys Ser Phe Asp Ser Ser lie Cys Ser Gly Glu Gly Asp Asp Ser 1105 1110 1115 1120 Leu Arg lie Gly Gly Gin Val His Ala Val Gin Ala Leu Val Gin Leu 1125 1130 1135 Phe Leu Glu Arg Glu Arg Ala Ala Gin Leu Ala Glu Ser Lys Thr Asp 1140 1145 1150 Glu Leu lie Lys Asp Ala Pro Thr Thr Gin His Asp Lys Ser Gly Glu S* 1155 1160 1165 Trp Gin Glu Thr Ser Gly Glu lie Gin Trp Val Ser Thr Glu Lys Thr 1170 1175 1180 Asp Gly Thr Glu Glu Lys His Lys Lys Glu Glu Glu Asp Glu Glu Leu 1185 1190 1195 1200 Asp Leu Asn Lys Ala Leu Gin His Ala Gly Lys His Met Glu Asp Cys 1205 1210 1215 lie Val Ala Ser Tyr Thr Ala Leu Leu Leu Gly Cys Leu Cys Gin Glu 1220 1225 1230 Ser Pro lie Asn Val Thr Thr Val Arg Glu Tyr Leu Pro Glu Gly Asp 1235 1240 1245 Phe Ser lie Met Thr Glu Met Leu Lys Lys Phe Leu Ser Phe Met Asn 1250 1255 1260 Leu Thr Cys Ala Val Gly Thr Thr Gly Gin Lys Ser lie Ser Arg Val 1265 1270 1275 1280 lie Glu Tyr Leu Glu His Cys 1285 <210>10 <211> 591 <212> PRT <213> Mus musculus <300> <301> Schreiber, K. L.

<302> Class II histocompatibility molecules associate with calnexin duringassembly in the endoplasmatic reticulum <303> Int. Immunol.

<304> 1994 <305> 6 <306> 101-111 <313>1 TO 591 .<400> Met Glu Gly Lys Trp Leu Leu Cys Leu Leu Leu Val Leu Gly Thr Ala 1 5 10 Ala Val Glu Ala His Asp Gly His Asp Asp Asp Ala lie Asp lie Glu 25 Asp Asp Leu Asp Asp Val lie Glu Glu Val Glu Asp Ser Lys Ser Lys 35 40 Ser Asp Ala Ser Thr Pro Pro Ser Pro Lys Val Thr Tyr Lys Ala Pro 50 55 Val Pro Thr Gly Glu Val Tyr Phe Ala Asp Ser Phe Asp Arg Gly Ser 70 75 Leu Ser Gly Trp lie Leu Ser Lys Ala Lys Lys Asp Asp Thr Asp Asp 90 Glu lie Ala Lys Tyr Asp Gly Lys Trp Glu Val Asp Glu Met Lys Glu 100 105 110 Thr Lys Leu Pro Gly Asp Lys Gly Leu Val Leu Met Ser Arg Ala Lys 115 120 125 His His Ala lie Ser Ala Lys Leu Asn Lys Pro Phe Leu Phe Asp Thr 130 135 140 Lys Pro Leu lie Val Gin Tyr Glu Val Asn Phe Gin Asn Gly lie Glu 145 150 155 160 Cys Gly Gly Ala Tyr Val Lys Leu Leu Ser Lys Thr Ala Glu Leu Ser 165 170 175 Leu Asp Gin Phe His Asp Lys Thr Pro Tyr Thr lie Met Phe Gly Pro 180 185 190 Asp Lys Cys Gly Glu Asp Tyr Lys Leu His Phe lie Phe Arg His Lys 195 200 205 Asn Pro Lys Thr Gly Val Tyr Glu Glu Lys His Ala Lys Arg Pro Asp 210 215 220 Ala Asp Leu Lys Thr Tyr Phe Thr Asp Lys Lys Thr His Leu Tyr Thr 225 230 235 240 Leu lie Leu Asn Pro Asp Asn Ser Phe Glu lie Leu Val Asp Gin Ser 245 250 255 Val Val Asn Ser Gly Asn Leu Leu Asn Asp Met Thr Pro Pro Val Asn 260 265 270 Pro Ser Arg Glu lie Glu Asp Pro Glu Asp Arg Lys Pro Glu Asp Trp 275 280 285 Asp Glu Arg Pro Lys lie Ala Asp Pro Asp Ala Val Lys Pro Asp Asp 290 295 300 Trp Asp Glu Asp Ala Pro Ser Lys lie Pro Asp Glu Glu Ala Thr Lys 305 310 315 320 i Pro Glu Gly Trp Leu Asp Asp Glu Pro Glu Tyr lie Pro Asp Pro Asp 325 330 335 Ala Glu Lys Pro Glu Asp Trp Asp Glu Asp Met Asp Gly Glu Trp Glu 340 345 350 Ala Pro Gin lie Ala Asn Pro Lys Cys Glu Ser Ala Pro Gly Cys Gly 355 360 365 Val Trp Gin Arg Pro Met lie Asp Asn Pro Asn Tyr Lys Gly Lys Trp 370 375 380 Lys Pro Pro Met lie Asp Asn Pro Asn Tyr Gin Gly lie Trp Lys Pro 385 390 395 400 Arg Lys lie Pro Asn Pro Asp Phe Phe Glu Asp Leu Glu Pro Phe Lys 405 410 415 Met Thr Pro Phe Ser Ala lie Gly Leu Glu Leu Trp Ser Met Thr Ser 420 425 430 Asp lie Phe Phe Asp Asn Phe lie lie Ser Gly Asp Arg Arg Val Val 435 440 445 Asp Asp Trp Ala Asn Asp Gly Trp Gly Leu Lys Lys Ala Ala Asp Gly 450 455 460 Ala Ala Glu Pro Gly Val Val Leu Gin Met Leu Glu Ala Ala Glu Glu 465 470 475 480 Arg Pro Trp Leu Trp Val Val Tyr lie Leu Thr Val Ala Leu Pro Val 485 490 495 Phe Leu Val lie Leu Phe Cys Cys Ser Gly Lys Lys Gin Ser Asn Ala 500 505 510 Met Glu Tyr Lys Lys Thr Asp Ala Pro Gin Pro Asp Val Lys Asp Glu 515 520 525 Glu Gly Lys Glu Glu Glu Lys Asn Lys Arg Asp Glu Glu Glu Glu Glu 530 535 540 Glu Lys Leu Glu Glu Lys Gin Lys Ser Asp Ala Glu Glu Asp Gly Val 545 550 555 560 Thr Gly Ser Gin Asp Glu Glu Asp Ser Lys Pro Lys Ala Glu Glu Asp 565 570 575 Glu lie Leu Asn Arg Ser Pro Arg Asn Arg Lys Pro Arg Arg Glu 580 585 590 <210>11 <211> 592 <212> PRT <213> Homo sapiens <400> 11 Met Glu Gly Lys Trp Leu Leu Cys Met Leu Leu Val Leu Gly Thr Ala 1 5 10 lie Val Glu Ala His Asp Gly His Asp Asp Asp Val lie Asp lie Glu 20 25 Asp Asp Leu Asp Asp Val lie Glu Glu Val Glu Asp Ser Lys Pro Asp 35 40 Thr Thr Ala Pro Pro Ser Ser Pro Lys Val Thr Tyr Lys Ala Pro Val 55 Pro Thr Gly Glu Val Tyr Phe Ala Asp Ser Phe Asp Arg Gly Thr Leu *i 65 70 75 O Ser Gly Trp lie Leu Ser Lys Ala Lys Lys Asp Asp Thr Asp Asp Glu 85 90 Slie Ala Lys Tyr Asp Gly Lys Trp Glu Val Glu Glu Met Lys Glu Ser 100 105 110 Lys Leu Pro Gly Asp Lys Gly Leu Val Leu Met Ser Arg Ala Lys His 115 120 125 His Ala lie Ser Ala Lys Leu Asn Lys Pro Phe Leu Phe Asp Thr Lys 130 135 140 Pro Leu lie Val Gin Tyr Glu Val Asn Phe Gin Asn Gly lie Glu Cys 145 150 155 160 Gly Gly Ala Tyr Val Lys Leu Leu Ser Lys Thr Pro Glu Leu Asn Leu 165 170 175 Asp Gin Leu His Asp Lys Thr Pro Tyr Thr lie Met Phe Gly Pro Asp 180 185 190 Lys Cys Gly Glu Asp Tyr Lys Leu His Phe lie Phe Arg His Lys Asn 195 200 205 Pro Lys Thr Gly lie Tyr Glu Glu Lys His Ala Lys Arg Pro Asp Ala 210 215 220 Asp Leu Lys Thr Tyr Phe Thr Asp Lys Lys Thr His Leu Tyr Thr Leu 225 230 235 240 lie Leu Asn Pro Asp Asn Ser Phe Glu lie Leu Val Asp Gin Ser Val 245 250 255 Val Asn Ser Gly Asn Leu Leu Asn Asp Met Thr Pro Pro Val Asn Pro 260 265 270 Ser Arg Glu lie Glu Asp Pro Glu Asp Arg Lys Pro Glu Asp Trp Asp 275 280 285 Glu Arg Pro Lys lie Pro Asp Pro Glu Ala Val Lys Pro Asp Asp Trp 290 295 300 i Asp Glu Asp Ala Pro Ala Lys lie Pro Asp Glu Glu Ala Thr Lys Pro 305 310 315 320 Glu Gly Trp Leu Asp Asp Glu Pro Glu Tyr Val Pro Asp Pro Asp Ala 325 330 335 Glu Lys Pro Glu Asp Trp Asp Glu Asp Met Asp Gly Glu Trp Glu Ala 340 345 350 Pro Gin lie Ala Asn Pro Arg Cys Glu Ser Ala Pro Gly Cys Gly Val 355 360 365 Trp Gin Arg Pro Val lie Asp Asn Pro Asn Tyr Lys Gly Lys Trp Lys 370 375 380 Pro Pro Met lie Asp Asn Pro Ser Tyr Gin Gly lie Trp Lys Pro Arg 385 390 395 400 Lys lie Pro Asn Pro Asp Phe Phe Glu Asp Leu Glu Pro Phe Arg Met 405 410 415 Thr Pro Phe Ser Ala lie Gly Leu Glu Leu Trp Ser Met Thr Ser Asp 420 425 430 lie Phe Phe Asp Asn Phe lie lie Cys Ala Asp Arg Arg lie Val Asp 435 440 445 Asp Trp Ala Asn Asp Gly Trp Gly Leu Lys Lys Ala Ala Asp Gly Ala 450 455 460 Ala Glu Pro Gly Val Val Gly Gin Met lie Glu Ala Ala Glu Glu Arg 465 470 475 480 Pro Trp Leu Trp Val Val Tyr lie Leu Thr Val Ala Leu Pro Val Phe 485 490 495 Leu Val lie Leu Phe Cys Cys Ser Gly Lys Lys Gin Thr Ser Gly Met 500 505 510 Glu Tyr Lys Lys Thr Asp Ala Pro Gin Pro Asp Val Lys Glu Glu Glu 515 520 525 Glu Glu Lys Glu Glu Glu Lys Asp Lys Gly Asp Glu Glu Glu Glu Gly 530 535 540 Glu Glu Lys Leu Glu Glu Lys Gin Lys Ser Asp Ala Glu Glu Asp Gly 545 550 555 560 Gly Thr Val Ser Gin Glu Glu Glu Asp Arg Lys Pro Lys Ala Glu Glu 565 570 575 Asp Glu lie Leu Asn Arg Ser Pro Arg Asn Arg Lys Pro Arg Arg Glu 580 585 590 <210> 12 <211> 2441 <212> PRT S <213> Mus musculus <300> <301> Chrivia, J. C.

<302> Phosphorylated CREB binds specifically to the nuclear protein CBP S <303> Nature <304> 1993 <305> 365 <306> 855-859 <313> 1 TO 2441 .<400> 12 Met Ala Glu Asn Leu Leu Asp Gly Pro Pro Asn Pro Lys Arg Ala Lys 1 5 10 SLeu Ser Ser Pro Gly Phe Ser Ala Asn Asp Asn Thr Asp Phe Gly Ser 20 25 Leu Phe Asp Leu Glu Asn Asp Leu Pro Asp Glu Leu lie Pro Asn Gly 40 Glu Leu Ser Leu Leu Asn Ser Gly Asn Leu Val Pro Asp Ala Ala Ser 55 Lys His Lys Gin Leu Ser Glu Leu Leu Arg Gly Gly Ser Gly Ser Ser 70 75 lie Asn Pro Gly lie Gly Asn Val Ser Ala Ser Ser Pro Val Gin Gin 90 Gly Leu Gly Gly Gin Ala Gin Gly Gin Pro Asn Ser Thr Asn Met Ala 100 105 110 Ser Leu Gly Ala Met Gly Lys Ser Pro Leu Asn Gin Gly Asp Ser Ser 115 120 125 Thr Pro Asn Leu Pro Lys Gin Ala Ala Ser Thr Ser Gly Pro Thr Pro 130 135 140 Pro Ala Ser Gin Ala Leu Asn Pro Gin Ala Gin Lys Gin Val Gly Leu 145 150 155 160 Val Thr Ser Ser Pro Ala Thr Ser Gin Thr Gly Pro Gly lie Cys Met 165 170 175 Asn Ala Asn Phe Asn Gin Thr His Pro Gly Leu Leu Asn Ser Asn Ser 180 185 190 Gly His Ser Leu Met Asn Gin Ala Gin Gin Gly Gin Ala Gin Val Met 195 200 205 Asn Gly Ser Leu Gly Ala Ala Gly Arg Gly Arg Gly Ala Gly Met Pro 210 215 220 Tyr Pro Ala Pro Ala Met Gin Gly Ala Thr Ser Ser Val Leu Ala Glu 225 230 235 240 Thr Leu Thr Gin Val Ser Pro Gin Met Ala Gly His Ala Gly Leu Asn 245 250 255 Thr Ala Gin Ala Gly Gly Met Thr Lys Met Gly Met Thr Gly Thr Thr 260 265 270 Ser Pro Phe Gly Gin Pro Phe Ser Gin Thr Gly Gly Gin Gin Met Gly 275 280 285 Ala Thr Gly Val Asn Pro Gin Leu Ala Ser Lys Gin Ser Met Val Asn 290 295 300 Ser Leu Pro Ala Phe Pro Thr Asp lie Lys Asn Thr Ser Val Thr Thr 305 310 315 320 Val Pro Asn Met Ser Gin Leu Gin Thr Ser Val Gly lie Val Pro Thr 325 330 335 Gin Ala lie Ala Thr Gly Pro Thr Ala Asp Pro Glu Lys Arg Lys Leu 340 345 350 lie Gin Gin Gin Leu Val Leu Leu Leu His Ala His Lys Cys Gin Arg 355 360 365 Arg Glu Gin Ala Asn Gly Glu Val Arg Ala Cys Ser Leu Pro His Cys 370 375 380 Arg Thr Met Lys Asn Val Leu Asn His Met Thr His Cys Gin Ala Pro 385 390 395 400 Lys Ala Cys Gin Val Ala His Cys Ala Ser Ser Arg Gin lie lie Ser 405 410 415 His Trp Lys Asn Cys Thr Arg His Asp Cys Pro Val Cys Leu Pro Leu 420 425 430 Lys Asn Ala Ser Asp Lys Arg Asn Gin Gin Thr lie Leu Gly Ser Pro 435 440 445 Ala Ser Gly lie Gin Asn Thr lie Gly Ser Val Gly Ala Gly Gin Gin 450 455 460 Asn Ala Thr Ser Leu Ser Asn Pro Asn Pro lie Asp Pro Ser Ser Met 465 470 475 480 Gin Arg Ala Tyr Ala Ala Leu Gly Leu Pro Tyr Met Asn Gin Pro Gin 485 490 495 Thr Gin Leu Gin Pro Gin Val Pro Gly Gin Gin Pro Ala Gin Pro Pro 500 505 510 Ala His Gin Gin Met Arg Thr Leu Asn Ala Leu Gly Asn Asn Pro Met 515 520 525 Ser Val Pro Ala Gly Gly lie Thr Thr Asp Gin Gin Pro Pro Asn Leu 530 535 540 lie Ser Glu Ser Ala Leu Pro Thr Ser Leu Gly Ala Thr Asn Pro Leu 545 550 555 560 Met Asn Asp Gly Ser Asn Ser Gly Asn lie Gly Ser Leu Ser Thr lie 565 570 575 Pro Thr Ala Ala Pro Pro Ser Ser Thr Gly Val Arg Lys Gly Trp His 580 585 590 Glu His Val Thr Gin Asp Leu Arg Ser His Leu Val His Lys Leu Val 595 600 605 Gin Ala lie Phe Pro Thr Pro Asp Pro Ala Ala Leu Lys Asp Arg Arg 610 615 620 Met Glu Asn Leu Val Ala Tyr Ala Lys Lys Val Glu Gly Asp Met Tyr 625 630 635 640 Glu Ser Ala Asn Ser Arg Asp Glu Tyr Tyr His Leu Leu Ala Glu Lys 645 650 655 lie Tyr Lys lie Gin Lys Glu Leu Glu Glu Lys Arg Arg Thr Arg Leu 660 665 670 His Lys Gin Gly lie Leu Gly Asn Gin Pro Ala Leu Pro Ala Ser Gly 675 680 685 Ala Gin Pro Pro Val lie Pro Pro Ala Gin Ser Val Arg Pro Pro Asn 690 695 700 Gly Pro Leu Pro Leu Pro Val Asn Arg Met Gin Val Ser Gin Gly Met 705 710 715 720 Asn Ser Phe Asn Pro Met Ser Leu Gly Asn Val Gin Leu Pro Gin Ala 725 730 735 Pro Met Gly Pro Arg Ala Ala Ser Pro Met Asn His Ser Val Gin Met 740 745 750 Asn Ser Met Ala Ser Val Pro Gly Met Ala lie Ser Pro Ser Arg Met 755 760 765 Pro Gin Pro Pro Asn Met Met Gly Thr His Ala Asn Asn lie Met Ala 770 775 780 Gin Ala Pro Thr Gin Asn Gin Phe Leu Pro Gin Asn Gin Phe Pro Ser 785 790 795 800 Ser Ser Gly Ala Met Ser Val Asn Ser Val Gly Met Gly Gin Pro Ala 805 810 815 Ala Gin Ala Gly Val Ser Gin Gly Gin Glu Pro Gly Ala Ala Leu Pro 820 825 830 Asn Pro Leu Asn Met Leu Ala Pro Gin Ala Ser Gin Leu Pro Cys Pro 835 840 845 Pro Val Thr Gin Ser Pro Leu His Pro Thr Pro Pro Pro Ala Ser Thr 850 855 860 Ala Ala Gly Met Pro Ser Leu Gin His Pro Thr Ala Pro Gly Met Thr 865 870 875 880 ro Pro Gin Pro Ala Ala Pro Thr Gin Pro Ser Thr Pro Val Ser Ser 885 890 895 Gly Gin Thr Pro Thr Pro Thr Pro Gly Ser Val Pro Ser Ala Ala Gin 900 905 910 Thr Gin Ser Thr Pro Thr Val Gin Ala Ala Ala Gin Ala Gin Val Thr 915 920 925 Pro Gin Pro Gin Thr Pro Val Gin Pro Pro Ser Val Ala Thr Pro Gin 930 935 940 Ser Ser Gin Gin Gin Pro Thr Pro Val His Thr Gin Pro Pro Gly Thr 945 950 955 960 Pro Leu Ser Gin Ala Ala Ala Ser lie Asp Asn Arg Val Pro Thr Pro 965 970 975 Ser Thr Val Thr Ser Ala Glu Thr Ser Ser Gin Gin Pro Gly Pro Asp 980 985 990 Val Pro Met Leu Glu Met Lys Thr Glu Val Gin Thr Asp Asp Ala Glu 995 1000 1005 Pro Glu Pro Thr Glu Ser Lys Gly Glu Pro Arg Ser Glu Met Met Glu 1010 1015 1020 Glu Asp Leu Gin Gly Ser Ser Gin Val Lys Glu Glu Thr Asp Thr Thr 1025 1030 1035 1040 Glu Gin Lys Ser Glu Pro Met Glu Val Glu Glu Lys Lys Pro Glu Val 1045 1050 1055 Lys Val Glu Ala Lys Glu Glu Glu Glu Asn Ser Ser Asn Asp Thr Ala 1060 1065 1070 Ser Gin Ser Thr Ser Pro Ser Gin Pro Arg Lys Lys lie Phe Lys Pro 1075 1080 1085 Glu Glu Leu Arg Gin Ala Leu Met Pro Thr Leu Glu Ala Leu Tyr Arg 1090 1095 1100 Gin Asp Pro Glu Ser Leu Pro Phe Arg Gin Pro Val Asp Pro Gin Leu 1105 1110 1115 1120 Leu Gly lie Pro Asp Tyr Phe Asp lie Val Lys Asn Pro Met Asp Leu 1125 1130 1135 Ser Thr lie Lys Arg Lys Leu Asp Thr Gly Gin Tyr Gin Glu Pro Trp 1140 1145 1150 Gin Tyr Val Asp Asp Val Arg Leu Met Phe Asn Asn Ala Trp Leu Tyr 1155 1160 1165 Asn Arg Lys Thr Ser Arg Val Tyr Lys Phe Cys Ser Lys Leu Ala Glu 1170 1175 1180 Val Phe Glu Gin Glu lie Asp Pro Val Met Gin Ser Leu Gly Tyr Cys 1185 1190 1195 1200 Cys Gly Arg Lys Tyr Glu Phe Ser Pro Gin Thr Leu Cys Cys Tyr Gly 1205 1210 1215 Lys Gin Leu Cys Thr lie Pro Arg Asp Ala Ala Tyr Tyr Ser Tyr Gin 1220 1225 1230 Asn Arg Tyr His Phe Cys Gly Lys Cys Phe Thr Glu lie Gin Gly Glu 1235 1240 1245 Asn Val Thr Leu Gly Asp Asp Pro Ser Gin Pro Gin Thr Thr lie Ser 1250 1255 1260 Lys Asp Gin Phe Glu Lys Lys Lys Asn Asp Thr Leu Asp Pro Glu Pro 1265 1270 1275 1280 Phe Val Asp Cys Lys Glu Cys Gly Arg Lys Met His Gin lie Cys Val 1285 1290 1295 Leu His Tyr Asp lie lie Trp Pro Ser Gly Phe Val Cys Asp Asn Cys 1300 1305 1310 Leu Lys Lys Thr Gly Arg Pro Arg Lys Glu Asn Lys Phe Ser Ala Lys 1315 1320 1325 Arg Leu Gin Thr Thr Arg Leu Gly Asn His Leu Glu Asp Arg Val Asn 1330 1335 1340 Lys Phe Leu Arg Arg Gin Asn His Pro Glu Ala Gly Glu Val Phe Val 1345 1350 1355 1360 Arg Val Val Ala Ser Ser Asp Lys Thr Val Glu Val Lys Pro Gly Met 1365 1370 1375 Lys Ser Arg Phe Val Asp Ser Gly Glu Met Ser Glu Ser Phe Pro Tyr 1380 1385 1390 Arg Thr Lys Ala Leu Phe Ala Phe Glu Glu lie Asp Gly Val Asp Val 1395 1400 1405 Cys Phe Phe Gly Met His Val Gin Asp Thr Ala Leu lie Ala Pro His 1410 1415 1420 Gin lie Gin Gly Cys Val Tyr lie Ser Tyr Leu Asp Ser lie His Phe 1425 1430 1435 1440 Phe Arg Pro Arg Cys Leu Arg Thr Ala Val Tyr His Glu lie Leu lie 1445 1450 1455 Gly Tyr Leu Glu Tyr Val Lys Lys Leu Val Tyr Val Thr Ala His lie 1460 1465 1470 Trp Ala Cys Pro Pro Ser Glu Gly Asp Asp Tyr lie Phe His Cys His 1475 1480 1485 Pro Pro Asp Gin Lys lie Pro Lys Pro Lys Arg Leu Gin Glu Trp Tyr 1490 1495 1500 Lys Lys Met Leu Asp Lys Ala Phe Ala Glu Arg lie lie Asn Asp Tyr 1505 1510 1515 1520 Lys Asp lie Phe Lys Gin Ala Asn Glu Asp Arg Leu Thr Ser Ala Lys 1525 1530 1535 Glu Leu Pro Tyr Phe Glu Gly Asp Phe Trp Pro Asn Val Leu Glu Glu 1540 1545 1550 Ser lie Lys Glu Leu Glu Gin Glu Glu Glu Glu Arg Lys Lys Glu Glu 1555 1560 1565 Ser Thr Ala Ala Ser Glu Thr Pro Glu Gly Ser Gin Gly Asp Ser Lys 1570 1575 1580 Asn Ala Lys Lys Lys Asn Asn Lys Lys Thr Asn Lys Asn Lys Ser Ser 1585 1590 1595 1600 lie Ser Arg Ala Asn Lys Lys Lys Pro Ser Met Pro Asn Val Ser Asn 1605 1610 1615 Asp Leu Ser Gin Lys Leu Tyr Ala Thr Met Glu Lys His Lys Glu Val 1620 1625 1630 Phe Phe Val lie His Leu His Ala Gly Pro Val lie Ser Thr Gin Pro 1635 1640 1645 Pro lie Val Asp Pro Asp Pro Leu Leu Ser Cys Asp Leu Met Asp Gly 1650 1655 1660 Arg Asp Ala Phe Leu Thr Leu Ala Arg Asp Lys His Trp Glu Phe Ser 1665 1670 1675 1680 Ser Leu Arg Arg Ser Lys Trp Ser Thr Leu Cys Met Leu Val Glu Leu 1685 1690 1695 His Thr Gin Gly Gin Asp Arg Phe Val Tyr Thr Cys Asn Glu Cys Lys 1700 1705 1710 His His Val Glu Thr Arg Trp His Cys Thr Val Cys Glu Asp Tyr Asp 1715 1720 1725 Leu Cys lie Asn Cys Tyr Asn Thr Lys Ser His Thr His Lys Met Val 1730 1735 1740 Lys Trp Gly Leu Gly Leu Asp Asp Glu Gly Ser Ser Gin Gly Glu Pro 1745 1750 1755 1760 Gin Ser Lys Ser Pro Gin Glu Ser Arg Arg Leu Ser lie Gin Arg Cys 1765 1770 1775 lie Gin Ser Leu Val His Ala Cys Gin Cys Arg Asn Ala Asn Cys Ser 1780 1785 1790 Leu Pro Ser Cys Gin Lys Met Lys Arg Val Val Gin His Thr Lys Gly 1795 1800 1805 Cys Lys Arg Lys Thr Asn Gly Gly Cys Pro Val Cys Lys Gin Leu lie 1810 1815 1820 Ala Leu Cys Cys Tyr His Ala Lys His Cys Gin Glu Asn Lys Cys Pro 1825 1830 1835 1840 Val Pro Phe Cys Leu Asn lie Lys His Asn Val Arg Gin Gin Gin lie 1845 1850 1855 *l Gin His Cys Leu Gin Gin Ala Gin Leu Met Arg Arg Arg Met Ala Thr 1860 1865 1870 Met Asn Thr Arg Asn Val Pro Gin Gin Ser Leu Pro Ser Pro Thr Ser 1875 1880 1885 Ala Pro Pro Gly Thr Pro Thr Gin Gin Pro Ser Thr Pro Gin Thr Pro 1890 1895 1900 Gin Pro Pro Ala Gin Pro Gin Pro Ser Pro Val Asn Met Ser Pro Ala 1905 1910 1915 1920 Gly Phe Pro Asn Val Ala Arg Thr Gin Pro Pro Thr lie Val Ser Ala 1925 1930 1935 Gly Lys Pro Thr Asn Gin Val Pro Ala Pro Pro Pro Pro Ala Gin Pro 1940 1945 1950 Pro Pro Ala Ala Val Glu Ala Ala Arg Gin lie Glu Arg Glu Ala Gin 1955 1960 1965 Gin Gin Gin His Leu Tyr Arg Ala Asn lie Asn Asn Gly Met Pro Pro 1970 1975 1980 Gly Arg Asp Gly Met Gly Thr Pro Gly Ser Gin Met Thr Pro Val Gly 1985 1990 1995 2000 Leu Asn Val Pro Arg Pro Asn Gin Val Ser Gly Pro Val Met Ser Ser 2005 2010 2015 Met Pro Pro Gly Gin Trp Gin Gin Ala Pro lie Pro Gin Gin Gin Pro 2020 2025 2030 Met Pro Gly Met Pro Arg Pro Val Met Ser Met Gin Ala Gin Ala Ala 2035 2040 2045 Val Ala Gly Pro Arg Met Pro Asn Val Gin Pro Asn Arg Ser lie Ser 2050 2055 2060 Pro Ser Ala Leu Gin Asp Leu Leu Arg Thr Leu Lys Ser Pro Ser Ser 2065 2070 2075 2080 Pro Gin Gin Gin Gin Gin Val Leu Asn lie Leu Lys Ser Asn Pro Gin 2085 2090 2095 Leu Met Ala Ala Phe lie Lys Gin Arg Thr Ala Lys Tyr Val Ala Asn 2100 2105 2110 Gin Pro Gly Met Gin Pro Gin Pro Gly Leu Gin Ser Gin Pro Gly Met 2115 2120 2125 Gin Pro Gin Pro Gly Met His Gin Gin Pro Ser Leu Gin Asn Leu Asn 2130 2135 2140 Ala Met Gin Ala Gly Val Pro Arg Pro Gly Val Pro Pro Pro Gin Pro 2145 2150 2155 2160 Ala Met Gly Gly Leu Asn Pro Gin Gly Gin Ala Leu Asn lie Met Asn 2165 2170 2175 Pro Gly His Asn Pro Asn Met Thr Asn Met Asn Pro Gin Tyr Arg Glu 2180 2185 2190 Met Val Arg Arg Gin Leu Leu Gin His Gin Gin Gin Gin Gin Gin Gin 2195 2200 2205 Gin Gin Gin Gin Gin Gin Gin Gin Asn Ser Ala Ser Leu Ala Gly Gly 2210 2215 2220 Met Ala Gly His Ser Gin Phe Gin Gin Pro Gin Gly Pro Gly Gly Tyr 2225 2230 2235 2240 Ala Pro Ala Met Gin Gin Gin Arg Met Gin Gin His Leu Pro lie Gin 2245 2250 2255 Gly Ser Ser Met Gly Gin Met Ala Ala Pro Met Gly Gin Leu Gly Gin 2260 2265 2270 Met Gly Gin Pro Gly Leu Gly Ala Asp Ser Thr Pro Asn lie Gin Gin 2275 2280 2285 Ala Leu Gin Gin Arg lie Leu Gin Gin Gin Gin Met Lys Gin Gin lie 2290 2295 2300 Gly Ser Pro Gly Gin Pro Asn Pro Met Ser Pro Gin Gin His Met Leu 2305 2310 2315 2320 Ser Gly Gin Pro Gin Ala Ser His Leu Pro Gly Gin Gin lie Ala Thr 2325 2330 2335 Ser Leu Ser Asn Gin Val Arg Ser Pro Ala Pro Val Gin Ser Pro Arg 2340 2345 2350 Pro Gin Ser Gin Pro Pro His Ser Ser Pro Ser Pro Arg lie Gin Pro 2355 2360 2365 Gin Pro Ser Pro His His Val Ser Pro Gin Thr Gly Thr Pro His Pro 2370 2375 2380 Gly Leu Ala Val Thr Met Ala Ser Ser Met Asp Gin Gly His Leu Gly 2385 2390 2395 2400 Asn Pro Glu Gin Ser Ala Met Leu Pro Gin Leu Asn Thr Pro Asn Arg 2405 2410 2415 Ser Ala Leu Ser Ser Glu Leu Ser Leu Val Gly Asp Thr Thr Gly Asp 2420 2425 2430 Thr Leu Glu Lys Phe Val Glu Gly Leu 2435 2440 <210> 13 <211> 2442 <212> PRT o <213> Homo sapiens <400> 13 Met Ala Glu Asn Leu Leu Asp Gly Pro Pro Asn Pro Lys Arg Ala Lys 1 5 10 Leu Ser Ser Pro Gly Phe Ser Ala Asn Asp Ser Thr Asp Phe Gly Ser 25 Leu Phe Asp Leu Glu Asn Asp Leu Pro Asp Glu Leu lie Pro Asn Gly 35 40 Gly Glu Leu Gly Leu Leu Asn Ser Gly Asn Leu Val Pro Asp Ala Ala 50 55 Ser Lys His Lys Gin Leu Ser Glu Leu Leu Arg Gly Gly Ser Gly Ser 70 75 Ser lie Asn Pro Gly lie Gly Asn Val Ser Ala Ser Ser Pro Val Gin 85 90 Gin Gly Leu Gly Gly Gin Ala Gin Gly Gin Pro Asn Ser Ala Asn Met 100 105 110 Ala Ser Leu Ser Ala Met Gly Lys Ser Pro Leu Ser Gin Gly Asp Ser 115 120 125 Ser Ala Pro Ser Leu Pro Lys Gin Ala Ala Ser Thr Ser Gly Pro Thr 130 135 140 Pro Ala Ala Ser Gin Ala Leu Asn Pro Gin Ala Gin Lys Gin Val Gly 145 150 155 160 Leu Ala Thr Ser Ser Pro Ala Thr Ser Gin Thr Gly Pro Gly lie Cys 165 170 175 Met Asn Ala Asn Phe Asn Gin Thr His Pro Gly Leu Leu Asn Ser Asn 180 185 190 Ser Gly His Ser Leu lie Asn Gin Ala Ser Gin Gly Gin Ala Gin Val 195 200 205 Met Asn Gly Ser Leu Gly Ala Ala Gly Arg Gly Arg Gly Ala Gly Met 210 215 220 Pro Tyr Pro Thr Pro Ala Met Gin Gly Ala Ser Ser Ser Val Leu Ala 225 230 235 240 Glu Thr Leu Thr Gin Val Ser Pro Gin Met Thr Gly His Ala Gly Leu 245 250 255 Asn Thr Ala Gin Ala Gly Gly Met Ala Lys Met Gly lie Thr Gly Asn 260 265 270 Thr Ser Pro Phe Gly Gin Pro Phe Ser Gin Ala Gly Gly Gin Pro Met 275 280 285 Gly Ala Thr Gly Val Asn Pro Gin Leu Ala Ser Lys Gin Ser Met Val S290 295 300 Asn Ser Leu Pro Thr Phe Pro Thr Asp lie Lys Asn Thr Ser Val Thr 305 310 315 320 Asn Val Pro Asn Met Ser Gin Met Gin Thr Ser Val Gly lie Val Pro 325 330 335 Thr Gin Ala lie Ala Thr Gly Pro Thr Ala Asp Pro Glu Lys Arg Lys 340 345 350 Leu lie Gin Gin Gin Leu Val Leu Leu Leu His Ala His Lys Cys Gin 355 360 365 Arg Arg Glu Gin Ala Asn Gly Glu Val Arg Ala Cys Ser Leu Pro His 370 375 380 Cys Arg Thr Met Lys Asn Val Leu Asn His Met Thr His Cys Gin Ala 385 390 395 400 Gly Lys Ala Cys Gin Val Ala His Cys Ala Ser Ser Arg Gin lie lie S405 410 415 Ser His Trp Lys Asn Cys Thr Arg His Asp Cys Pro Val Cys Leu Pro 420 425 430 Leu Lys Asn Ala Ser Asp Lys Arg Asn Gin Gin Thr lie Leu Gly Ser 435 440 445 Pro Ala Ser Gly lie Gin Asn Thr lie Gly Ser Val Gly Thr Gly Gin 450 455 460 Gin Asn Ala Thr Ser Leu Ser Asn Pro Asn Pro lie Asp Pro Ser Ser 465 470 475 480 Met Gin Arg Ala Tyr Ala Ala Leu Gly Leu Pro Tyr Met Asn Gin Pro 485 490 495 Gin Thr Gin Leu Gin Pro Gin Val Pro Gly Gin Gin Pro Ala Gin Pro 500 505 510 Gin Thr His Gin Gin Met Arg Thr Leu Asn Pro Leu Gly Asn Asn Pro 515 520 525 Met Asn lie Pro Ala Gly Gly lie Thr Thr Asp Gin Gin Pro Pro Asn 530 535 540 Leu lie Ser Glu Ser Ala Leu Pro Thr Ser Leu Gly Ala Thr Asn Pro 545 550 555 560 Leu Met Asn Asp Gly Ser Asn Ser Gly Asn lie Gly Thr Leu Ser Thr 565 570 575 lie Pro Thr Ala Ala Pro Pro Ser Ser Thr Gly Val Arg Lys Gly Trp 580 585 590 His Glu His Val Thr Gin Asp Leu Arg Ser His Leu Val His Lys Leu 595 600 605 Val Gin Ala lie Phe Pro Thr Pro Asp Pro Ala Ala Leu Lys Asp Arg S. 610 615 620 Arg Met Glu Asn Leu Val Ala Tyr Ala Lys Lys Val Glu Gly Asp Met 625 630 635 640 Tyr Glu Ser Ala Asn Ser Arg Asp Glu Tyr Tyr His Leu Leu Ala Glu 645 650 655 Lys lie Tyr Lys lie Gin Lys Glu Leu Glu Glu Lys Arg Arg Ser Arg 660 665 670 Leu His Lys Gin Gly lie Leu Gly Asn Gin Pro Ala Leu Pro Ala Pro 675 680 685 Gly Ala Gin Pro Pro Val lie Pro Gin Ala Gin Pro Val Arg Pro Pro 690 695 700 Asn Gly Pro Leu Ser Leu Pro Val Asn Arg Met Gin Val Ser Gin Gly 705 710 715 720 Met Asn Ser Phe Asn Pro Met Ser Leu Gly Asn Val Gin Leu Pro Gin 725 730 735 Ala Pro Met Gly Pro Arg Ala Ala Ser Pro Met Asn His Ser Val Gin 740 745 750 Met Asn Ser Met Gly Ser Val Pro Gly Met Ala lie Ser Pro Ser Arg 755 760 765 Met Pro Gin Pro Pro Asn Met Met Gly Ala His Thr Asn Asn Met Met 770 775 780 Ala Gin Ala Pro Ala Gin Ser Gin Phe Leu Pro Gin Asn Gin Phe Pro 785 790 795 800 Ser Ser Ser Gly Ala Met Ser Val Gly Met Gly Gin Pro Pro Ala Gin 805 810 815 Thr Gly Val Ser Gin Gly Gin Val Pro Gly Ala Ala Leu Pro Asn Pro 820 825 830 Leu Asn Met Leu Gly Pro Gin Ala Ser Gin Leu Pro Cys Pro Pro Val 835 840 845 Thr Gin Ser Pro Leu His Pro Thr Pro Pro Pro Ala Ser Thr Ala Ala 850 855 860 Gly Met Pro Ser Leu Gin His Thr Thr Pro Pro Gly Met Thr Pro Pro 865 870 875 880 Gin Pro Ala Ala Pro Thr Gin Pro Ser Thr Pro Val Ser Ser Ser Gly 885 890 895 Gin Thr Pro Thr Pro Thr Pro Gly Ser Val Pro Ser Ala Thr Gin Thr 900 905 910 Gin Ser Thr Pro Thr Val Gin Ala Ala Ala Gin Ala Gin Val Thr Pro 915 920 925 i Gin Pro Gin Thr Pro Val Gin Pro Pro Ser Val Ala Thr Pro Gin Ser 930 935 940 Ser Gin Gin Gin Pro Thr Pro Val His Ala Gin Pro Pro Gly Thr Pro 945 950 955 960 Leu Ser Gin Ala Ala Ala Ser lie Asp Asn Arg Val Pro Thr Pro Ser 965 970 975 Ser Val Ala Ser Ala Glu Thr Asn Ser Gin Gin Pro Gly Pro Asp Val 980 985 990 Pro Val Leu Glu Met Lys Thr Glu Thr Gin Ala Glu Asp Thr Glu Pro 995 1000 1005 Asp Pro Gly Glu Ser Lys Gly Glu Pro Arg Ser Glu Met Met Glu Glu ':*1010 1015 1020 Asp Leu Gin Gly Ala Ser Gin Val Lys Glu Glu Thr Asp lie Ala Glu 1025 1030 1035 1040 Gin Lys Ser Glu Pro Met Glu Val Asp Glu Lys Lys Pro Glu Val Lys 1045 1050 1055 Val Glu Val Lys Glu Glu Glu Glu Ser Ser Ser Asn Gly Thr Ala Ser 1060 1065 1070 Gin Ser Thr Ser Pro Ser Gin Pro Arg Lys Lys lie Phe Lys Pro Glu 1075 1080 1085 Glu Leu Arg Gin Ala Leu Met Pro Thr Leu Glu Ala Leu Tyr Arg Gin 1090 1095 1100 Asp Pro Glu Ser Leu Pro Phe Arg Gin Pro Val Asp Pro Gin Leu Leu 1105 1110 1115 1120 Gly lie Pro Asp Tyr Phe Asp lie Val Lys Asn Pro Met Asp Leu Ser 1125 1130 1135 Thr lie Lys Arg Lys Leu Asp Thr Gly Gin Tyr Gin Glu Pro Trp Gin 1140 1145 1150 Tyr Val Asp Asp Val Trp Leu Met Phe Asn Asn Ala Trp Leu Tyr Asn 1155 1160 1165 Arg Lys Thr Ser Arg Val Tyr Lys Phe Cys Ser Lys Leu Ala Glu Val 1170 1175 1180 Phe Glu Gin Glu lie Asp Pro Val Met Gin Ser Leu Gly Tyr Cys Cys 1185 1190 1195 1200 Gly Arg Lys Tyr Glu Phe Ser Pro Gin Thr Leu Cys Cys Tyr Gly Lys 1205 1210 1215 Gin Leu Cys Thr lie Pro Arg Asp Ala Ala Tyr Tyr Ser Tyr Gin Asn 1220 1225 1230 Arg Tyr His Phe Cys Glu Lys Cys Phe Thr Glu lie Gin Gly Glu Asn 1235 1240 1245 Val Thr Leu Gly Asp Asp Pro Ser Gin Pro Gin Thr Thr lie Ser Lys 1250 1255 1260 Asp Gin Phe Glu Lys Lys Lys Asn Asp Thr Leu Asp Pro Glu Pro Phe 1265 1270 1275 1280 Val Asp Cys Lys Glu Cys Gly Arg Lys Met His Gin lie Cys Val Leu 1285 1290 1295 His Tyr Asp lie lie Trp Pro Ser Gly Phe Val Cys Asp Asn Cys Leu 1300 1305 1310 Lys Lys Thr Gly Arg Pro Arg Lys Glu Asn Lys Phe Ser Ala Lys Arg 1315 1320 1325 Leu Gin Thr Thr Arg Leu Gly Asn His Leu Glu Asp Arg Val Asn Lys *1330 1335 1340 Phe Leu Arg Arg Gin Asn His Pro Glu Ala Gly Glu Val Phe Val Arg 1345 1350 1355 1360 Val Val Ala Ser Ser Asp Lys Thr Val Glu Val Lys Pro Gly Met Lys 1365 1370 1375 Ser Arg Phe Val Asp Ser Gly Glu Met Ser Glu Ser Phe Pro Tyr Arg 1380 1385 1390 Thr Lys Ala Leu Phe Ala Phe Glu Glu lie Asp Gly Val Asp Val Cys 1395 1400 1405 Phe Phe Gly Met His Val Gin Glu Tyr Gly Ser Asp Cys Pro Pro Pro 1410 1415 1420 Asn Thr Arg Arg Val Tyr lie Ser Tyr Leu Asp Ser lie His Phe Phe 1425 1430 1435 1440 Arg Pro Arg Cys Leu Arg Thr Ala Val Tyr His Glu lie Leu lie Gly 1445 1450 1455 Tyr Leu Glu Tyr Val Lys Lys Leu Gly Tyr Val Thr Gly His lie Trp 1460 1465 1470 Ala Cys Pro Pro Ser Glu Gly Asp Asp Tyr lie Phe His Cys His Pro 1475 1480 1485 Pro Asp Gin Lys lie Pro Lys Pro Lys Arg Leu Gin Glu Trp Tyr Lys 1490 1495 1500 Lys Met Leu Asp Lys Ala Phe Ala Glu Arg lie lie His Asp Tyr Lys 1505 1510 1515 1520 Asp lie Phe Lys Gin Ala Thr Glu Asp Arg Leu Thr Ser Ala Lys Glu 1525 1530 1535 Leu Pro Tyr Phe Glu Gly Asp Phe Trp Pro Asn Val Leu Glu Glu Ser 1540 1545 1550 lie Lys Glu Leu Glu Gin Glu Glu Glu Glu Arg Lys Lys Glu Glu Ser 1555 1560 1565 Thr Ala Ala Ser Glu Thr Thr Glu Gly Ser Gin Gly Asp Ser Lys Asn 1570 1575 1580 Ala Lys Lys Lys Asn Asn Lys Lys Thr Asn Lys Asn Lys Ser Ser lie 1585 1590 1595 1600 Ser Arg Ala Asn Lys Lys Lys Pro Ser Met Pro Asn Val Ser Asn Asp 1605 1610 1615 Leu Ser Gin Lys Leu Tyr Ala Thr Met Glu Lys His Lys Glu Val Phe 1620 1625 1630 Phe Val lie His Leu His Ala Gly Pro Val lie Asn Thr Leu Pro Pro 1635 1640 1645 *lie Val Asp Pro Asp Pro Leu Leu Ser Cys Asp Leu Met Asp Gly Arg 1650 1655 1660 Asp Ala Phe Leu Thr Leu Ala Arg Asp Lys His Trp Glu Phe Ser Ser 1665 1670 1675 1680 Leu Arg Arg Ser Lys Trp Ser Thr Leu Cys Met Leu Val Glu Leu His 1685 1690 1695 Thr Gin Gly Gin Asp Arg Phe Val Tyr Thr Cys Asn Glu Cys Lys His 1700 1705 1710 His Val Glu Thr Arg Trp His Cys Thr Val Cys Glu Asp Tyr Asp Leu 1715 1720 1725 Cys lie Asn Cys Tyr Asn Thr Lys Ser His Ala His Lys Met Val Lys 1730 1735 1740 Trp Gly Leu Gly Leu Asp Asp Glu Gly Ser Ser Gin Gly Glu Pro Gin 1745 1750 1755 1760 Ser Lys Ser Pro Gin Glu Ser Arg Arg Val Ser lie Gin Arg Cys lie 1765 1770 1775 Gin Ser Leu Val His Ala Cys Gin Cys Arg Asn Ala Asn Cys Ser Leu 1780 1785 1790 Pro Ser Cys Gin Lys Met Lys Arg Val Val Gin His Thr Lys Gly Cys 1795 1800 1805 Lys Arg Lys Thr Asn Gly Gly Cys Pro Val Cys Lys Gin Leu lie Ala 1810 1815 1820 Leu Cys Cys Tyr His Ala Lys His Cys Gin Glu Asn Lys Cys Pro Val 1825 1830 1835 1840 Pro Phe Cys Leu Asn lie Lys His Lys Leu Arg Gin Gin Gin lie Gin 1845 1850 1855 His Arg Leu Gin Gin Ala Gin Leu Met Arg Arg Arg Met Ala Thr Met 1860 1865 1870 Asn Thr Arg Asn Val Pro Gin Gin Ser Leu Pro Ser Pro Thr Ser Ala 1875 1880 1885 Pro Pro Gly Thr Pro Thr Gin Gin Pro Ser Thr Pro Gin Thr Pro Gin 1890 1895 1900 Pro Pro Ala Gin Pro Gin Pro Ser Pro Val Ser Met Ser Pro Ala Gly 1905 1910 1915 1920 SPhe Pro Ser Val Ala Arg Thr Gin Pro Pro Thr Thr Val Ser Thr Gly 1925 1930 1935 Lys Pro Thr Ser Gin Val Pro Ala Pro Pro Pro Pro Ala Gin Pro Pro 1940 1945 1950 Pro Ala Ala Val Glu Ala Ala Arg Gin lie Glu Arg Glu Ala Gin Gin 1955 1960 1965 Gin Gin His Leu Tyr Arg Val Asn lie Asn Asn Ser Met Pro Pro Gly 1970 1975 1980 Arg Thr Gly Met Gly Thr Pro Gly Ser Gin Met Ala Pro Val Ser Leu 1985 1990 1995 2000 Asn Val Pro Arg Pro Asn Gin Val Ser Gly Pro Val Met Pro Ser Met 2005 2010 2015 Pro Pro Gly Gin Trp Gin Gin Ala Pro Leu Pro Gin Gin Gin Pro Met 2020 2025 2030 Pro Gly Leu Pro Arg Pro Val lie Ser Met Gin Ala Gin Ala Ala Val 2035 2040 2045' Ala Gly Pro Arg Met Pro Ser Val Gin Pro Pro Arg Ser lie Ser Pro 2050 2055 2060 Ser Ala Leu Gin Asp Leu Leu Arg Thr Leu Lys Ser Pro Ser Ser Pro 2065 2070 2075 2080 Gin Gin Gin Gin Gin Val Leu Asn lie Leu Lys Ser Asn Pro Gin Leu 2085 2090 2095 Met Ala Ala Phe lie Lys Gin Arg Thr Ala Lys Tyr Val Ala Asn Gin 2100 2105 2110 Pro Gly Met Gin Pro Gin Pro Gly Leu Gin Ser Gin Pro Gly Met Gin 2115 2120 2125 Pro Gin Pro Gly Met His Gin Gin Pro Ser Leu Gin Asn Leu Asn Ala 2130 2135 2140 Met Gin Ala Gly Val Pro Arg Pro Gly Val Pro Pro Gin Gin Gin Ala 2145 2150 2155 2160 Met Gly Gly Leu Asn Pro Gin Gly Gin Ala Leu Asn lie Met Asn Pro 2165 2170 2175 Gly His Asn Pro Asn Met Ala Ser Met Asn Pro Gin Tyr Arg Glu Met 2180 2185 2190 Leu Arg Arg Gin Leu Leu Gin Gin Gin Gin Gin Gin Gin Gin Gin Gin 2195 2200 2205 Gin Gin Gin Gin Gin Gin Gin Gin Gly Ser Ala Gly Met Ala Gly Gly 2210 2215 2220 Met Ala Gly His Gly Gin Phe Gin Gin Pro Gin Gly Pro Gly Gly Tyr 2225 2230 2235 2240 Pro Pro Ala Met Gin Gin Gin Gin Arg Met Gin Gin His Leu Pro Leu 2245 2250 2255 Gin Gly Ser Ser Met Gly Gin Met Ala Ala Gin Met Gly Gin Leu Gly 2260 2265 2270 Gin Met Gly Gin Pro Gly Leu Gly Ala Asp Ser Thr Pro Asn lie Gin 2275 2280 2285 Gin Ala Leu Gin Gin Arg lie Leu Gin Gin Gin Gin Met Lys Gin Gin 2290 2295 2300 lie Gly Ser Pro Gly Gin Pro Asn Pro Met Ser Pro Gin Gin His Met 2305 2310 2315 2320 Leu Ser Gly Gin Pro Gin Ala Ser His Leu Pro Gly Gin Gin lie Ala 2325 2330 2335 Thr Ser Leu Ser Asn Gin Val Arg Ser Pro Ala Pro Val Gin Ser Pro 2340 2345 2350 Arg Pro Gin Ser Gin Pro Pro His Ser Ser Pro Ser Pro Arg lie Gin 2355 2360 2365 Pro Gin Pro Ser Pro His His Val Ser Pro Gin Thr Gly Ser Pro His 2370 2375 2380 Pro Gly Leu Ala Val Thr Met Ala Ser Ser lie Asp Gin Gly His Leu 2385 2390 2395 2400 Gly Asn Pro Glu Gin Ser Ala Met Leu Pro Gin Leu Asn Thr Pro Ser 2405 2410 2415 Arg Ser Ala Leu Ser Ser Glu Leu Ser Leu Val Gly Asp Thr Thr Gly 2420 2425 2430 Asp Thr Leu Glu Lys Phe Val Glu Gly Leu 2435 2440 <210>14 <211> 324 <212> PRT <213> Mus musculus <300> <301> Metzger, R.

<302> Expression of the mouse and rat proto-oncogene in the brain and peripheral tissues <303> FEBS Lett.

<304> 1995 <305> 3570 <306> 27-32 <313> 1 TO 324 <400>14 Met Asp Gin Ser Asn Met Thr Ser Leu Ala Glu Glu Lys Ala Met Asn 1 5 10 Thr Ser Ser Arg Asn Ala Ser Leu Gly Ser Ser His Pro Pro lie Pro 20 25 lie Val His Trp Val lie Met Ser lie Ser Pro Leu Gly Phe Val Glu 35 40 Asn Gly lie Leu Leu Trp Phe Leu Cys Phe Arg Met Arg Arg Asn Pro 55 Phe Thr Val Tyr lie Thr His Leu Ser Met Ala Asp lie Ser Leu Leu 65 70 75 Phe Cys lie Phe lie Leu Ser Thr Asp Tyr Ala Leu Asp Tyr Glu Leu 90 Ser Ser Gly His His Tyr Thr lie Val Thr Leu Ser Val Thr Phe Leu 100 105 110 Phe Gly Tyr Asn Thr Gly Leu Tyr Leu Leu Thr Ala lie Ser Val Glu 115 120 125 Arg Cys Leu Ser Val Leu Tyr Pro lie Trp Tyr Thr Ser His Arg Pro 130 135 140 Lys His Gin Ser Ala Phe Val Cys Ala Leu Leu Cys Ala Leu Ser Cys 145 150 155 160 Leu Val Thr Thr Met Glu Tyr Val Met Cys lie Asp Ser Gly Glu Glu 165 170 175 Ser His Ser Arg Ser Asp Cys Arg Ala Val lie lie Phe lie Ala lie 180 185 190 Leu Ser Phe Leu Val Phe Thr Pro Leu Met Leu Val Ser Ser Ser lie 195 200 205 Leu Val Val Lys lie Arg Lys Asn Thr Trp Ala Ser His Ser Ser Lys 210 215 220 Leu Tyr lie Val lie Met Val Thr lie lie lie Phe Leu lie Phe Ala 225 230 235 240 Met Pro Met Arg Val Leu Tyr Leu Leu Tyr Tyr Glu Tyr Trp Ser Ala 245 250 255 Phe Gly Asn Leu His Asn lie Ser Leu Leu Phe Ser Thr lie Asn Ser 260 265 270 Ser Ala Asn Pro Phe lie Tyr Phe Phe Val Gly Ser Ser Lys Lys Lys 275 280 285 Arg Phe Arg Glu Ser Leu Lys Val Val Leu Thr Arg Ala Phe Lys Asp 290 295 300 Glu Met Gin Pro Arg Arg Gin Glu Gly Asn Gly Asn Thr Val Ser lie 305 310 315 320 Glu Thr Val Val a <210> <211> 378 <212> PRT <213> Homo sapiens <400> Met Val Trp Gly Lys lie Cys Trp Phe Ser Gin Arg Ala Gly Trp Thr 1 5 10 Val Phe Ala Glu Ser Gin lie Ser Leu Ser Cys Ser Leu Cys Leu His 25 Ser Gly Asp Gin Glu Ala Gin Asn Pro Asn Leu Val Ser Gin Leu Cys 35 40 Gly Val Phe Leu Gin Asn Glu Thr Asn Glu Thr lie His Met Gin Met 55 Ser Met Ala Val Gly Gin Gin Ala Leu Pro Leu Asn lie lie Ala Pro 70 75 Lys Ala Val Leu Val Ser Leu Cys Gly Val Leu Leu Asn Gly Thr Val 90 Phe Trp Leu Leu Cys Cys Gly Ala Thr Asn Pro Tyr Met Val Tyr lie 100 105 110 Leu His Leu Val Ala Ala Asp Val lie Tyr Leu Cys Cys Ser Ala Val 115 120 125 Gly Phe Leu Gin Val Thr Leu Leu Thr Tyr His Gly Val Val Phe Phe 130 135 140 lie Pro Asp Phe Leu Ala lie Leu Ser Pro Phe Ser Phe Glu Val Cys 145 150 155 160 Leu Cys Leu Leu Val Ala lie Ser Thr Glu Arg Cys Val Cys Val Leu 165 170 175 Phe Pro lie Trp Tyr Arg Cys His Arg Pro Lys Tyr Thr Ser Asn Val 180 185 190 Val Cys Thr Leu lie Trp Gly Leu Pro Phe Cys lie Asn lie Val Lys 195 200 205 Ser Leu Phe Leu Thr Tyr Trp Lys His Val Lys Ala Cys Val lie Phe 210 215 220 Leu Lys Leu Ser Gly Leu Phe His Ala lie Leu Ser Leu Val Met Cys 225 230 235 240 Val Ser Ser Leu Thr Leu Leu lie Arg Phe Leu Cys Cys Ser Gin Gin 245 250 255 Gin Lys Ala Thr Arg Val Tyr Ala Val Val Gin lie Ser Ala Pro Met 260 265 270 Phe Leu Leu Trp Ala Leu Pro Leu Ser Val Ala Pro Leu lie Thr Asp 275 280 285 Phe Lys Met Phe Val Thr Thr Ser Tyr Leu lie Ser Leu Phe Leu lie 290 295 300 lie Asn Ser Ser Ala Asn Pro lie lie Tyr Phe Phe Val Gly Ser Leu 305 310 315 320 Arg Lys Lys Arg Leu Lys Glu Ser Leu Arg Val lie Leu Gin Arg Ala 325 330 335 Leu Ala Asp Lys Pro Glu Val Gly Arg Asn Lys Lys Ala Ala Gly lie 340 345 350 Asp Pro Met Glu Gin Pro His Ser Thr Gin His Val Glu Asn Leu Leu 355 360 365 Pro Arg Glu His Arg Val Asp Val Glu Thr 370 375 <210> 16 <211> 732 <212> PRT <213> Homo sapiens <400> 16 Met Glu Arg Gin Val Leu Leu Ser Glu Pro Glu Glu Ala Ala Ala Leu 1 5 10 Tyr Arg Gly Leu Ser Arg Gin Pro Ala Leu Ser Ala Ala Cys Leu Gly 25 Pro Glu Val Thr Thr Gin Tyr Gly Gly Gin Tyr Arg Thr Val His Thr 40 Glu Trp Thr Gin Arg Asp Leu Glu Arg Met Glu Asn lie Arg Phe Cys 55 Arg Gin Tyr Leu Val Phe His Asp Gly Asp Ser Val Val Phe Ala Gly 70 75 Pro Ala Gly Asn Ser Val Glu Thr Arg Gly Glu Leu Leu Ser Arg Glu 90 Ser Pro Ser Gly Ser Met Lys Ala Val Leu Arg Lys Ala Gly Gly Thr 100 105 110 Gly Pro Gly Glu Glu Lys Gin Phe Leu Glu Val Trp Glu Lys Asn Arg 115 120 125 Lys Leu Lys Ser Phe Asn Leu Ser Val Leu Glu Lys His Gly Pro Val 130 135 140 Tyr Glu Asp Asp Cys Phe Gly Cys Leu Ser Trp Ser His Ser Glu Thr 145 150 155 160 His Leu Leu Tyr Val Ala Glu Arg Lys Arg Pro Lys Ala Glu Ser Phe 165 170 175 Phe Gin Thr Lys Ala Leu Asp Val Ser Ala Ser Asp Asp Glu lie Ala 180 185 190 Arg Leu Lys Lys Pro Asp Gin Pro lie Lys Gly Asp Gin Phe Val Phe *.195 200 205 Tyr Glu Asp Trp Gly Glu Asn Met Val Ser Lys.Ser lie Pro Val Leu 210 215 220 Cys Val Leu Asp Val Glu Ser Gly Asn lie Ser Val Leu Glu Gly Val 225 230 235 240 Pro Glu Asn Val Ser Pro Gly Gin Ala Phe Trp Ala Pro Gly Asp Ala 245 250 255 Gly Val Val Phe Val Gly Trp Trp His Glu Pro Phe Arg Leu Gly lie 260 265 270 Arg Phe Cys Thr Asn Arg Arg Ser Ala Leu Tyr Tyr Val Asp Leu lie 275 280 285 Gly Gly Lys Cys Glu Leu Leu Ser Asp Asp Ser Leu Ala Val Ser Ser 290 295 300 Pro Arg Leu Ser Pro Asp Gin Cys Arg lie Val Tyr Leu Gin Tyr Pro 305 310 315 320 Ser Leu lie Pro His His Gin Cys Ser Gin Leu Cys Leu Tyr Asp Trp 325 330 335 Tyr Thr Lys Val Thr Ser Val Val Val Asp Val Val Pro Arg Gin Leu 340 345 350 Gly Glu Asn Phe Ser Gly lie Tyr Cys Ser Leu Leu Pro Leu Gly Cys 355 360 365 Trp Ser Ala Asp Ser Gin Arg Val Val Phe Asp Ser Ala Gin Arg Ser 370 375 380 Arg Gin Asp Leu Phe Ala Val Asp Thr Gin Val Gly Thr Val Thr Ser 385 390 395 400 Leu Thr Ala Gly Gly Ser Gly Gly Ser Trp Lys Leu Leu Thr lie Asp 405 410 415 Gin Asp Leu Met Val Ala Gin Phe Ser Thr Pro Ser Leu Pro Pro Thr 420 425 430 Leu Lys Val Gly Phe Leu Pro Ser Ala Gly Lys Glu Gin Ser Val Leu 435 440 445 Trp Val Ser Leu Glu Glu Ala Glu Pro lie Pro Asp lie His Trp Gly 450 455 460 lie Arg Val Leu Gin Pro Pro Pro Glu Gin Glu Asn Val Gin Tyr Ala 465 470 475 480 Gly Leu Asp Phe Glu Ala lie Leu Leu Gin Pro Gly Ser Pro Pro Asp 485 490 495 Lys Thr Gin Val Pro Met Val Val Met Pro His Gly Gly Pro His Ser 500 505 510 Ser Phe Val Thr Ala Trp Met Leu Phe Pro Ala Met Leu Cys Lys Met 515 520 525 Gly Phe Ala Val Leu Leu Val Asn Tyr Arg Gly Ser Thr Gly Phe Gly 530 535 540 Gin Asp Ser lie Leu Ser Leu Pro Gly Asn Val Gly His Gin Asp Val 545 550 555 560 Lys Asp Val Gin Phe Ala Val Glu Gin Val Leu Gin Glu Glu His Phe 565 570 575 Asp Ala Ser His Val Ala Leu Met Gly Gly Ser His Gly Gly Phe lie 580 585 590 Ser Cys His Leu lie Gly Gin Tyr Pro Glu Thr Tyr Arg Ala Cys Val 595 600 605 Ala Arg Asn Pro Val lie Asn lie Ala Ser Met Leu Gly Ser Thr Asp 610 615 620 Ilie Pro Asp Trp Cys Val Val Glu Ala Gly Phe Pro Phe Ser Ser Asp 625 630 635 640 Cys Leu Pro Asp Leu Ser Val Trp Ala Glu Met Leu Asp Lys Ser Pro 645 650 655 Ilie Arg Tyr Ile Pro Gin Val Lys Thr Pro Leu Leu Leu Met Leu Gly 660 665 670 Gin Glu Asp Arg Arg Val Pro Phe Lys GIn Gly Met Glu Tyr Tyr Arg 675 680 685 Ala Leu Lys Thr Arg Asn Val Pro Val Arg Leu Leu Leu Tyr Pro Lys 690 695 700 Ser Thr His Ala Leu Ser Glu Val Glu Val Glu Ser Asp Ser Phe Met 705 710 715 720 Asn Ala Val Leu Trp Leu Arg Thr His Leu Gly Ser 725 730 <210> 17 <21 1> 400 <212> PRT <213> Homo sapiens <300> <301> Duprez, ER.

<302> Direct Submissin <303> Inserm U-301 <304> 1996 <309> 1996-11-26 <400> 17 Met Thr Thr Lys Asn Leu Glu Thr Lys Val Thr Val Thr Ser Ser Pro 1 5 10 .Il~e Arg Gly Ala Gly Asp Gly Met Glu Thr Glu Glu Pro Pro Lys Ser 25 Val Glu Val Thr Ser Gly Val GIn Ser Arg Lys His His Ser Leu Gin 40 Ser Pro Trp Lys Lys Ala Val Pro Ser Glu Ser Pro Gly Val Leu GIn :050 55 Leu Gly Lys Met Leu Thr Glu Lys Ala Met Glu Val Lys Ala Val Arg 70 75 Ile Leu Val Pro Lys Ala Ala Ilie Thr His Asp Ilie Pro Asn Lys Asn 90 Thr Lys Val Lys Ser Leu Gly His His Lys Gly Glu Phe Leu Gly GIn 100 105 110 Ser Glu Gly Val Ilie Glu Pro Asn Lys Glu Leu Ser Glu Val Lys Asn 115 120 125 Val Leu Glu Lys Leu Lys Asn Ser Glu Arg Arg Leu Leu Gin Asp Lys 130 135 140 Glu Gly Leu Ser Asn Gin Leu Arg Val Gin Thr Glu Val Asn Arg Glu 145 150 155 160 Leu Lys Lys Leu Leu Val Ala Ser Val Gly Asp Asp Leu Gin Tyr His 165 170 175 Phe Glu Arg Leu Ala Arg Glu Lys Asn Gin Leu lie Leu Glu Asn Glu 180 185 190 Ala Leu Gly Arg Asn Thr Ala Gin Leu Ser Glu Gin Leu Glu Arg Met 195 200 205 Ser lie Gin Cys Asp Val Trp Arg Ser Lys Phe Leu Ala Ser Arg Val 210 215 220 Met Ala Asp Glu Leu Thr Asn Ser Arg Ala Ala Leu Gin Arg Gin Asn 225 230 235 240 Arg Asp Ala His Gly Ala lie Gin Asp Leu Leu Ser Glu Arg Glu Gin 245 250 255 Phe Arg Gin Glu Met lie Ala Thr Gin Lys Leu Leu Glu Glu Leu Leu 260 265 270 Val Ser Leu Gin Trp Gly Arg Glu Gin Thr Tyr Ser Pro Ser Val Gin 275 280 285 Pro His Ser Thr Ala Glu Leu Ala Leu Thr Asn His Lys Leu Ala Lys 290 295 300 Ala Val Asn Ser His Leu Leu Gly Asn Val Gly lie Asn Asn Gin Lys 305 310 315 320 Lys lie Pro Ser Thr Val Glu Phe Cys Ser Thr Pro Ala Glu Lys Met 325 330 335

S

Ala Glu Thr Val Leu Arg lie Leu Asp Pro Val Thr Cys Lys Glu Ser 340 345 350 Ser Pro Asp Asn Pro Phe Phe Glu Ser Ser Pro Thr Thr Leu Leu Ala 355 360 365 Thr Lys Lys Asn lie Gly Arg Phe His Pro Tyr Thr Arg Tyr Glu Asn 370 375 380 lie Thr Phe Asn Cys Cys Asn His Cys Arg Gly Glu Leu lie Ala Leu 385 390 395 400 <210> 18 <211> 319 <212> PRT <213> Mus musculus <300> <301> Zou, Y.

<302> CARP, a cardiac ankyrin repea protein, is downstream in the Nkx2-5 homeobox gene pathway <303> Development <304> 1996 <305> 124 <306> 793-804 <313> 1 TO 319 <400> 18 Met Met Val Leu Arg Val Glu Glu Leu Val Thr Gly Lys Lys Asn Ser 1 5 10 Asn Gly Ala Ala Gly Glu Phe Leu Pro Gly Glu Phe Arg Asn Gly Glu 25 Tyr Glu Ala Ala Val Ala Leu Glu Lys Gin Glu Asp Leu Lys Thr Leu 40 Pro Ala Asn Ser Val Lys Gin Gly Glu Glu Gin Arg Lys Ser Glu Lys 55 Leu Arg Glu Ala Glu Leu Lys Lys Lys Lys Leu Glu Gin Arg Ser Lys 70 75 Leu Glu Asn Leu Glu Asp Leu Glu lie lie Val Gin Leu Lys Lys Arg 85 90 Lys Lys Tyr Lys Lys Thr Lys Val Pro Val Val Lys Glu Pro Glu Pro 100 105 110 Glu lie Met Thr Glu Pro Val Asp Val Pro Arg Phe Leu Lys Ala Ala 115 120 125 Leu Glu Asn Lys Leu Pro Val Val Glu Lys Leu Val Ser Asp Lys Asn 130 135 140 Ser Pro Asp Val Cys Asp Glu Tyr Lys Arg Thr Ala Leu His Arg Ala 145 150 155 160 Cys Leu Glu Gly His Leu Ala lie Val Glu Lys Leu Met Glu Ala Gly 165 170 175 0 Ala Gin lie Glu Phe Arg Asp Met Leu Glu Ser Thr Ala lie His Trp 180 185 190 Ala Cys Arg Gly Gly Asn Ala Asp Val Leu Lys Leu Leu Leu Asn Lys 195 200 205 Gly Ala Lys lie Ser Ala Arg Asp Lys Leu Leu Ser Thr Ala Leu His 210 215 220 Val Ala Val Arg Thr Gly His Tyr Glu Cys Ala Glu His Leu lie Ala 225 230 235 240 Cys Glu Ala Asp Leu Asn Ala Lys Asp Arg Glu Gly Asp Thr Pro Leu 245 250 255 His Asp Ala Val Arg Leu Asn Arg Tyr Lys Met lie Arg Leu Leu Met 260 265 270 Thr Phe Gly Ala Asp Leu Lys Val Lys Asn Cys Ala Gly Lys Thr Pro 275 280 285 Met Asp Leu Val Leu His Trp Gin Ser Gly Thr Lys Ala lie Phe Asp 290 295 300 Ser Pro Lys Glu Asn Ala Tyr Lys Asn Ser Arg lie Ala Thr Phe 305 310 315 <210>19 <211> 319 <212> PRT <213> Homo sapiens <400> 19 Met Met Val Leu Lys Val Glu Glu Leu Val Thr Gly Lys Lys Asn Gly 1 5 10 Asn Gly Glu Ala Gly Glu Phe Leu Pro Glu Asp Phe Arg Asp Gly Glu 25 Tyr Glu Ala Ala Val Thr Leu Glu Lys Gin Glu Asp Leu Lys Thr Leu 40 Leu Ala His Pro Val Thr Leu Gly Glu Gin Gin Trp Lys Ser Glu Lys 55 Gin Arg Glu Ala Glu Leu Pro Lys Lys Lys Leu Glu Gin Arg Ser Lys 65 70 75 Leu Glu Asn Leu Glu Asp Leu Glu lie lie lie Gin Leu Lys Lys Arg 85 90 Lys Lys Tyr Arg Lys Thr Lys Val Pro Val Val Lys Glu Pro Glu Pro 100 105 110 Glu lie lie Thr Glu Pro Val Asp Val Pro Thr Phe Leu Lys Ala Ala 115 120 125 Leu Glu Asn Lys Leu Pro Val Val Glu Lys Phe Leu Ser Asp Lys Asn 130 135 140 Asn Pro Asp Val Cys Asp Glu Tyr Lys Arg Thr Ala Leu His Arg Ala 145 150 155 160 Cys Leu Glu Gly His Leu Ala lie Val Glu Lys Leu Met Glu Ala Gly 165 170 175 Ala Gin lie Glu Phe Arg Asp Met Leu Glu Ser Thr Ala lie His Trp 180 185 190 Ala Ser Arg Gly Gly Asn Leu Asp Val Leu Lys Leu Leu Leu Asn Lys 195 200 205 Gly Ala Lys lie Ser Ala Arg Asp Lys Leu Leu Ser Thr Ala Leu His 210 215 220 Val Ala Val Arg Thr Gly His Tyr Glu Cys Ala Glu His Leu lie Ala 225 230 235 240 Cys Glu Ala Asp Leu Asn Ala Lys Asp Arg Glu Gly Asp Thr Pro Leu 245 250 255 His Asp Ala Val Arg Leu Asn Arg Tyr Lys Met lie Arg Leu Leu lie 260 265 270 Met Tyr Gly Ala Asp Leu Asn lie Lys Asn Cys Ala Gly Lys Thr Pro 275 280 285 Met Asp Leu Val Leu His Trp Gin Asn Gly Thr Lys Ala lie Phe Asp 290 295 300 Ser Leu Arg Glu Asn Ser Tyr Lys Thr Ser Arg lie Ala Thr Phe 305 310 315 <210> <211> 490 <212> PRT <213> Homo sapiens <300> <301> Field, L. L.

<302> Susceptibility to insulin-dependent diabetes mellitus maps to a locus (IDDM11) on human chromosome 14q24.3-q31 <303> Genomics <304> 1996 S. <305> 33 <306> 1-8 S <313> 1 TO 490 <400> Met Gly Pro Val Met Pro Pro Ser Lys Lys Pro Glu Ser Ser Gly lie 1 5 10 Ser Val Ser Ser Gly Leu Ser Gin Cys Tyr Gly Gly Ser Gly Phe Ser 20 25 Lys Ala Leu Gin Glu Asp Asp Asp Leu Asp Phe Ser Leu Pro Asp lie 40 Arg Leu Glu Glu Gly Ala Met Glu Asp Glu Glu Leu Thr Asn Leu Asn 50 55 Trp Leu His Glu Ser Lys Asn Leu Leu Lys Ser Phe Gly Glu Ser Val 70 75 Leu Arg Ser Val Ser Pro Val Gin Asp Leu Asp Asp Asp Thr Pro Pro 90 Ser Pro Ala His Ser Asp Met Pro Tyr Asp Ala Arg Gin Asn Pro Asn 100 105 110 Cys Lys Pro Pro Tyr Ser Phe Ser Cys Leu lie Phe Met Ala lie Glu 115 120 125 Asp Ser Pro Thr Lys Arg Leu Pro Val Lys Asp lie Tyr Asn Trp lie 130 135 140 Leu Glu His Phe Pro Tyr Phe Ala Asn Ala Pro Thr Gly Trp Lys Asn 145 150 155 160 Ser Val Arg His Asn Leu Ser Leu Asn Lys Cys Phe Lys Lys Val Asp 165 170 175 Lys Glu Arg Ser Gin Ser lie Gly Lys Gly Ser Leu Trp Cys lie Asp 180 185 190 Pro Glu Tyr Arg Gin Asn Leu lie Gin Ala Leu Lys Lys Thr Pro Tyr 195 200 205 His Pro His Pro His Val Phe Asn Thr Pro Pro Thr Cys Pro Gin Ala 210 215 220 Tyr Gin Ser Thr Ser Gly Pro Pro lie Trp Pro Gly Ser Thr Phe Phe 225 230 235 240 Lys Arg Asn Gly Ala Leu Leu Gin Asp Pro Asp lie Asp Ala Ala Ser 245 250 255 Ala Met Met Leu Leu Asn Thr Pro Pro Glu lie Gin Ala Gly Phe Pro 260 265 270 Pro Gly Val lie Gin Asn Gly Ala Arg Val Leu Ser Arg Gly Leu Phe 275 280 285 Pro Gly Val Arg Pro Leu Pro lie Thr Pro lie Gly Val Thr Ala Ala 290 295 300 Met Arg Asn Gly lie Thr Ser Cys Arg Met Arg Thr Glu Ser Glu Pro 305 310 315 320 Ser Cys Gly Ser Pro Val Val Ser Gly Asp Pro Lys Glu Asp His Asn 325 330 335 Tyr Ser Ser Ala Lys Ser Ser Asn Ala Arg Ser Thr Ser Pro Thr Ser 340 345 350 Asp Ser lie Ser Ser Ser Ser Ser Ser Ala Asp Asp His Tyr Glu Phe 355 360 365 Ala Thr Lys Gly Ser Gin Glu Gly Ser Glu Gly Ser Glu Gly Ser Phe 370 375 380 Arg Ser His Glu Ser Pro Ser Asp Thr Glu Glu Asp Asp Arg Lys His 385 390 395 400 Ser Gin Lys Glu Pro Lys Asp Ser Leu Gly Asp Ser Gly Tyr Ala Ser 405 410 415 Gin His Lys Lys Arg Gin His Phe Ala Lys Ala Arg Lys Val Pro Ser 420 425 430 Asp Thr Leu Pro Leu Lys Lys Arg Arg Thr Glu Lys Pro Pro Glu Ser 435 440 445 Asp Asp Glu Glu Met Lys Glu Ala Ala Gly Ser Leu Leu His Leu Ala 450 455 460 Gly lie Arg Ser Cys Leu Asn Asn lie Thr Asn Arg Thr Ala Lys Gly 465 470 475 480 Gin Lys Glu Gin Lys Glu Thr Thr Lys Asn 485 490 <210> 21 <211> 212 <212> PRT <213> Mus musculus <300> <301> Laufer, W.

<302> GTP-binding protein (rab2) <400> 21 Met Ala Tyr Ala Tyr Leu Phe Lys Tyr lie lie lie Gly Asp Thr Gly 1 5 10 Val Gly Lys Ser Cys Leu Leu Leu Gin Phe Thr Asp Lys Arg Phe Gin 25 Pro Val His Asp Leu Thr lie Gly Val Glu Phe Gly Ala Arg Met lie 40 Thr lie Asp Gly Lys Gin lie Lys Leu Gin lie Trp Asp Thr Ala Gly 55 S* Gin Glu Ser Phe Arg Ser lie Thr Arg Ser Tyr Tyr Arg Gly Ala Ala 65 70 75 Gly Ala Leu Leu Val Tyr Asp lie Thr Arg Arg Asp Thr Phe Asn His 85 90 Leu Thr Thr Trp Leu Glu Asp Ala Arg Gin His Ser Asn Ser Asn Met 100 105 110 Val lie Met Leu lie Gly Asn Lys Ser Asp Leu Glu Ser Arg Arg Glu 115 120 125 Val Lys Lys Glu Glu Gly Glu Ala Phe Ala Arg Glu His Gly Leu lie 130 135 140 Phe Met Glu Thr Ser Ala Lys Thr Ala Ser Asn Val Glu Glu Ala Phe 145 150 155 160 lie Asn Thr Ala Lys Glu lie Tyr Glu Lys lie Gin Glu Gly Val Phe 165 170 175 Asp lie Asn Asn Glu Ala Asn Gly lie Lys lie Gly Pro Gin His Ala 180 185 190 Ala Thr Asn Ala Ser His Gly Ser Asn Gin Gly Gly Gin Gin Ala Gly 195 200 205 Gly Gly Cys Cys 210 <210> 22 <211> 212 <212> PRT <213> Homo sapiens <300> <301> Tachibana, K.

<302> Nucleotide sequence of a new YPT1-related human cDNA which belongs to the ras gene superfamily <303> Nucleic Acids Res.

<304> 1988 <305> 16 <306> 10368- <313> 1 TO 212 <400> 22 Met Ala Tyr Ala Tyr Leu Phe Lys Tyr lie lie lie Gly Asp Thr Gly 1 5 10 Val Gly Lys Ser Cys Leu Leu Leu Gin Phe Thr Asp Lys Arg Phe Gin 25 Pro Val His Asp Leu Thr lie Gly Val Glu Phe Gly Ala Arg Met lie 40 Thr lie Asp Gly Lys Gin lie Lys Leu Gin lie Trp Asp Thr Ala Gly 55 .Gin Glu Ser Phe Arg Ser lie Thr Arg Ser Tyr Tyr Arg Gly Ala Ala 70 75 Gly Ala Leu Leu Val Tyr Asp lie Thr Arg Arg Asp Thr Phe Asn His 90 Leu Thr Thr Trp Leu Glu Asp Ala Arg Gin His Ser Asn Ser Asn Met 100 105 110 Val lie Met Leu lie Gly Asn Lys Ser Asp Leu Glu Ser Arg Arg Glu 115 120 125 S Val Lys Lys Glu Glu Gly Glu Ala Phe Ala Arg Glu His Gly Leu Met S* 130 135 140 Phe Met Glu Thr Ser Ala Lys Thr Ala Ser Asn Val Glu Glu Ala Phe 145 150 155 160 Slie Asn Thr Ala Lys Glu lie Tyr Glu Lys lie Gin Glu Gly Val Phe 165 170 175 Asp lie Asn Asn Glu Ala Asn Gly lie Lys lie Gly Pro Gin His Ala 180 185 190 Ala Thr Asn Ala Thr His Ala Gly Asn Gin Gly Gly Gin Gin Ala Gly 195 200 205 Gly Gly Cys Cys 210 <210> 23 <211> 1712 <212> PRT <213> Homo sapiens <300> <301> Fontoura, B. M.

<302> A conserved biogenesis pathway for nucleoporins: proteolytic processing of a 186-kilodalton precursor generates Nup98 and the novel nucleoporin nup96 <303> J. Cell Biol.

<304> 1999 <305> 144 <306> ^1097-1112 <313> 1 TO 1712 <400> 23 Met Phe Asn Lys Ser Phe Gly Thr Pro Phe Gly Gly Gly Thr Gly Gly 1 5 10 Phe Gly Thr Thr Ser Thr Phe Gly Gin Asn Thr Gly Phe Gly Thr Thr 25 Ser Gly Gly Ala Phe Gly Thr Ser Ala Phe Gly Ser Ser Asn Asn Thr 40 Gly Gly Leu Phe Gly Asn Ser Gin Thr Lys Pro Gly Gly Leu Phe Gly 50 55 Thr Ser Ser Phe Ser Gin Pro Ala Thr Ser Thr Ser Thr Gly Phe Gly 65 70 75 S" Phe Gly Thr Ser Thr Gly Thr Ala Asn Thr Leu Phe Gly Thr Ala Ser 90 Thr Gly Thr Ser Leu Phe Ser Ser Gin Asn Asn Ala Phe Ala Gin Asn 100 105 110 Lys Pro Thr Gly Phe Gly Asn Phe Gly Thr Ser Thr Ser Ser Gly Gly 115 120 125 Leu Phe Gly Thr Thr Asn Thr Thr Ser Asn Pro Phe Gly Ser Thr Ser 130 135 140 Gly Ser Leu Phe Gly Pro Ser Ser Phe Thr Ala Ala Pro Thr Gly Thr 145 150 155 160 Thr lie Lys Phe Asn Pro Pro Thr Gly Thr Asp Thr Met Val Lys Ala 165 170 175 Gly Val Ser Thr Asn lie Ser Thr Lys His Gin Cys lie Thr Ala Met 180 185 190 Lys Glu Tyr Glu Ser Lys Ser Leu Glu Glu Leu Arg Leu Glu Asp Tyr 195 200 205 Gin Ala Asn Arg Lys Gly Pro Gin Asn Gin Val Gly Ala Gly Thr Thr 210 215 220 Thr Gly Leu Phe Gly Ser Ser Pro Ala Thr Ser Ser Ala Thr Gly Leu 225 230 235 240 Phe Ser Ser Ser Thr Thr Asn Ser Gly Phe Ala Tyr Gly Gin Asn Lys 245 250 255 Thr Ala Phe Gly Thr Ser Thr Thr Gly Phe Gly Thr Asn Pro Gly Gly 260 265 270 Leu Phe Gly Gin Gin Asn Gin Gin Thr Thr Ser Leu Phe Ser Lys Pro 275 280 285 Phe Gly Gin Ala Thr Thr Thr Gin Asn Thr Gly Phe Ser Phe Gly Asn 290 295 300 Thr Ser Thr lie Gly Gin Pro Ser Thr Asn Thr Met Gly Leu Phe Gly 305 310 315 320 Val Thr Gin Ala Ser Gin Pro Gly Gly Leu Phe Gly Thr Ala Thr Asn 325 330 335 Thr Ser Thr Gly Thr Ala Phe Gly Thr Gly Thr Gly Leu Phe Gly Gin 340 345 350 Thr Asn Thr Gly Phe Gly Ala Val Gly Ser Thr Leu Phe Gly Asn Asn 355 360 365 Lys Leu Thr Thr Phe Gly Ser Ser Thr Thr Ser Ala Pro Ser Phe Gly 370 375 380 Thr Thr Ser Gly Gly Leu Phe Gly Phe Gly Thr Asn Thr Ser Gly Asn 385 390 395 400 Ser lie Phe Gly Ser Lys Pro Ala Pro Gly Thr Leu Gly Thr Gly Leu 405 410 415 Gly Ala Gly Phe Gly Thr Ala Leu Gly Ala Gly Gin Ala Ser Leu Phe 420 425 430 Gly Asn Asn Gin Pro Lys lie Gly Gly Pro Leu Gly Thr Gly Ala Phe 435 440 445 Gly Ala Pro Gly Phe Asn Thr Thr Thr Ala Thr Leu Gly Phe Gly Ala 450 455 460 Pro Gin Ala Pro Val Ala Leu Thr Asp Pro Asn Ala Ser Ala Ala Gin 465 470 475 480 Gin Ala Val Leu Gin Gin His lie Asn Ser Leu Thr Tyr Ser Pro Phe 485 490 495 Gly Asp Ser Pro Leu Phe Arg Asn Pro Met Ser Asp Pro Lys Lys Lys 500 505 510 Glu Glu Arg Leu Lys Pro Thr Asn Pro Ala Ala Gin Lys Ala Leu Thr 515 520 525 Thr Pro Thr His Tyr Lys Leu Thr Pro Arg Pro Ala Thr Arg Val Arg 530 535 540 Pro Lys Ala Leu Gin Thr Thr Gly Thr Ala Lys Ser His Leu Phe Asp 545 550 555 560 Gly Leu Asp Asp Asp Glu Pro Ser Leu Ala Asn Gly Ala Phe Met Pro 565 570 575 Lys Lys Ser lie Lys Lys Leu Val Leu Lys Asn Leu Asn Asn Ser Asn 580 585 590 Leu Phe Ser Pro Val Asn Arg Asp Ser Glu Asn Leu Ala Ser Pro Ser 595 600 605 Glu Tyr Pro Glu Asn Gly Glu Arg Phe Ser Phe Leu Ser Lys Pro Val 610 615 620 Asp Glu Asn His Gin Gin Asp Gly Asp Glu Asp Ser Leu Val Ser His 625 630 635 640 Phe Tyr Thr Asn Pro lie Ala Lys Pro lie Pro Gin Thr Pro Glu Ser 645 650 655 Ala Gly Asn Lys His Ser Asn Ser Asn Ser Val Asp Asp Thr lie Val 660 665 670 Ala Leu Asn Met Arg Ala Ala Leu Arg Asn Gly Leu Glu Gly Ser Ser 675 680 685 Glu Glu Thr Ser Phe His Asp Glu Ser Leu Gin Asp Asp Arg Glu Glu 690 695 700 lie Glu Asn Asn Ser Tyr His Met His Pro Ala Gly lie lie Leu Thr 705 710 715 720 Lys Val Gly Tyr Tyr Thr lie Pro Ser Met Asp Asp Leu Ala Lys lie 725 730 735 Thr Asn Val Phe Gly Glu Cys lie Val Ser Asp Phe Thr lie Gly Arg 740 745 750 Lys Gly Tyr Gly Ser lie Tyr Phe Glu Gly Asp Val Asn Leu Thr Asn 755 760 765 Leu Asn Leu Asp Asp lie Val His lie Arg Arg Lys Glu Val Val Val 770 775 780 Tyr Leu Asp Asp Asn Gin Lys Pro Pro Val Gly Glu Gly Leu Asn Arg 785 790 795 800 Lys Ala Glu Val Thr Leu Asp Gly Val Trp Pro Thr Asp Lys Thr Ser 805 810 815 Arg Cys Leu lie Lys Ser Pro Asp Arg Leu Ala Asp lie Asn Tyr Glu 820 825 830 Gly Arg Leu Glu Ala Val Ser Arg Lys Gin Gly Ala Gin Phe Lys Glu 835 840 845 Tyr Arg Pro Glu Thr Gly Ser Trp Val Phe Lys Val Ser His Phe Ser 850 855 860 Lys Tyr Gly Leu Gin Asp Ser Asp Glu Glu Glu Glu Glu His Pro Ser 865 870 875 880 Lys Thr Ser Thr Lys Lys Leu Lys Thr Ala Pro Leu Pro Pro Ala Ser 885 890 895 Gin Thr Thr Pro Leu Gin Met Ala Leu Asn Gly Lys Pro Ala Pro Pro 900 905 910 Pro Gin Ser Gin Ser Pro Glu Val Glu Gin Leu Gly Arg Val Val Glu 915 920 925 Leu Asp Ser Asp Met Val Asp lie Thr Gin Glu Pro Val Leu Asp Thr 930 935 940 Met Leu Glu Glu Ser Met Pro Glu Asp Gin Glu Pro Val Ser Ala Ser 945 950 955 960 Thr His lie Ala Ser Ser Leu Gly lie Asn Pro His Val Leu Gin lie 965 970 975 Met Lys Ala Ser Leu Leu Thr Asp Glu Glu Asp Val Asp Met Ala Leu 980 985 990 Asp Gin Arg Phe Ser Arg Leu Pro Ser Lys Ala Asp Thr Ser Gin Glu 995 1000 1005 lie Cys Ser Pro Arg Leu Pro lie Ser Ala Ser His Ser Ser Lys Thr 1010 1015 1020 Arg Ser Leu Val Gly Gly Leu Leu Gin Ser Lys Phe Thr Ser Gly Ala 1025 1030 1035 1040 Phe Leu Ser Pro Ser Val Ser Val Gin Glu Cys Arg Thr Pro Arg Ala 1045 1050 1055 Ala Ser Leu Met Asn lie Pro Ser Thr Ser Ser Trp Ser Val Pro Pro 1060 1065 1070 Pro Leu Thr Ser Val Phe Thr Met Pro Ser Pro Ala Pro Glu Val Pro 1075 1080 1085 Leu Lys Thr Val Gly Thr Arg Arg Gin Leu Gly Leu Val Pro Arg Glu 1090 1095 1100 Lys Ser Val Thr Tyr Gly Lys Gly Lys Leu Leu Met Asp Met Ala Leu 1105 1110 1115 1120 Phe Met Gly Arg Ser Phe Arg Val Gly Trp Gly Pro Asn Trp Thr Leu 1125 1130 1135 Ala Asn Ser Gly Glu Gin Leu Asn Gly Ser His Glu Leu Glu Asn His 1140 1145 1150 Gin lie Ala Asp Ser Met Glu Phe Gly Phe Leu Pro Asn Pro Val Ala 1155 1160 1165 Val Lys Pro Leu Thr Glu Ser Pro Phe Lys Val His Leu Glu Lys Leu 1170 1175 1180 Ser Leu Arg Gin Arg Lys Pro Asp Glu Asp Met Lys Leu Tyr Gin Thr 1185 1190 1195 1200 Pro Leu Glu Leu Lys Leu Lys His Ser Thr Val His Val Asp Glu Leu 1205 1210 1215 Cys Pro Leu lie Val Pro Asn Leu Gly Val Ala Val lie His Asp Tyr 1220 1225 1230 Ala Asp Trp Val Lys Glu Ala Ser Gly Asp Leu Pro Glu Ala Gin lie 1235 1240 1245 Val Lys His Trp Ser Leu Thr Trp Thr Leu Cys Glu Ala Leu Trp Ala 1250 1255 1260 His Leu Lys Glu Leu Asp Ser Gin Leu Asn Glu Pro Arg Glu Tyr lie 1265 1270 1275 1280 Gin lie Leu Glu Arg Arg Arg Ala Phe Ser Arg Trp Leu Ser Cys Thr 1285 1290 1295 Ala Thr Pro Gin lie Glu Glu Glu Val Ser Leu Thr Gin Lys Asn Ser 1300 1305 1310 Pro Val Glu Ala Val Phe Ser Tyr Leu Thr Gly Lys Arg lie Ser Glu 1315 1320 1325 Ala Cys Ser Leu Ala Gin Gin Ser Gly Asp His Arg Leu Ala Leu Leu 1330 1335 1340 Leu Ser Gin Phe Val Gly Ser Gin Ser Val Arg Glu Leu Leu Thr Met 1345 1350 1355 1360 Gin Leu Val Asp Trp His Gin Leu Gin Ala Asp Ser Phe lie Gin Asp 1365 1370 1375 Glu Arg Leu Arg lie Phe Ala Leu Leu Ala Gly Lys Pro Val Trp Gin 1380 1385 1390 Leu Ser Glu Lys Lys Gin lie Asn Val Cys Ser Gin Leu Asp Trp Lys 1395 1400 1405 Arg Ser Leu Ala lie His Leu Trp Tyr Leu Leu Pro Pro Thr Ala Ser 1410 1415 1420 lie Ser Arg Ala Leu Ser Met Tyr Glu Glu Ala Phe Gin Asn Thr Ser 1425 1430 1435 1440 Asp Ser Asp Arg Tyr Ala Cys Ser Pro Leu Pro Ser Tyr Leu Glu Gly 1445 1450 1455 Ser Gly Cys Val lie Ala Glu Glu Gin Asn Ser Gin Thr Pro Leu Arg 1460 1465 1470 Asp Val Cys Phe His Leu Leu Lys Leu Tyr Ser Asp Arg His Tyr Asp 1475 1480 1485 Leu Asn Gin Leu Leu Glu Pro Arg Ser lie Thr Ala Asp Pro Leu Asp 1490 1495 1500 Tyr Arg Leu Ser Trp His Leu Trp Glu Val Leu Arg Asp Leu Lys Tyr 1505 1510 1515 1520 Thr His Leu Ser Ala Gin Cys Glu Gly Val Leu Gin Ala Ser Tyr Ala 1525 1530 1535 Gly Gin Leu Glu Ser Glu Gly Leu Trp Glu Trp Ala lie Phe Val Leu 1540 1545 1550 Leu His lie Asp Asn Ser Gly lie Arg Glu Lys Ala Val Arg Glu Leu 1555 1560 1565 Leu Thr Arg His Cys Gin Leu Leu Glu Thr Pro Glu Ser Trp Ala Lys 1570 1575 1580 Glu Thr Phe Leu Thr Gin Lys Leu Arg Val Pro Ala Lys Trp lie His 1585 1590 1595 1600 Glu Ala Lys Ala Val Arg Ala His Met Glu Ser Asp Lys His Leu Glu 1605 1610 1615 Ala Leu Cys Leu Phe Lys Ala Glu His Trp Asn Arg Cys His Lys Leu 1620 1625 1630 lie lie Arg His Leu Ala Ser Asp Ala lie lie Asn Glu Asn Tyr Asp 1635 1640 1645 to. Tyr Leu Lys Gly Phe Leu Glu Asp Leu Ala Pro Pro Glu Arg Ser Ser 1650 1655 1660 Leu lie Gin Asp Trp Glu Thr Ser Gly Leu Val Tyr Leu Asp Tyr lie 1665 1670 1675 1680 S'Arg Val lie Glu Met Leu Arg His lie Gin Gin Val Glu His Phe Asn 1685 1690 1695 Asp Ser Asn lie Val Gin Val Met Thr Trp Ser Ser Tyr Thr Ser Lys 1700 1705 1710 *too <210> 24 <211> 599 <212> PRT <213> Mus musculus <300> <301> De Coignac, A. B.

<302> cDNA cloning and expression analysis of the murine ribonuclease L inhibitor <303> Gene <304> 1998 <305> 209 <306> 149-156 <313> 1 TO 599 <400> 24 Met Ala Asp Lys Leu Thr Arg lie Ala lie Val Asn His Asp Lys Cys 1 5 10 Lys Pro Lys Lys Cys Arg Gin Glu Cys Lys Lys Ser Cys Pro Val Val 25 Arg Met Gly Lys Leu Cys lie Glu Val Thr Pro Gin Ser Lys lie Ala 40 Trp lie Ser Glu Thr Leu Cys lie Gly Cys Gly lie Cys lie Lys Lys 55 Cys Pro Phe Gly Ala Leu Ser lie Val Asn Leu Pro Ser Asn Leu Glu 70 75 Lys Glu Thr Thr His Arg Tyr Cys Ala Asn Ala Phe Lys Leu His Arg 90 Leu Pro lie Pro Arg Pro Gly Glu Val Leu Gly Leu Val Gly Thr Asn 100 105 110 Gly lie Gly Lys Ser Thr Ala Leu Lys lie Leu Ala Gly Lys Gin Lys 115 120 125 Pro Asn Leu Gly Lys Tyr Asp Asp Pro Pro Asp Trp Gin Glu lie Leu 130 135 140 Thr Tyr Phe Arg Gly Ser Glu Leu Lys Asn Tyr Phe Thr Thr lie Leu 145 150 155 160 Glu Asp Asp Leu Lys Ala lie lie Lys Pro Gin Tyr Val Asp Gin lie 165 170 175 Pro Lys Ala Ala Lys Gly Thr Val Gly Ser lie Leu Asp Arg Lys Asp 180 185 190 Glu Thr Lys Thr Gin Ala lie Val Cys Gin Gin Leu Asp Leu Thr His 195 200 205 Leu Lys Glu Arg Asn Val Glu Asp Leu Ser Gly Gly Glu Leu Gin Arg 210 215 220 Phe Ala Cys Ala Val Val Cys lie Gin Lys Ala Asp lie Phe Met Phe 225 230 235 240 Asp Glu Pro Ser Ser Tyr Leu Asp Val Lys Gin Arg Leu Lys Ala Ala 245 250 255 lie Thr lie Arg Ser Leu lie Asn Pro Asp Arg Tyr lie lie Val Val 260 265 270 Glu His Asp Leu Ser Val Leu Asp Tyr Leu Ser Asp Phe lie Cys Cys 275 280 285 Leu Tyr Gly Val Pro Ser Ala Tyr Gly Val Val Thr Met Pro Phe Ser 290 295 300 Val Arg Glu Gly lie Asn lie Phe Leu Asp Gly Tyr Val Pro Thr Glu 305 310 315 320 Asn Leu Arg Phe Arg Asp Ala Ser Leu Val Phe Lys Val Ala Glu Thr 325 330 335 Ala Asn Glu Glu Glu Val Lys Lys Met Cys Met Tyr Lys Tyr Pro Gly 340 345 350 Met Lys Lys Lys Met Gly Glu Phe Glu Leu Ala lie Val Ala Gly Glu 355 360 365 Phe Thr Asp Ser Glu lie Met Val Met Leu Gly Glu Asn Gly Thr Gly 370 375 380 Lys Thr Thr Phe lie Arg Met Leu Ala Gly Arg Leu Lys Pro Asp Glu 385 390 395 400 Gly Gly Glu Val Pro Val Leu Asn Val Ser Tyr Lys Pro Gin Lys lie 405 410 415 Ser Pro Lys Ser Thr Gly Ser Val Arg Gin Leu Leu His Glu Lys lie 420 425 430 Arg Asp Ala Tyr Thr His Pro Gin Phe Val Thr Asp Val Met Lys Pro 435 440 445 Leu GIn lie Glu Asn lie lie Asp GIn Glu Val Gin Thr Leu Ser Gly 450 455 460 Gly Glu Leu Gin Arg Val Ala Leu Ala Leu Cys Leu Gly Lys Pro Ala 465 470 475 480 Asp Val Tyr Leu lie Asp Glu Pro Ser Ala Tyr Leu Asp Ser Glu Gin 485 490 495 Arg Leu Met Ala Ala Arg Val Val Lys Arg Phe lie Leu His Ala Lys 500 505 510 Lys Thr Ala Phe Val Val Glu His Asp Phe lie Met Ala Thr Tyr Leu 515 520 525 .Ala Asp Arg Val lie Val Phe Asp Gly Val Pro Ser Lys Asn Thr Val S 530 535 540 Ala Asn Ser Pro Gin Thr Leu Leu Ala Gly Met Asn Lys Phe Leu Ser 545 550 555 560 Gin Leu Glu lie Thr Phe Arg Arg Asp Pro Asn Asn Tyr Arg Pro Arg 565 570 575 lie Asn Lys Leu Asn Ser lie Lys Asp Val Glu Gin Lys Lys Ser Gly 580 585 590 Asn Tyr Phe Phe Leu Asp Asp 595 <210> <211> 599 <212> PRT <213> Homo sapiens <300> <301> Bisbal, C.

<302> Cloning and characterization of a RNAse L inhibitor. A new component of the interferon-regulated 2-5A pathway <303> J. Biol. Chem.

<304> 1995 <305> 270 <306> 13308-13317 <313> 1 TO 599 <400> Met Ala Asp Lys Leu Thr Arg lie Ala lie Val Asn His Asp Lys Cys 1 5 10 Lys Pro Lys Lys Cys Arg Gin Glu Cys Lys Lys Ser Cys Pro Val Val 25 Arg Met Gly Lys Leu Cys lie Glu Val Thr Pro Gin Ser Lys lie Ala 40 Trp lie Ser Glu Thr Leu Cys lie Gly Cys Gly lie Cys lie Lys Lys 55 Cys Pro Phe Gly Ala Leu Ser lie Val Asn Leu Pro Ser Asn Leu Glu 65 70 75 Lys Glu Thr Thr His Arg Tyr Cys Ala Asn Ala Phe Lys Leu His Arg 85 90 Leu Pro lie Pro Arg Pro Gly Glu Val Leu Gly Leu Val Gly Thr Asn 100 105 110 Gly lie Gly Lys Ser Ala Ala Leu Lys lie Leu Ala Gly Lys Gin Lys 115 120 125 Pro Asn Leu Gly Lys Tyr Asp Asp Pro Pro Asp Trp Gin Glu lie Leu 130, 135 140 Thr Tyr Phe Arg Gly Ser Glu Leu Gin Asn Tyr Phe Thr Lys lie Leu 145 150 155 160 Glu Asp Asp Leu Lys Ala lie lie Lys Pro Gin Tyr Val Ala Arg Phe 165 170 175 Leu Arg Leu Ala Lys Gly Thr Val Gly Ser lie Leu Asp Arg Lys Asp 180 185 190 Glu Thr Lys Thr Gin Ala lie Val Cys Gin Gin Leu Asp Leu Thr His 195 200 205 Leu Lys Glu Arg Asn Val Glu Asp Leu Ser Gly Gly Glu Leu Gin Arg 210 215 220 Phe Ala Cys Ala Val Val Cys lie Gin Lys Ala Asp lie Phe Met Phe 225 230 235 240 Asp Glu Pro Ser Ser Tyr Leu Asp Val Lys Gin Arg Leu Lys Ala Ala 245 250 255 lie Thr lie Arg Ser Leu lie Asn Pro Asp Arg Tyr lie lie Val Val 260 265 270 Glu His Asp Leu Ser Val Leu Asp Tyr Leu Ser Asp Phe lie Cys Cys 275 280 285 Leu Tyr Gly Val Pro Ser Ala Tyr Gly Val Val Thr Met Pro Phe Ser 290 295 300 Val Arg Glu Gly lie Asn lie Phe Leu Asp Gly Tyr Val Pro Thr Glu 305 310 315 320 Asn Leu Arg Phe Arg Asp Ala Ser Leu Val Phe Lys Val Ala Glu Thr 325 330 335 Ala Asn Glu Glu Glu Val Lys Lys Met Cys Met Tyr Lys Tyr Pro Gly 340 345 350 Met Lys Lys Lys Met Gly Glu Phe Glu Leu Ala lie Val Ala Gly Glu 355 360 365 Phe Thr Asp Ser Glu lie Met Val Met Leu Gly Glu Asn Gly Thr Gly 370 375 380 Lys Thr Thr Phe lie Arg Met Leu Ala Gly Arg Leu Lys Pro Asp Glu 385 390 395 400 Gly Gly Glu Val Pro Val Leu Asn Val Ser Tyr Lys Pro Gin Lys lie 405 410 415 Ser Pro Lys Ser Thr Gly Ser Val Arg Gin Leu Leu His Glu Lys lie 420 425 430 Arg Asp Ala Tyr Thr His Pro Gin Phe Val Thr Asp Val Met Lys Pro 435 440 445 Leu Gin lie Glu Asn lie lie Asp Gin Glu Val Gin Thr Leu Ser Gly 450 455 460 Gly Glu Leu Gin Arg Val Arg Leu Arg Leu Cys Leu Gly Lys Pro Ala 465 470 475 480 Asp Val Tyr Leu lie Asp Glu Pro Ser Ala Tyr Leu Asp Ser Glu Gin 485 490 495 Arg Leu Met Ala Ala Arg Val Val Lys Arg Phe lie Leu His Ala Lys 500 505 510 Lys Thr Ala Phe Val Val Glu His Asp Phe lie Met Ala Thr Tyr Leu 515 520 525 Ala Asp Arg Val lie Val Phe Asp Gly Val Pro Ser Lys Asn Thr Val 530 535 540 Ala Asn Ser Pro Gin Thr Leu Leu Ala Gly Met Asn Lys Phe Leu Ser 545 550 555 560 Gin Leu Glu lie Thr Phe Arg Arg Asp Pro Asn Asn Tyr Arg Pro Arg 565 570 575 lie Asn Lys Leu Asn Ser lie Lys Asp Val Glu Gin Lys Lys Ser Gly 580 585 590 Asn Tyr Phe Phe Leu Asp Asp 595 <210> 26 <211> 599 <212> PRT <213> Mus musculus <400> 26 Met Ala Asp Lys Leu Thr Arg lie Ala lie Val Asn His Asp Lys Cys 1 5 10 Lys Pro Lys Lys Cys Arg Gin Glu Cys Lys Lys Ser Cys Pro Val Val 25 Arg Met Gly Lys Leu Cys lie Glu Val Thr Pro Gin Ser Lys lie Ala 40 Trp lie Ser Glu Thr Leu Cys lie Gly Cys Gly lie Cys lie Lys Lys 55 Cys Pro Phe Gly Ala Leu Ser lie Val Asn Leu Pro Ser Asn Leu Glu 65 70 75 Lys Glu Thr Thr His Arg Tyr Cys Ala Asn Ala Phe Lys Leu His Arg 85 90 Leu Pro lie Pro Arg Pro Gly Glu Val Leu Gly Leu Val Gly Thr Asn 100 105 110 Gly lie Gly Lys Ser Thr Ala Leu Lys lie Leu Ala Gly Lys Gin Lys 115 120 125 Pro Asn Leu Gly Lys Tyr Asp Asp Pro Pro Asp Trp Gin Glu lie Leu 130 135 140 Thr Tyr Phe Arg Gly Ser Glu Leu Gin Asn Tyr Phe Thr Lys lie Leu 145 150 155 160 Glu Asp Asp Leu Lys Ala lie lie Lys Pro Gin Tyr Val Asp Gin lie 165 170 175 Pro Lys Ala Ala Lys Gly Thr Val Gly Ser lie Leu Asp Arg Lys Asp 180 185 190 Glu Thr Lys Thr Gin Ala lie Val Cys Gin Gin Leu Asp Leu Thr His 195 200 205 Leu Lys Glu Arg Asn Val Glu Asp Leu Ser Gly Gly Glu Leu Gin Arg 210 215 220 Phe Ala Cys Ala Val Val Cys lie Gin Lys Ala Asp lie Phe Met Phe 225 230 235 240 Asp Glu Pro Ser Ser Tyr Leu Asp Val Lys Gin Arg Leu Lys Ala Ala 245 250 255 lie Thr lie Arg Ser Leu lie Asn Pro Asp Arg Tyr lie lie Val Val 260 265 270 Glu His Asp Leu Ser Val Leu Asp Tyr Leu Ser Asp Phe lie Cys Cys 275 280 285 Leu Tyr Gly Val Pro Ser Ala Tyr Gly Val Val Thr Met Pro Phe Ser 290 295 300 Val Arg Glu Gly lie Asn lie Phe Leu Asp Gly Tyr Val Pro Thr Glu 305 310 315 320 Asn Leu Arg Phe Arg Asp Ala Ser Leu Val Phe Lys Val Ala Glu Thr 325 330 335 Ala Asn Glu Glu Glu Val Lys Lys Met Cys Met Tyr Lys Tyr Pro Gly 340 345 350 Met Lys Lys Lys Met Gly Glu Phe Glu Leu Ala lie Val Ala Gly Glu 355 360 365 Phe Thr Asp Ser Glu lie Met Val Met Leu Gly Glu Asn Gly Thr Gly 370 375 380 Lys Thr Thr Phe lie Arg Met Leu Ala Gly Arg Leu Lys Pro Asp Glu S. 385 390 395 400 Gly Gly Glu Val Pro Val Leu Asn Val Ser Tyr Lys Pro Gin Lys lie 405 410 415 Ser Pro Lys Ser Thr Gly Ser Val Arg Gin Leu Leu His Glu Lys lie 420 425 430 Arg Asp Ala Tyr Thr His Pro Gin Phe Val Thr Asp Val Met Lys Pro 435 440 445 Leu Gin lie Glu Asn lie lie Asp Gin Glu Val Gin Thr Leu Ser Gly S450 455 460 Gly Glu Leu Gin Arg Val Ala Leu Ala Leu Cys Leu Gly Lys Pro Ala 465 470 475 480 Asp Val Tyr Leu lie Asp Glu Pro Ser Ala Tyr Leu Asp Ser Glu Gin 485 490 495 Arg Leu Met Ala Ala Arg Val Val Lys Arg Phe lie Leu His Ala Lys 500 505 510 Lys Thr Ala Phe Val Val Glu His Asp Phe lie Met Ala Thr Tyr Leu 515 520 525 Ala Asp Arg Val lie Val Phe Asp Gly Val Pro Ser Lys Asn Thr Val 530 535 540 Ala Asn Ser Pro Gin Thr Leu Leu Ala Gly Met Asn Lys Phe Leu Ser 545 550 555 560 Gin Leu Glu lie Thr Phe Arg Arg Asp Pro Asn Asn Tyr Arg Pro Arg 565 570 575 lie Asn Lys Leu Asn Ser lie Lys Asp Val Glu Gin Lys Lys Ser Gly 580 585 590 Asn Tyr Phe Phe Leu Asp Asp 595 <210> 27 <211> 599 <212> PRT <213> Homo sapiens <400> 27 Met Ala Asp Lys Leu Thr Arg lie Ala lie Val Asn His Asp Lys Cys 1 5 10 Lys Pro Lys Lys Cys Arg Gin Glu Cys Lys Lys Ser Cys Pro Val Val 25 Arg Met Gly Lys Leu Cys lie Glu Val Thr Pro Gin Ser Lys lie Ala 40 Trp lie Ser Glu Thr Leu Cys lie Gly Cys Gly lie Cys lie Lys Lys 50 55 Cys Pro Phe Gly Ala Leu Ser lie Val Asn Leu Pro Ser Asn Leu Glu .65 70 75 Lys Glu Thr Thr His Arg Tyr Cys Ala Asn Ala Phe Lys Leu His Arg 90 Leu Pro lie Pro Arg Pro Gly Glu Val Leu Gly Leu Val Gly Thr Asn 100 105 110 Gly lie Gly Lys Ser Thr Ala Leu Lys lie Leu Ala Gly Lys Gin Lys 115 120 125 Pro Asn Leu Gly Lys Tyr Asp Asp Pro Pro Asp Trp Gin Glu lie Leu 130 135 140 Thr Tyr Phe Arg Gly Ser Glu Leu Gin Asn Tyr Phe Thr Lys lie Leu 145 150 155 160 Glu Asp Asp Leu Lys Ala lie lie Lys Pro Gin Tyr Val Asp Gin lie 165 170 175 Pro Lys Ala Ala Lys Gly Thr Val Gly Ser lie Leu Asp Arg Lys Asp 180 185 190 Glu Thr Lys Thr Gin Ala lie Val Cys Gin Gin Leu Asp Leu Thr His 195 200 205 Leu Lys Glu Arg Asn Val Glu Asp Leu Ser Gly Gly Glu Leu Gin Arg 210 215 220 Phe Ala Cys Ala Val Val Cys lie Gin Lys Ala Asp lie Phe Met Phe 225 230 235 240 Asp Glu Pro Ser Ser Tyr Leu Asp Val Lys Gin Arg Leu Lys Ala Ala 245 250 255 lie Thr lie Arg Ser Leu lie Asn Pro Asp Arg Tyr lie lie Val Val 260 265 270 Glu His Asp Leu Ser Val Leu Asp Tyr Leu Ser Asp Phe lie Cys Cys 275 280 285 Leu Tyr Gly Val Pro Ser Ala Tyr Gly Val Val Thr Met Pro Phe Ser 290 295 300 Val Arg Glu Gly lie Asn lie Phe Leu Asp Gly Tyr Val Pro Thr Glu 305 310 315 320 Asn Leu Arg Phe Arg Asp Ala Ser Leu Val Phe Lys Val Ala Glu Thr 325 330 335 Ala Asn Glu Glu Glu Val Lys Lys Met Cys Met Tyr Lys Tyr Pro Gly 340 345 350 Met Lys Lys Lys Met Gly Glu Phe Glu Leu Ala lie Val Ala Gly Glu 355 360 365 Phe Thr Asp Ser Glu lie Met Val Met Leu Gly Glu Asn Gly Thr Gly 370 375 380 Lys Thr Thr Phe lie Arg Met Leu Ala Gly Arg Leu Lys Pro Asp Glu 385 390 395 400 Gly Gly Glu Val Pro Val Leu Asn Val Ser Tyr Lys Pro Gin Lys lie 405 410 415 Ser Pro Lys Ser Thr Gly Ser Val Arg Gin Leu Leu His Glu Lys lie 420 425 430 Arg Asp Ala Tyr Thr His Pro Gin Phe Val Thr Asp Val Met Lys Pro 435 440 445 Leu Gin lie Glu Asn lie lie Asp Gin Glu Val Gin Thr Leu Ser Gly 450 455 460 Gly Glu Leu Gin Arg Val Ala Leu Ala Leu Cys Leu Gly Lys Pro Ala 465 470 475 480 Asp Val Tyr Leu lie Asp Glu Pro Ser Ala Tyr Leu Asp Ser Glu Gin 485 490 495 Arg Leu Met Ala Ala Arg Val Val Lys Arg Phe lie Leu His Ala Lys 500 505 510 Lys Thr Ala Phe Val Val Glu His Asp Phe lie Met Ala Thr Tyr Leu 515 520 525 Ala Asp Arg Val lie Val Phe Asp Gly Val Pro Ser Lys Asn Thr Val 530 535 540 Ala Asn Ser Pro Gin Thr Leu Leu Ala Gly Met Asn Lys Phe Leu Ser 545 550 555 560 Gin Leu Glu lie Thr Phe Arg Arg Asp Pro Asn Asn Tyr Arg Pro Arg 565 570 575 lie Asn Lys Leu Asn Ser lie Lys Asp Val Glu Gin Lys Lys Ser Gly 580 585 590 Asn Tyr Phe Phe Leu Asp Asp 595 <210> 28 <211> 614 <212> PRT <213> Mus musculus <300> <301> Lemaire, L.

<302> High-level expression in male germ cells of murine p68 RNA helicase mRNA <303> Life Sci.

<304> 1993 <305> 52 <306> 917-926 <313> 1 TO614 <400> 28 Met Ser Ser Tyr Ser Ser Asp Arg Asp Arg Gly Arg Asp Arg Gly Phe 1 5 10 Gly Ala Pro Arg Phe Gly Gly Ser Arg Thr Gly Pro Leu Ser Gly Lys 20 25 Lys Phe Gly Asn Pro Gly Glu Lys Leu Val Lys Lys Lys Trp Asn Leu 40 Asp Glu Leu Pro Lys Phe Glu Lys Asn Phe Tyr Gin Glu His Pro Asp 55 Leu Ala Arg Arg Thr Ala Gin Glu Val Asp Thr Tyr Arg Arg Ser Lys 65 70 75 Glu lie Thr Val Arg Gly His Asn Cys Pro Lys Pro Val Leu Asn Phe 90 Tyr Glu Ala Asn Phe Pro Ala Asn Val Met Asp Val lie Ala Arg His 100 105 110 Asn Phe Thr Glu Pro Thr Ala lie Gin Ala Gin Gly Trp Pro Val Ala 115 120 125 Leu Ser Gly Leu Asp Met Val Gly Val Ala Gin Thr Gly Ser Gly Lys 130 135 140 Thr Leu Ser Tyr Leu Leu Pro Ala lie Val His lie Asn His His Pro 145 150 155 160 Phe Leu Glu Arg Gly Asp Gly Pro lie Cys Leu Val Leu Ala Pro Thr 165 170 175 Arg Glu Leu Ala Gin Gin Val Gin Gin Val Ala Ala Glu Tyr Cys Arg 180 185 190 Ala Cys Arg Leu Lys Ser Thr Cys lie Tyr Gly Gly Ala Pro Lys Gly 195 200 205 Pro Gin lie Arg Asp Leu Glu Arg Gly Val Glu lie Cys lie Ala Thr 210 215 220 Pro Gly Arg Leu lie Asp Phe Leu Glu Cys Gly Lys Thr Asn Leu Arg 225 230 235 240 Arg Thr Thr Tyr Leu Val Leu Asp Glu Ala Asp Arg Met Leu Asp Met 245 250 255 Gly Phe Glu Pro Gin lie Arg Lys lie Val Asp Gin lie Arg Pro Asp 260 265 270 Arg Gin Thr Leu Met Trp Ser Ala Thr Trp Pro Lys Glu Val Arg Gin 275 280 285 Leu Ala Glu Asp Phe Leu Lys Asp Tyr lie His lie Asn lie Gly Ala 290 295 300 Leu Glu Leu Ser Ala Asn His Asn lie Leu Gin lie Val Asp Val Cys 305 310 315 320 His Asp Val Glu Lys Asp Glu Lys Leu lie Arg Leu Met Glu Glu lie 325 330 335 Met Ser Glu Lys Glu Asn Lys Thr lie Val Phe Val Glu Thr Lys Arg 340 345 350 Arg Cys Asp Glu Leu Thr Arg Lys Met Arg Arg Asp Gly Trp Pro Ala 355 360 365 Met Gly lie His Gly Asp Lys Ser Gin Gin Glu Arg Asp Trp Val Leu 370 375 380 Asn Glu Phe Lys His Gly Lys Ala Pro lie Leu lie Ala Thr Asp Val S" 385 390 395 400 Ala Ser Arg Gly Leu Asp Val Glu Asp Val Lys Phe Val lie Asn Tyr 405 410 415 Asp Tyr Pro Asn Ser Ser Glu Asp Tyr lie His Arg lie Gly Arg Thr 420 425 430 Ala Arg Ser Thr Lys Thr Gly Thr Ala Tyr Thr Phe Phe Thr Pro Asn 435 440 445 Asn lie Lys Gin Val Ser Asp Leu lie Ser Val Leu Arg Glu Ala Asn 450 455 460 Gin Ala lie Asn Pro Lys Leu Leu Gin Leu Val Glu Asp Arg Gly Ser 465 470 475 480 Gly Arg Ser Arg Gly Arg Gly Gly Met Lys Asp Asp Arg Arg Asp Arg 485 490 495 Tyr Ser Ala Gly Lys Arg Gly Gly Phe Asn Thr Phe Arg Asp Arg Glu 500 505 510 Asn Tyr Asp Arg Gly Tyr Ser Asn Leu Leu Lys Arg Asp Phe Gly Ala 515 520 525 Lys Thr Gin Asn Gly Val Tyr Ser Ala Ala Asn Tyr Thr Asn Gly Ser 530 535 540 Phe Gly Ser Asn Phe Val Ser Ala Gly lie Gin Thr Ser Phe Arg Thr 545 550 555 560 Gly Asn Pro Thr Gly Thr Tyr Gin Asn Gly Tyr Asp Ser Thr Gin Gin 565 570 575 Tyr Gly Ser Asn Val Ala Asn Met His Asn Gly Met Asn Gin Gin Ala 580 585 590 Tyr Ala Tyr Pro Val Pro Gin Pro Ala Pro Met lie Gly Tyr Pro Met 595 600 605 Pro Thr Gly Tyr Ser Gin 610 9* S <210> 29 <211>614 <212> PRT <213> Homo sapiens <300> <301> Ford, M. J.

<302> Nuclear protein with sequence homology to translation initiation factor elF-4A <303> Nature <304> 1988 <305> 332 <306> 736-738 <313> 1 TO 614 <400> 29 Met Ser Gly Tyr Ser Ser Asp Arg Asp Arg Gly Arg Asp Arg Gly Phe 1 5 10 Gly Ala Pro Arg Phe Gly Gly Ser Arg Ala Gly Pro Leu Ser Gly Lys 25 Lys Phe Gly Asn Pro Gly Glu Lys Leu Val Lys Lys Lys Trp Asn Leu 40 Asp Glu Leu Pro Lys Phe Glu Lys Asn Phe Tyr Gin Glu His Pro Asp 55 Leu Ala Arg Arg Thr Ala Gin Glu Val Glu Thr Tyr Arg Arg Ser Lys 70 75 Glu lie Thr Val Arg Gly His Asn Cys Pro Lys Pro Val Leu Asn Phe 90 Tyr Glu Ala Asn Phe Pro Ala Asn Val Met Asp Val lie Ala Arg Gin 100 105 110 Asn Phe Thr Glu Pro Thr Ala lie Gin Ala Gin Gly Trp Pro Val Ala 115 120 125 Leu Ser Gly Leu Asp Met Val Gly Val Ala Gin Thr Gly Ser Gly Lys 130 135 140 Thr Leu Ser Tyr Leu Leu Pro Ala lie Val His lie Asn His Gin Pro 145 150 155 160 Phe Leu Glu Arg Gly Asp Gly Pro lie Cys Leu Val Leu Ala Pro Thr 165 170 175 Arg Glu Leu Ala Gin Gin Val Gin Gin Val Ala Ala Glu Tyr Cys Arg 180 185 190 Ala Cys Arg Leu Lys Ser Thr Cys lie Tyr Gly Gly Ala Pro Lys Gly 195 200 205 Pro Gin lie Arg Asp Leu Glu Arg Gly Val Glu lie Cys lie Ala Thr 210 215 220 a Pro Gly Arg Leu lie Asp Phe Leu Glu Cys Gly Lys Thr Asn Leu Arg .225 230 235 240 Arg Thr Thr Tyr Leu Val Leu Asp Glu Ala Asp Arg Met Leu Asp Met 245 250 255 Gly Phe Glu Pro Gin lie Arg Lys lie Val Asp Gin lie Arg Pro Asp 260 265 270 Arg Gin Thr Leu Met Trp Ser Ala Thr Trp Pro Lys Glu Val Arg Gin 275 280 285 Leu Ala Glu Asp Phe Leu Lys Asp Tyr lie His lie Asn lie Gly Ala 290 295 300 Leu Glu Leu Ser Ala Asn His Asn lie Leu Gin lie Val Asp Val Cys 305 310 315 320 His Asp Val Glu Lys Asp Glu Lys Leu lie Arg Leu Met Glu Glu lie 325 330 335 Met Ser Glu Lys Glu Asn Lys Thr lie Val Phe Val Glu Thr Lys Arg 340 345 350 Arg Cys Asp Glu Leu Thr Arg Lys Met Arg Arg Asp Gly Trp Pro Ala 355 360 365 Met Gly lie His Gly Asp Lys Ser Gin Gin Glu Arg Asp Trp Val Leu 370 375 380 Asn Glu Phe Lys His Gly Lys Ala Pro lie Leu lie Ala Thr Asp Val 385 390 395 400 Ala Ser Arg Gly Leu Asp Val Glu Asp Val Lys Phe Val lie Asn Tyr 405 410 415 Asp Tyr Pro Asn Ser Ser Glu Asp Tyr lie His Arg lie Gly Arg Thr 420 425 430 Ala Arg Ser Thr Lys Thr Gly Thr Ala Tyr Thr Phe Phe Thr Pro Asn 435 440 445 Asn lie Lys Gin Val Ser Asp Leu lie Ser Val Leu Arg Glu Ala Asn 450 455 460 Gin Ala lie Asn Pro Lys Leu Leu Gin Leu Val Glu Asp Arg Gly Ser 465 470 475 480 Gly Arg Ser Arg Gly Arg Gly Gly Met Lys Asp Asp Arg Arg Asp Arg 485 490 495 Tyr Ser Ala Gly Lys Arg Gly Gly Phe Asn Thr Phe Arg Asp Arg Glu 500 505 510 Asn Tyr Asp Arg Gly Tyr Ser Ser Leu Leu Lys Arg Asp Phe Gly Ala 515 520 525 S Lys Thr Gin Asn Gly Val Tyr Ser Ala Ala Asn Tyr Thr Asn Gly Ser S530 535 540 Phe Gly Ser Asn Phe Val Ser Ala Gly lie Gin Thr Ser Phe Arg Thr 545 550 555 560 0 Gly Asn Pro Thr Gly Thr Tyr Gin Asn Gly Tyr Asp Ser Thr Gin Gin 565 570 575 Tyr Gly Ser Asn Val Pro Asn Met His Asn Gly Met Asn Gin Gin Ala 580 585 590 Tyr Ala Tyr Pro Ala Thr Ala Ala Ala Pro Met lie Gly Tyr Pro Met 595 600 605 Pro Thr Gly Tyr Ser Gin S* 610 <210> <211> 615 <212> PRT <213> Mus musculus <400> Met Ser Ser Tyr Ser Ser Asp Arg Asp Arg Gly Arg Asp Arg Gly Phe 1 5 10 Gly Ala Pro Arg Phe Gly Gly Ser Arg Thr Gly Pro Leu Ser Gly Lys 25 Lys Phe Gly Asn Pro Gly Glu Lys Leu Val Lys Lys Lys Trp Asn Leu 40 Asp Glu Leu Pro Lys Phe Glu Lys Asn Phe Tyr Gin Glu His Pro Asp 55 Leu Ala Arg Arg Thr Ala Gin Glu Val Asp Thr Tyr Arg Arg Ser Lys 70 75 Glu lie Thr Val Arg Gly His Asn Cys Pro Lys Pro Val Leu Asn Phe 90 Tyr Glu Ala Asn Phe Pro Ala Asn Val Met Asp Val lie Ala Arg Gin 100 105 110 Asn Phe Thr Glu Pro Thr Ala lie Gin Ala Gin Gly Trp Pro Val Ala 115 120 125 Leu Ser Gly Leu Asp Met Val Gly Val Ala Gin Thr Gly Ser Gly Lys 130 135 140 Thr Leu Ser Tyr Leu Leu Pro Ala lie Val His lie Asn His Gin Pro 145 150 155 160 Phe Leu Glu Arg Gly Asp Gly Pro lie Cys Leu Val Leu Ala Pro Thr 165 170 175 Arg Glu Leu Ala Gin Gin Val Gin Gin Val Ala Ala Glu Tyr Cys Arg 180 185 190 Ala Cys Arg Leu Lys Ser Thr Cys lie Tyr Gly Gly Ala Pro Lys Gly 195 200 205 Pro Gin lie Arg Asp Leu Glu Arg Gly Val Glu lie Cys lie Ala Thr 210 215 220 Pro Gly Arg Leu lie Asp Phe Leu Glu Cys Gly Lys Thr Asn Leu Arg 225 230 235 240 Arg Thr Thr Tyr Leu Val Leu Asp Glu Ala Asp Arg Met Leu Asp Met 245 250 255 Gly Phe Glu Pro Gin lie Arg Lys lie Val Asp Gin lie Arg Pro Asp 260 265 270 Arg Gin Thr Leu Met Trp Ser Ala Thr Trp Pro Lys Glu Val Arg Gin 275 280 285 Leu Ala Glu Asp Phe Leu Lys Asp Tyr lie His lie Asn lie Gly Ala 290 295 300 Leu Glu Leu Ser Ala Asn His Asn lie Leu Gin lie Val Asp Val Cys 305 310 315 320 His Asp Val Glu Lys Asp Glu Lys Leu lie Arg Leu Met Glu Glu lie 325 330 335 Met Ser Glu Lys Glu Asn Lys Thr lie Val Phe Val Glu Thr Lys Arg 340 345 350 Arg Cys Asp Glu Leu Thr Arg Lys Met Arg Arg Asp Gly Trp Pro Ala 355 360 365 Met Gly lie His Gly Asp Lys Ser Gin Gin Glu Arg Asp Trp Val Leu 370 375 380 Asn Glu Phe Lys His Gly Lys Ala Pro lie Leu lie Ala Thr Asp Val 385 390 395 400 Ala Ser Arg Gly Leu Asp Val Glu Asp Val Lys Phe Val lie Asn Tyr 405 410 415 Asp Tyr Pro Asn Ser Ser Glu Asp Tyr lie His Arg lie Gly Arg Thr 420 425 430 Ala Arg Ser Thr Lys Thr Gly Thr Ala Tyr Thr Phe Phe Thr Pro Asn 435 440 445 Asn lie Lys Gin Val Ser Asp Leu lie Ser Val Leu Arg Glu Ala Asn 450 455 460 Gin Ala lie Asn Pro Lys Leu Leu Gin Leu Val Glu Asp Arg Gly Ser 465 470 475 480 Gly Arg Ser Arg Gly Arg Gly Gly Met Lys Asp Asp Arg Arg Asp Arg 485 490 495 Tyr Ser Ala Gly Lys Arg Gly Gly Phe Asn Thr Phe Arg Asp Arg Glu 500 505 510 .o Asn Tyr Asp Arg Gly Tyr Ser Asn Leu Leu Lys Arg Asp Phe Gly Ala 515 520 525 Lys Thr Gin Asn Gly Val Tyr Ser Ala Ala Asn Tyr Thr Asn Gly Ser 530 535 540 Phe Gly Ser Asn Phe Val Ser Ala Gly lie Gin Thr Ser Phe Arg Thr 545 550 555 560 Gly Asn Pro Thr Gly Thr Tyr Gin Asn Gly Tyr Asp Ser Thr Gin Gin 565 570 575 Tyr Gly Ser Asn Val Ala Asn Met His Asn Gly Met Asn Gin Gin Ala 580 585 590 Tyr Ala Tyr Pro Ala Thr Ala Ala Ala Ala Pro Met lie Gly Tyr Pro 595 600 605 Met Pro Thr Gly Tyr Ser Gin 610 615 <210> 31 <211> 167 <212> PRT <213> Mus musculus <300> <301> Aoki, N.

<302> Anagen-specific protein mKAP13 <400> 31 Met Ser Cys Asn Ser Cys Ser Gly Thr Phe Ser Gin Ser Phe Gly Gly 1 5 10 Gin Leu Gin Tyr Pro lie Ser Ser Cys Gly Ser Ser Tyr Pro Asn Asn 25 Val Phe Tyr Ser Thr Asp Leu Gin Thr Pro lie Thr His Gin Leu Gly 40 Ser Ser Leu His Ser Gly Cys Gin Glu Thr Phe Cys Glu Pro Thr Asn 55 Cys Gin Thr Ala Tyr Val Val Ser Arg Pro Cys Gin Arg Pro Phe Tyr 70 75 Ser Gin Arg lie Arg Gly Pro Cys Arg Pro Cys Gin Ser Thr Phe Ser 90 Gly Ser Leu Gly Phe Gly Ser Arg Gly Phe Gin Ser Phe Gly Cys Gly 100 105 110 Tyr Pro Ser Gin Gly Phe Gly Ser His Gly Phe Gin Ser Val Gly Cys 115 120 125 Gly Thr Pro Thr Phe Ser Ser Leu Asn Cys Gly Ser Ser Phe Tyr Arg 130 135 140 Pro Thr Cys Phe Ser Thr Lys Ser Cys Gin Ser Val Ser Tyr Gin Pro 145 150 155 160 Thr Cys Gly Thr Gly Phe Phe 165 <210> 32 <211> 150 <212> PRT <213> Mus musculus <300> S <301> Kuhn, F.

<302> Pmgl and Pmg2 constitute a novel family of KAP genes differentially expressed during skin and mammary gland development <303> Mech. Dev.

<304> 1999 <313>1 TO 150 <400> 32 Met Ser Tyr Thr Cys Asn Ser Gly Asn Tyr Ser Ser Gin Ser Phe Gly 1 5 10 Gly Phe Leu Arg Gin Pro Val Ser Thr Tyr Asn Ser Phe Tyr Pro Thr 25 Ser Asn Val Val Tyr Ser Pro Lys Asn Phe Gin Leu Gly Ser Ser Phe 40 Tyr Asn Gly Gin Gin Glu Thr Phe Ser Glu Pro Leu Glu Gly His Leu 55 Pro Cys Val Gly Ser Ala Ser Phe His Thr Ser Cys Phe Arg Pro Lys 70 75 Gin Tyr Phe Ser Ser Pro Cys Gin Gly Gly Phe Thr Gly Ser Phe Gly 90 Tyr Gly Asn Thr Gly Phe Gly Ala Phe Gly Phe Gly Ser Ser Gly lie 100 105 110 Arg Ser Gin Gly Cys Gly Ser Asn Phe Tyr Arg Pro Gly Tyr Phe Ser 115 120 125 Ser Lys Ser lie Gin Ser Ser Tyr Tyr Gin Pro Gly Tyr Ser Ser Gly 130 135 140 Phe Cys Gly Ser Asn Phe 145 150 <210> 33 <211> 469 <212> PRT <213> Mus musculus <300> <301> Shibahara, K.

<302> Isolation of a novel gene MA-3 that is induced upon programmed cell death S<303> Gene <304> 1995 <305> 166 <306> 297-301 <313> 1 TO 469 <400> 33 Met Asp lie Glu Asn Glu Gin Thr Leu Asn Val Asn Pro Thr Asp Pro 1 5 10 l Asp Asn Leu Ser Asp Ser Leu Phe Ser Gly Asp Glu Glu Asn Ala Gly 20 25 Thr Glu Glu lie Lys Asn Glu lie Asn Gly Asn Trp lie Ser Ala Ser 40 Thr lie Asn Glu Ala Arg lie Asn Ala Lys Ala Lys Arg Arg Leu Arg 55 Lys Asn Ser Ser Arg Asp Ser Gly Arg Gly Asp Ser Val Ser Asp Asn 70 75 Gly Ser Glu Ala Val Arg Ser Gly Val Ala Val Pro Thr Ser Pro Lys 90 Gly Arg Leu Leu Asp Arg Arg Ser Arg Ser Gly Lys Gly Arg Gly Leu 100 105 110 Pro Lys Lys Gly Gly Ala Gly Gly Lys Gly Val Trp Gly Thr Pro Gly 115 120 125 Gin Val Tyr Asp Val Glu Glu Val Asp Val Lys Asp Pro Asn Tyr Asp 130 135 140 Asp Asp Gin Glu Asn Cys Val Tyr Glu Thr Val Val Leu Pro Leu Asp 145 150 155 160 Glu Thr Ala Phe Glu Lys Thr Leu Thr Pro lie lie Gin Glu Tyr Phe 165 170 175 Glu His Gly Asp Thr Asn Glu Val Ala Glu Met Leu Arg Asp Leu Asn 180 185 190 Leu Gly Glu Met Lys Ser Gly Val Pro Val Leu Ala Val Ser Leu Ala 195 200 205 Leu Glu Gly Lys Ala Ser His Arg Glu Met Thr Ser Lys Leu Leu Ser 210 215 220 Asp Leu Cys Gly Thr Val Met Ser Thr Asn Asp Val Glu Lys Ser Phe 225 230 235 240 Asp Lys Leu Leu Lys Asp Leu Pro Glu Leu Ala Leu Asp Thr Pro Arg 245 250 255 Ala Pro Gin Leu Val Gly Gin Phe lie Ala Arg Ala Val Gly Asp Gly 260 265 270 o* lie Leu Cys Asn Thr Tyr lie Asp Ser Tyr Lys Gly Thr Val Asp Cys 275 280 285 Val Gin Ala Arg Ala Ala Leu Asp Lys Ala Thr Val Leu Leu Ser Met 290 295 300 Ser Lys Gly Gly Lys Arg Lys Asp Ser Val Trp Gly Ser Gly Gly Gly 305 310 315 320 Gin Gin Pro Val Asn His Leu Val Lys Glu lie Asp Met Leu Leu Lys 325 330 335 Glu Tyr Leu Leu Ser Gly Asp lie Ser Glu Ala Glu His Cys Leu Lys S° 340 345 350 Glu Leu Glu Val Pro His Phe His His Glu Leu Val Tyr Glu Ala lie 355 360 365 Val Met Val Leu Glu Ser Thr Gly Glu Ser Ala Phe Lys Met lie Leu 370 375 380 Asp Leu Leu Lys Ser Leu Trp Lys Ser Ser Thr lie Thr lie Asp Gin 385 390 395 400 Met Lys Arg Gly Tyr Glu Arg lie Tyr Asn Glu lie Pro Asp lie Asn 405 410 415 Leu Asp Val Pro His Ser Tyr Ser Val Leu Glu Arg Phe Val Glu Glu 420 425 430 Cys Phe Gin Ala Gly lie lie Ser Lys Gin Leu Arg Asp Leu Cys Pro 435 440 445 Ser Arg Gly Arg Lys Arg Phe Val Ser Glu Gly Asp Gly Gly Arg Leu 450 455 460 Lys Pro Glu Ser Tyr 465 <210> 34 <211> 458 <212> PRT <213> Homo sapiens <400> 34 Met Thr Lys Tyr Pro Asp Asn Leu Ser Asp Ser Leu Phe Ser Gly Asp 1 5 10 Glu Glu Asn Ala Gly Thr Glu Glu Val Lys Asn Glu lie Asn Gly Asn 25 Trp lie Ser Ala Ser Ser lie Asn Glu Ala Arg lie Asn Ala Lys Ala 40 Lys Arg Arg Leu Arg Lys Asn Ser Ser Arg Asp Ser Gly Arg Gly Asp 55 Ser Val Ser Glu Ser Gly Ser Asp Ala Leu Arg Ser Gly Leu Thr Val 70 75 Pro Thr Ser Pro Lys Gly Arg Leu Leu Asp Arg Arg Ser Arg Ser Gly 85 90 o Lys Gly Arg Gly Leu Pro Lys Lys Gly Gly Ala Gly Gly Lys Gly Val 100 105 110 Trp Gly Thr Pro Gly Gin Val Tyr Asp Val Glu Glu Val Asp Val Lys 115 120 125 Asp Pro Asn Tyr Asp Asp Asp Gin Glu Asn Cys Val Tyr Glu Thr Val 130 135 140 Val Leu Pro Leu Asp Glu Arg Ala Phe Glu Lys Thr Leu Thr Pro lie 145 150 155 160 lie Gin Glu Tyr Phe Glu His Gly Asp Thr Asn Glu Val Ala Glu Met 165 170 175 SLeu Arg Asp Leu Asn Leu Gly Glu Met Lys Ser Gly Val Pro Val Leu 180 185 190 Ala Val Ser Leu Ala Leu Glu Gly Lys Ala Ser His Arg Glu Met Thr 195 200 205 Thr Lys Leu Leu Ser Asp Leu Cys Gly Thr Val Met Ser Thr Thr Asp 210 215 220 Val Glu Lys Ser Phe Asp Lys Leu Leu Lys Asp Leu Pro Glu Leu Ala 225 230 235 240 Leu Asp Thr Pro Arg Ala Pro Gin Leu Val Gly Gin Phe lie Ala Arg 245 250 255 Ala Val Gly Asp Gly lie Leu Cys Asn Thr Tyr lie Asp Ser Tyr Lys 260 265 270 Gly Thr Val Asp Cys Val Gin Ala Arg Ala Ala Leu Asp Lys Ala Thr 275 280 285 Val Leu Leu Ser Met Ser Lys Gly Gly Lys Arg Lys Asp Ser Val Trp 290 295 300 Gly Ser Gly Gly Gly Gin Gin Ser Val Asn His Leu Val Lys Glu lie 305 310 315 320 Asp Met Leu Leu Lys Glu Tyr Leu Leu Ser Gly Asp lie Ser Glu Ala 325 330 335 Glu His Cys Leu Lys Glu Leu Glu Val Pro His Phe His His Glu Leu 340 345 350 Val Tyr Glu Ala lie lie Met Val Leu Glu Ser Thr Gly Glu Ser Thr 355 360 365 Phe Lys Met lie Leu Asp Leu Leu Lys Ser Leu Trp Lys Ser Ser Thr 370 375 380 lie Thr Val Asp Gin Met Lys Arg Gly Tyr Glu Arg lie Tyr Asn Glu 385 390 395 400 lie Pro Asp lie Asn Leu Asp Val Pro His Ser Tyr Ser Val Leu Glu 405 410 415 "Arg Phe Val Glu Glu Cys Phe Gin Ala Gly lie lie Ser Lys Gin Leu 420 425 430 Arg Asp Leu Cys Pro Ser Arg Gly Arg Lys Arg Phe Val Ser Glu Gly 435 440 445 Asp Gly Gly Arg Leu Lys Pro Glu Ser Tyr 450 455 <210> <211> 171 <212> PRT <213> Mus musculus <300> <301> Suk, K.

<302> Enhancement of B-cell translocation gene-1 expresion by prostaglandin E2 in macrophages and the relationship to proliferation <303> Immunology <304> 1997 <305> 91 <306> 121-129 <313>1 TO 171 <400> Met His Pro Phe Tyr Thr Arg Ala Ala Thr Met lie Gly Glu lie Ala 1 5 10 Ala Ala Val Ser Phe lie Ser Lys Phe Leu Arg Thr Lys Gly Leu Thr 25 Ser Glu Arg Gin Leu Gin Thr Phe Ser Gin Ser Leu Gin Glu Leu Leu 40 Ala Glu His Tyr Lys His His Trp Phe Pro Glu Lys Pro Cys Lys Gly 55 Ser Gly Tyr Arg Cys lie Arg lie Asn His Lys Met Asp Pro Leu lie 70 75 Gly Gin Ala Ala Gin Arg lie Gly Leu Ser Ser Gin Glu Leu Phe Arg 90 Leu Leu Pro Ser Glu Leu Thr Leu Trp Val Asp Pro Tyr Glu Val Ser 100 105 110 Tyr Arg lie Gly Glu Asp Gly Ser lie Cys Val Leu Tyr Glu Ala Ser 115 120 125 Pro Ala Gly Gly Ser Thr Gin Asn Ser Thr Asn Val Gin Met Val Asp 130 135 140 Ser Arg lie Ser Cys Lys Glu Glu Leu Leu Leu Gly Arg Thr Ser Pro 145 150 155 160 Ser Lys Asn Tyr Asn Met Met Thr Val Ser Gly 165 170 <210> 36 <211> 171 <212> PRT <213> Homo sapiens <400> 36 Met His Pro Phe Tyr Thr Arg Ala Ala Thr Met lie Gly Glu lie Ala 1 5 10 Ala Ala Val Ser Phe lie Ser Lys Phe Leu Arg Thr Lys Gly Leu Thr 20 25 SSer Glu Arg Gin Leu Gin Thr Phe Ser Gin Ser Leu Gin Glu Leu Leu 40 Ala Glu His Tyr Lys His His Trp Phe Pro Glu Lys Pro Cys Lys Gly 55 Ser Gly Tyr Arg Cys lie Arg lie Asn His Lys Met Asp Pro Leu lie 70 75 Gly Gin Ala Ala Gin Arg lie Gly Leu Ser Ser Gin Glu Leu Phe Arg 90 Leu Leu Pro Ser Glu Leu Thr Leu Trp Val Asp Pro Tyr Glu Val Ser 100 105 110 Tyr Arg lie Gly Glu Asp Gly Ser lie Cys Val Leu Tyr Glu Ala Ser 115 120 125 Pro Ala Gly Gly Ser Thr Gin Asn Ser Thr Asn Val Gin Met Val Asp 130 135 140 Ser Arg lie Ser Cys Lys Glu Glu Leu Leu Leu Gly Arg Thr Ser Pro 145 150 155 160 Ser Lys Asn Tyr Asn Met Met Thr Val Ser Gly 165 170 <210> 37 <211> 226 <212> PRT <213> Mus musculus <300> <301> Rubinstein, E.

<302> Molecular cloning of the mouse equivalent of CD9 <303> Thromb. Res.

<304> 1993 <305> 71 <306> 377-383 <313> 1 TO 226 <400> 37 Met Pro Val Lys Gly Gly Ser Lys Cys lie Lys Tyr Leu Leu Phe Gly 1 5 10 Phe Asn Phe lie Phe Trp Leu Ala Gly lie Ala Val Leu Ala lie Gly 20 25 Leu Trp Leu Arg Phe Asp Ser Gin Thr Lys Ser lie Phe Glu Gin Glu 40 Asn Asn His Ser Ser Phe Tyr Thr Gly Val Tyr lie Leu lie Gly Ala 50 55 Gly Ala Leu Met Met Leu Val Gly Phe Leu Gly Cys Cys Gly Ala Val 70 75 Gin Glu Ser Gin Cys Met Leu Gly Leu Phe Phe Gly Phe Leu Leu Val 85 90 lie Phe Ala lie Glu lie Ala Ala Ala Val Trp Gly Tyr Thr His Lys 100 105 110 Asp Glu Val lie Lys Glu Leu Gin Glu Phe Tyr Lys Asp Thr Tyr Gin 115 120 125 Lys Leu Arg Ser Lys Asp Glu Pro Gin Arg Glu Thr Leu Lys Ala lie 130 135 140 His Met Ala Leu Asp Cys Cys Gly lie Ala Gly Pro Leu Glu Gin Phe 145 150 155 160 lie Ser Asp Thr Cys Pro Lys Lys Gin Leu Leu Glu Ser Phe Gin Val 165 170 175 Lys Pro Cys Pro Glu Ala lie Ser Glu Val Phe Asn Asn Lys Phe His 180 185 190 lie lie Gly Ala Val Gly lie Gly lie Ala Val Val Met lie Phe Gly 195 200 205 Met lie Phe Ser Met lie Leu Cys Cys Ala lie Arg Arg Ser Arg Glu 210 215 220 Met Val 225 <210> 38 <211> 228 <212> PRT <213> Homo sapiens <300> <301> Higashihara, M.

<302> Purification and partial characterization of CD9 antigen of human platelets <303> FEBS Lett.

%<304> 1990 <305> 264(2) <306> 270-274 <313> 1 TO 228 <400> 38 Met Pro Val Lys Gly Gly Thr Lys Cys lie Lys Tyr Leu Leu Phe Gly 1 5 10 Phe Asn Phe lie Phe Trp Leu Ala Gly lie Ala Val Leu Ala lie Gly 20 25 Leu Trp Leu Arg Phe Asp Ser Gin Thr Lys Ser lie Phe Glu Gin Glu 35 40 :0"00i Thr Asn Asn Asn Asn Ser Ser Phe Tyr Thr Gly Val Tyr lie Leu lie 55 Gly Ala Gly Ala Leu Met Met Leu Val Gly Phe Leu Gly Cys Cys Gly S 65 70 75 Ala Val Gin Glu Ser Gin Cys Met Leu Gly Leu Phe Phe Gly Phe Leu 90 Leu Val lie Phe Ala lie Glu lie Ala Ala Ala lie Trp Gly Tyr Ser 100 105 110 His Lys Asp Glu Val lie Lys Glu Val Gin Glu Phe Tyr Lys Asp Thr 115 120 125 Tyr Asn Lys Leu Lys Thr Lys Asp Glu Pro Gin Arg Glu Thr Leu Lys 130 135 140 Ala lie His Tyr Ala Leu Asn Cys Cys Gly Leu Ala Gly Gly Val Glu 145 150 155 160 Gin Phe lie Ser Asp lie Cys Pro Lys Lys Asp Val Leu Glu Thr Phe 165 170 175 Thr Val Lys Ser Cys Pro Asp Ala lie Lys Glu Val Phe Asp Asn Lys 180 185 190 Phe His lie lie Gly Ala Val Gly lie Gly lie Ala Val Val Met lie 195 200 205 Phe Gly Met lie Phe Ser Met lie Leu Cys Cys Ala lie Arg Arg Asn 210 215 220 Arg Glu Met Val 225 <210> 39 <211> 358 <212> PRT <213> Mus musculus <300> <301> Kaestner, K. H.

:i <302> Differentiation-induced gene expression in 3T3-L1 preadipocytes. A second differentially expressed gene encoding stearoyl-CoA <303> J. Biol. Chem.

<304>1989 <305> 264 <306> 14755-14761 <313> 1 TO 358 <400> 39 S Met Pro Ala His lie Leu Gin Glu lie Ser Gly Ala Tyr Ser Ala Thr 1 5 10 Thr Thr lie Thr Ala Pro Pro Ser Gly Gly Gin Gin Asn Gly Gly Glu 20 25 Lys Phe Glu Lys Ser Ser His His Trp Gly Ala Asp Val Arg Pro Glu 40 Leu Lys Asp Asp Leu Tyr Asp Pro Thr Tyr Gin Asp Asp Glu Gly Pro 50 55 Pro Pro Lys Leu Glu Tyr Val Trp Arg Asn lie lie Leu Met Ala Leu 70 75 Leu His Leu Gly Ala Leu Tyr Gly lie Thr Leu Val Pro Ser Cys Lys 90 Leu Tyr Thr Cys Leu Phe Ala Tyr Leu Tyr Tyr Val lie Ser Ala Leu 100 105 110 Gly lie Thr Ala Gly Ala His Arg Leu Trp Ser His Arg Thr Tyr Lys 115 120 125 Ala Arg Leu Pro Leu Arg Leu Phe Leu lie lie Ala Asn Thr Met Ala 130 135 140 Phe Gin Asn Asp Val Tyr Glu Trp Ala Arg Asp His Arg Ala His His 145 150 155 160 Lys Phe Ser Glu Thr His Ala Asp Pro His Asn Ser Arg Arg Gly Phe 165 170 175 Phe Phe Ser His Val Gly Trp Leu Leu Val Arg Lys His Pro Ala Val 180 185 190 Lys Glu Lys Gly Gly Lys Leu Asp Met Ser Asp Leu Lys Ala Glu Lys 195 200 205 Leu Val Met Phe Gin Arg Arg Tyr Tyr Lys Pro Asp Leu Leu Leu Met 210 215 220 Cys Phe Val Leu Pro Thr Leu Val Pro Trp Tyr Cys Trp Gly Glu Thr 225 230 235 240 Phe Val Asn Ser Leu Cys Val Ser Thr Phe Leu Arg Tyr Ala Val Val 245 250 255 Leu Asn Ala Thr Trp Leu Val Asn Ser Ala Ala His Leu Tyr Gly Tyr 260 265 270 Arg Pro Tyr Asp Lys Asn lie Ser Ser Arg Glu Asn lie Leu Val Ser 275 280 285 i. Met Gly Ala Val Gly Glu Arg Phe His Asn Tyr His His Ala Phe Pro 290 295 300 Tyr Asp Tyr Ser Ala Ser Glu Tyr Arg Trp His lie Asn Phe Thr Thr 305 310 315 320 Phe Phe lie Asp Cys Met Ala Leu Leu Gly Leu Ala Tyr Asp Arg Lys 325 330 335 Arg Val Ser Arg Ala Ala Val Leu Ala Arg lie Lys Arg Thr Gly Asp S. 340 345 350 Gly Ser Cys Lys Ser Gly 355 <210> <211> 359 <212> PRT <213> Homo sapiens <300> <301> Zhang, L.

<302> Human stearoyl-CoA desaturase: alternative transcripts generated from a single gene by usage of tandem polyadenylation sites.

<303> Biochem. J.

<304> 1999 <305> 340 <306> 255-264 <313> 1 TO 359 <400> Met Pro Ala His Leu Leu Gin Asp Asp lie Ser Ser Ser Tyr Thr Thr 1 5 10 Thr Thr Thr lie Thr Ala Pro Pro Ser Arg Val Leu Gin Asn Gly Gly 25 Asp Lys Leu Glu Thr Met Pro Leu Tyr Leu Glu Asp Asp lie Arg Pro 40 Asp lie Lys Asp Asp lie Tyr Asp Pro Thr Tyr Lys Asp Lys Glu Gly 55 Pro Ser Pro Lys Val Glu Tyr Val Trp Arg Asn lie lie Leu Met Ser 70 75 Leu Leu His Leu Gly Ala Leu Tyr Gly lie Thr Leu lie Pro Thr Cys 90 Lys Phe Tyr Thr Trp Leu Trp Gly Val Phe Tyr Tyr Phe Val Ser Ala 100 105 110 Leu Gly lie Thr Ala Gly Ala His Arg Leu Trp Ser His Arg Ser Tyr S115 120 125 Lys Ala Arg Leu Pro Leu Arg Leu Phe Leu lie lie Ala Asn Thr Met 130 135 140 Ala Phe Gin Asn Asp Val Tyr Glu Trp Ala Arg Asp His Arg Ala His 145 150 155 160 His Lys Phe Ser Glu Thr His Ala Asp Pro His Asn Ser Arg Arg Gly 165 170 175 Phe Phe Phe Ser His Val Gly Trp Leu Leu Val Arg Lys His Pro Ala 180 185" 190 Val Lys Glu Lys Gly Ser Thr Leu Asp Leu Ser Asp Leu Glu Ala Glu 195 200 205 S Lys Leu Val Met Phe Gin Arg Arg Tyr Tyr Lys Pro Gly Leu Leu Leu 210 215 220 Met Cys Phe lie Leu Pro Thr Leu Val Pro Trp Tyr Phe Trp Gly Glu 225 230 235 240 Thr Phe Gin Asn Ser Val Phe Val Ala Thr Phe Leu Arg Tyr Ala Val 245 250 255 Val Leu Asn Ala Thr Trp Leu Val Asn Ser Ala Ala His Leu Phe Gly 260 265 270 Tyr Arg Pro Tyr Asp Lys Asn lie Ser Pro Arg Glu Asn lie Leu Val 275 280 285 Ser Leu Gly Ala Val Gly Glu Gly Phe His Asn Tyr His His Ser Phe 290 295 300 Pro Tyr Asp Tyr Ser Ala Ser Glu Tyr Arg Trp His lie Asn Phe Thr 305 310 315 320 Thr Phe Phe lie Asp Cys Met Ala Ala Leu Gly Leu Ala Tyr Asp Arg 325 330 335 Lys Lys Val Ser Lys Ala Ala lie Leu Ala Arg lie Lys Arg Thr Gly 340 345 350 Asp Gly Asn Tyr Lys Ser Gly 355 <210> 41 <211> 198 <212> PRT <213> Mus musculus <300> <301> Tsuzuki, S.

<302> Molecular cloning, enomic organisation, promoter activity, and tissue-specific expression of the mouse ryudocan gene <303> J. Biochem.

<304> 1997 <305> 122 <306> 17-24 <313> 1 TO 198 <400> 41 Met Ala Pro Ala Cys Leu Leu Ala Pro Leu Leu Leu Leu Leu Leu Gly 1 5 10 Gly Phe Pro Leu Val Pro Gly Glu Ser lie Arg Glu Thr Glu Val lie 25 Asp Pro Gin Asp Leu Leu Glu Gly Arg Tyr Phe Ser Gly Ala Leu Pro 35 40 Asp Asp Glu Asp Ala Gly Gly Ser Asp Asp Phe Glu Leu Ser Gly Ser 50 55 Gly Asp Leu Asp Asp Thr Glu Glu Pro Arg Pro Phe Pro Glu Val lie 70 75 Glu Pro Leu Val Pro Leu Asp Asn His lie Pro Glu Asn Ala Gin Pro 90 Gly lie Arg Val Pro Ser Glu Pro Lys Glu Leu Glu Glu Asn Glu Val 100 105 110 lie Pro Lys Arg Ala Pro Ser Asp Val Gly Asp Asp Met Ser Asn Lys 115 120 125 Val Ser Met Ser Ser Thr Ala Gin Gly Ser Asn lie Phe Glu Arg Thr 130 135 140 Glu Val Leu Ala Ala Leu lie Val Gly Gly Val Val Gly lie Leu Phe 145 150 155 160 Ala Val Phe Leu lie Leu Leu Leu Val Tyr Arg Met Lys Lys Lys Asp 165 170 175 Glu Gly Ser Tyr Asp Leu Gly Lys Lys Pro lie Tyr Lys Lys Ala Pro 180 185 190 Thr Asn Glu Phe Tyr Ala 195 <210> 42 <211> 198 <212> PRT <213> Homo sapiens <300> <301> Kojima, T.

<302> Human ryudocan core protein: molecular cloning and characterization of the cDNA, and chromosomal localization of the gene <303> Biochem. Biophys. Res. Commun.

<304> 1993 <305> 190 <306> 814-822 <313>1 TO 198 S<400> 42 Met Ala Pro Ala Arg Leu Phe Ala Leu Leu Leu Phe Phe Val Gly Gly 1 5 10 Val Ala Glu Ser lie Arg Glu Thr Glu Val lie Asp Pro Gin Asp Leu 20 25 Leu Glu Gly Arg Tyr Phe Ser Gly Ala Leu Pro Asp Asp Glu Asp Val 40 Val Gly Pro Gly Gin Glu Ser Asp Asp Phe Glu Leu Ser Gly Ser Gly 55 Asp Leu Asp Asp Leu Glu Asp Ser Met lie Gly Pro Glu Val Val His 70 75 Pro Leu Val Pro Leu Asp Asn His lie Pro Glu Arg Ala Gly Ser Gly 90 Ser Gin Val Pro Thr Glu Pro Lys Lys Leu Glu Glu Asn Glu Val lie 100 105 110 Pro Lys Arg lie Ser Pro Val Glu Glu Ser Glu Asp Val Ser Asn Lys 115 120 125 Val Ser Met Ser Ser Thr Val Gin Gly Ser Asn lie Phe Glu Arg Thr 130 135 140 Glu Val Leu Ala Ala Leu lie Val Gly Gly lie Val Gly lie Leu Phe 145 150 155 160 Ala Val Phe Leu lie Leu Leu Leu Met Tyr Arg Met Lys Lys Lys Asp 165 170 175 Glu Gly Ser Tyr Asp Leu Gly Lys Lys Pro lie Tyr Lys Lys Ala Pro 180 185 190 Thr Asn Glu Phe Tyr Ala 195 <210> 43 <211> 706 <212> PRT <213> Mus musculus <300> <301> Nielsen, A. L.

<302> Murine helix-loop-helix transcriptional activator proteins to the E-box motif of the Akv murine leukemia virus enhancer identified by cDNA cloning <303> Mol. Cell. Biol.

<304> 1992 <305> 12 <306> 3449-3459 <313> 1 TO 706 <400> 43 S Met Asn Pro Gin Gin Gin Arg Met Ala Ala lie Gly Thr Asp Lys Glu S 1 5 10 Leu Ser Asp Leu Leu Asp Phe Ser Ala Met Phe Ser Pro Pro Val Asn 25 Ser Gly Lys Thr Arg Pro Thr Thr Leu Gly Ser Ser Gin Phe Ser Gly 35 40 Ser Gly Met Asp Glu Arg Gly Gly Thr Thr Ser Trp Gly Thr Ser Gly 55 Gin Pro Ser Pro Ser Tyr Asp Ser Ser Arg Gly Phe Thr Asp Ser Pro 70 75 His Tyr Ser Asp His Leu Asn Asp Ser Arg Leu Gly Thr His Glu Gly 90 Leu Ser Pro Thr Pro Phe Met Asn Ser Asn Leu lie Gly Lys Thr Ser 100 105 110 Glu Arg Gly Ser Phe Ser Leu Tyr Ser Arg Asp Ser Ala Leu Ser Gly 115 120 125 Cys Gin Ser Ser Leu Leu Arg Ala Ser Ser Arg Thr Trp Glu Pro Ala 130 135 140 Gin Leu Ser Ser Ser Gly Lys Pro Gly Thr Pro Tyr Tyr Ser Phe Ser 145 150 155 160 Ala Thr Ser Ser Arg Arg Arg Pro Leu His Asp Ser Val Ala Leu Asp 165 170 175 Pro Leu Gin Ala Lys Lys Val Arg Lys Val Pro Pro Gly Leu Pro Ser 180 185 190 Ser Val Tyr Ala Pro Ser Pro Asn Ser Asp Asp Phe Asn Arg Glu Ser 195 200 205 Pro Ser Tyr Pro Ser Pro Lys Pro Pro Thr Ser Met Phe Ala Ser Thr 210 215 220 Phe Phe Met Gin Asp Gly Thr His Ser Ser Ser Asp Leu Trp Ser Ser 225 230 235 240 Ser Asn Gly Met Ser Gin Pro Gly Phe Gly Gly lie Leu Gly Thr Ser 245 250 255 Thr Ser His Met Ser Gin Ser Ser Ser Tyr Gly Ser Leu His Ser His 260 265 270 Asp Arg Leu Ser Tyr Pro Pro His Ser Val Ser Pro Thr Asp lie Asn 275 280 285 Thr Ser Leu Pro Pro Met Ser Ser Phe His Arg Gly Ser Thr Ser Ser 290 295 300 i Ser Pro Tyr Val Ala Ala Ser His Thr Pro Pro lie Asn Gly Ser Asp 305 310 315 320 Ser lie Leu Gly Thr Arg Gly Asn Ala Ala Gly Ser Ser Gin Thr Gly 325 330 335 Asp Ala Leu Gly Lys Ala Leu Ala Ser lie Tyr Ser Pro Asp His Thr 340 345 350 Ser Ser Ser Phe Pro Ser Asn Pro Ser Thr Pro Val Gly Ser Pro Ser 355 360 365 Pro Leu Thr Gly Thr Ser Gin Trp Pro Arg Ala Gly Gly Gin Ala Pro 370 375 380 Ser Ser Pro Ser Tyr Glu Asn Ser Leu His Ser Leu Lys Asn Arg Val 385 390 395 400 Glu Gin Gin Leu His Glu His Leu Gin Asp Ala Met Ser Phe Leu Lys 405 410 415 Asp Val Cys Glu Gin Ser Arg Met Glu Asp Arg Leu Asp Arg Leu Asp 420 425 430 Asp Ala lie His Val Leu Arg Asn His Ala Val Gly Pro Ser Thr Ser 435 440 445 Leu Pro Thr Ser His Ser Asp lie His Ser Leu Leu Gly Pro Ser His 450 455 460 Asn Ala Ser lie Gly Asn Leu Asn Ser Asn Tyr Gly Gly Ser Ser Leu 465 470 475 480 Val Thr Asn Ser Arg Ser Ala Ser Met Val Gly Thr His Arg Glu Asp 485 490 495 Ser Val Ser Leu Asn Gly Asn His Ser Val Leu Ser Ser Thr Val Ala 500 505 510 Ala Ser Asn Thr Glu Leu Asn His Lys Thr Pro Glu Asn Phe Arg Gly 515 520 525 Gly Val Gin Asn Gin Ser Gly Ser Val Val Pro Thr Glu lie Lys Thr 530 535 540 Glu Asn Lys Glu Lys Asp Glu Asn Leu His Glu Pro Pro Ser Ser Asp 545 550 555 560 Asp Met Lys Ser Asp Asp Glu Ser Ser Gin Lys Asp lie Lys Val Ser 565 570 575 Ser Arg Gly Arg Thr Ser Ser Thr Asn Glu Asp Glu Asp Leu Asn Pro 580 585 590 Glu Gin Lys lie Glu Arg Glu Lys Glu Arg Arg Met Ala Asn Asn Ala 595 600 605 Arg Glu Arg Leu Arg Val Arg Asp lie Asn Glu Ala Phe Lys Glu Leu 610 615 620 Gly Arg Met Cys Gin Leu His Leu Lys Ser Glu Lys Pro Gin Thr Lys 625 630 635 640 Leu Leu lie Leu His Gin Ala Val Ala Val lie Leu Ser Leu Glu Gin 645 650 655 Gin Val Arg Glu Arg Asn Leu Asn Pro Lys Ala Ala Cys Leu Lys Arg 660 665 670 Arg Glu Glu Glu Lys Val Ser Ala Ala Ser Ala Glu Pro Pro Ser Thr 675 680 685 Leu Pro Gly Ala His Pro Gly Leu Ser Glu Ser Thr Asn Pro Met Gly 690 695 700 His Leu 705 9 <210> 44 <211> 682 <212> PRT <213> Homo sapiens <400> 44 Met Asn Pro Gin Gin Gin Arg Met Ala Ala lie Gly Thr Asp Lys Glu 1 5 10 Leu Ser Asp Leu Leu Asp Phe Ser Ala Met Phe Ser Pro Pro Val Asn 25 Ser Gly Lys Thr Arg Pro Thr Thr Leu Gly Ser Ser Gin Phe Ser Gly 40 Ser Gly lie Asp Glu Arg Gly Gly Thr Thr Ser Trp Gly Thr Ser Gly 55 Gin Pro Ser Pro Ser Tyr Asp Ser Ser Arg Gly Phe Thr Asp Ser Pro 70 75 His Tyr Ser Asp His Leu Asn Asp Ser Arg Leu Gly Ala His Glu Gly 90 Leu Ser Pro Thr Pro Phe Met Asn Ser Asn Leu Met Gly Lys Thr Ser 100 105 110 Glu Arg Gly Ser Phe Ser Leu Tyr Ser Arg Asp Thr Gly Leu Pro Gly 115 120 125 Cys Gin Ser Ser Leu Leu Arg Gin Asp Leu Gly Leu Gly Ser Pro Ala 130 135 140 Gin Leu Ser Ser Ser Gly Lys Pro Gly Thr Ala Tyr Tyr Ser Phe Ser 145 150 155 160 Ala Thr Ser Ser Arg Arg Arg Pro Leu His Asp Ser Ala Ala Leu Asp 165 170 175 Pro Leu Gin Ala Lys Lys Val Arg Lys Val Pro Pro Gly Leu Pro Ser 180 185 190 Ser Val Tyr Ala Pro Ser Pro Asn Ser Asp Asp Phe Asn Arg Glu Ser S195 200 205 Pro Ser Tyr Pro Ser Pro Lys Pro Pro Thr Ser Met Phe Ala Ser Thr 210 215 220 Phe Phe Met Gin Asp Gly Thr His Asn Ser Ser Asp Leu Trp Ser Ser 225 230 235 240 Ser Asn Gly Met Ser Gin Pro Gly Phe Gly Gly lie Leu Gly Thr Ser 245 250 255 Thr Ser His Met Ser Gin Ser Ser Ser Tyr Gly Asn Leu His Ser His 260 265 270 Asp Arg Leu Ser Tyr Pro Pro His Ser Val Ser Pro Thr Asp lie Asn 275 280 285 Thr Ser Leu Pro Pro Met Ser Ser Phe His Arg Gly Ser Thr Ser Ser 290 295 300 Ser Pro Tyr Val Ala Ala Ser His Thr Pro Pro lie Asn Gly Ser Asp 305 310 315 320 Ser lie Leu Gly Thr Arg Gly Asn Ala Ala Gly Ser Ser Gin Thr Gly 325 330 335 Asp Ala Leu Gly Lys Ala Leu Ala Ser lie Tyr Ser Pro Asp His Thr 340 345 350 Ser Ser Ser Phe Pro Ser Asn Pro Ser Thr Pro Val Gly Ser Pro Ser 355 360 365 Pro Leu Thr Gly Thr Ser Gin Trp Pro Arg Pro Gly Gly Gin Ala Pro 370 375 380 Ser Ser Pro Ser Tyr Glu Asn Ser Leu His Ser Leu Gin Ser Arg Met 385 390 395 400 Glu Asp Arg Leu Asp Arg Leu Asp Asp Ala lie His Val Leu Arg Asn 405 410 415 His Ala Val Gly Pro Ser Thr Ser Leu Pro Ala Gly His Ser Asp lie 420 425 430 His Ser Leu Leu Gly Pro Ser His Asn Ala Pro lie Gly Ser Leu Asn 435 440 445 Ser Asn Tyr Gly Gly Ser Ser Leu Val Ala Ser Ser Arg Ser Ala Ser 450 455 460 Met Val Gly Thr His Arg Glu Asp Ser Val Ser Leu Asn Gly Asn His 465 470 475 480 Ser Val Leu Ser Ser Thr Val Thr Thr Ser Ser Thr Asp Leu Asn His 485 490 495 Lys Thr Gin Glu Asn Tyr Arg Gly Gly Leu Gin Ser Gin Ser Gly Thr 500 505 510 Val Val Thr Thr Glu lie Lys Thr Glu Asn Lys Glu Lys Asp Glu Asn 515 520 525 Leu His Glu Pro Pro Ser Ser Asp Asp Met Lys Ser Asp Asp Glu Ser 530 535 540 Ser Gin Lys Asp lie Lys Val Ser Ser Arg Gly Arg Thr Ser Ser Thr 545 550 555 560 Asn Glu Asp Glu Asp Leu Asn Pro Glu Gin Lys lie Glu Arg Glu Lys 565 570 575 Glu Arg Arg Met Ala Asn Asn Ala Arg Glu Arg Leu Arg Val Arg Asp 580 585 590 lie Asn Glu Ala Phe Lys Glu Leu Gly Arg Met Cys Gin Leu His Leu 595 600 605 Lys Ser Glu Lys Pro Gin Thr Lys Leu Leu lie Leu His Gin Ala Val 610 615 620 Ala Val lie Leu Ser Leu Glu Gin Gin Val Arg Glu Arg Asn Leu Asn 625 630 635 640 Pro Lys Ala Ala Cys Leu Lys Arg Arg Glu Glu Glu Lys Val Ser Ala 645 650 655 Val Ser Ala Glu Pro Pro Thr Thr Leu Pro Gly Thr His Pro Gly Leu 660 665 670 Ser Glu Thr Thr Asn Pro Met Gly His Met 675 680 <210> <211> 167 <212> PRT <213> Mus musculus <300> <301> Zeng, Q.

<302> Mouse PRL-2 and PRL-3, two potentially prenylated protein tyrosine phosphatase homologues to PRL-1 <303> Biochem. Biophys. Res. Commun.

<304> 1998 <305> 244 <306> 421-427 <313> 1 TO 167 <400> Met Asn Arg Pro Ala Pro Val Glu lie Ser Tyr Glu Asn Met Arg Phe 1 5 10 Leu lie Thr His Asn Pro Thr Asn Ala Thr Leu Asn Lys Phe Thr Glu 25 Glu Leu Lys Lys Tyr Gly Val Thr Thr Leu Val Arg Val Cys Asp Ala 35 40 Thr Tyr Asp Lys Ala Pro Val Glu Lys Glu Gly lie His Val Leu Asp 50 55 Trp Pro Phe Asp Asp Gly Ala Pro Pro Pro Asn Gin lie Val Asp Asp 65 70 75 Trp Leu Asn Leu Leu Lys Thr Leu Phe Arg Glu Glu Pro Gly Cys Cys 85 90 Val Ala Val His Cys Val Ala Gly lie Gly Arg Ala Pro Val Leu Val 100 105 110 Ala Leu Ala Leu lie Glu Cys Gly Met Lys Tyr Glu Asp Ala Val Gin 115 120 125 Phe lie Arg Gin Lys Arg Arg Gly Ala Phe Asn Ser Lys Gin Leu Leu 130 135 140 Tyr Leu Glu Lys Tyr Arg Pro Lys Met Arg Leu Arg Phe Arg Asp Thr 145 150 155 160 Asn Gly His Cys Cys Val Gin 165 <210> 46 <211> 167 <212> PRT <213> Homo sapiens <300> <301> Montagna, M.

<302> A 100-kb physical and transcriptional map around the EDH17B2 gene: identification of three novel genes and a pseudogene of a human homologue of the rat PRL-1 tyrosine phosphatase <303> Hum. Genet.

<304> 1995 <305> 96 <306> 532-538 <400> 46 Met Asn Arg Pro Ala Pro Val Glu lie Ser Tyr Glu Asn Met Arg Phe 1 5 10 Leu lie Thr His Asn Pro Thr Asn Ala Thr Leu Asn Lys Phe Thr Glu 25 Glu Leu Lys Lys Tyr Gly Val Thr Thr Leu Val Arg Val Cys Asp Ala 40 Thr Tyr Asp Lys Ala Pro Val Glu Lys Glu Gly lie His Val Leu Asp 55 Trp Pro Phe Asp Asp Gly Ala Pro Pro Pro Asn Gin lie Val Asp Asp 70 75 Trp Leu Asn Leu Leu Lys Thr Lys Phe Arg Glu Glu Pro Gly Cys Cys 85 90 Val Ala Val His Cys Val Ala Gly Leu Gly Arg Ala Pro Val Leu Val 100 105 110 Ala Leu Ala Leu lie Glu Cys Gly Met Lys Tyr Glu Asp Ala Val Gin 115 120 125 Phe lie Arg Gin Lys Arg Arg Gly Ala Phe Asn Ser Lys Gin Leu Leu 130 135 140 Tyr Leu Glu Lys Tyr Arg Pro Lys Met Arg Leu Arg Phe Arg Asp Thr 145 150 155 160 Asn Gly His Cys Cys Val Gin S* 165 S <210> 47 <211> 532 <212> PRT <213> Mus musculus <300> <301> Inoue, T.

<302> Isolation of complementary DNAs encoding a cerebellum-enriched nuclear factor I family that activates ranscription from the mouse myelin basic protein promoter <303> J. Biol. Chem.

<304> 1990 <305> 265 <306> 19065-19070 <313> 1 TO 532 <400> 47 Met Lys Leu Ala Asp Ser Val Met Ala Gly Lys Ala Ser Asp Gly Ser 1 5 10 lie Lys Trp Gin Leu Cys Tyr Asp lie Ser Ala Arg Thr Trp Trp Met 25 Asp Glu Phe His Pro Phe lie Glu Ala Leu Leu Pro His Val Arg Ala 40 Phe Ala Tyr Thr Trp Phe Asn Leu Gin Ala Arg Lys Arg Lys Tyr Phe 55 Lys Lys His Glu Lys Arg Met Ser Lys Glu Glu Glu Arg Ala Val Lys 70 75 Asp Glu Leu Leu Ser Glu Lys Pro Glu Val Lys Gin Lys Trp Ala Ser 90 Arg Leu Leu Ala Lys Leu Arg Lys Asp lie Arg Pro Glu Tyr Arg Glu 100 105 110 Asp Phe Val Leu Thr Val Thr Gly Lys Lys Pro Pro Cys Cys Val Leu 115 120 125 Ser Asn Pro Asp Gin Lys Gly Lys Met Arg Arg lie Asp Cys Leu Arg 130 135 140 Gin Ala Asp Lys Val Trp Arg Leu Asp Leu Val Met Val lie Leu Phe 145 150 155 160 Lys Gly lie Pro Leu Glu Ser Thr Asp Gly Glu Arg Leu Val Lys Ser 165 170 175 Pro Gin Cys Ser Asn Pro Gly Leu Cys Val Gin Pro His His lie Gly 180 185 190 Val Ser Val Lys Glu Leu Asp Leu Tyr Leu Ala Tyr Phe Val His Ala 195 200 205 Ala Asp Ser Ser Gin Ser Glu Ser Pro Ser Gin Pro Ser Glu Ala Asp 210 215 220 lie Lys Asp Gin Pro Glu Asn Gly His Leu Gly Phe Gin Asp Ser Phe 225 230 235 240 Val Thr Ser Gly Val Phe Ser Val Thr Glu Leu Val Arg Val Ser Gin 245 250 255 Thr Pro lie Ala Ala Gly Thr Gly Pro Asn Phe Ser Leu Ser Asp Leu 260 265 270 Glu Ser Ser Ser Tyr Tyr Ser Met Ser Pro Gly Ala Met Arg Arg Ser 275 280 285 Leu Pro Ser Thr Ser Ser Thr Ser Ser Thr Lys Arg Leu Lys Ser Val 290 295 300 Glu Asp Glu Met Asp Ser Pro Gly Glu Glu Pro Phe Tyr Thr Gly Gin 305 310 315 320 Gly Arg Ser Pro Gly Ser Gly Ser Gin Ser Ser Gly Trp His Glu Val 325 330 335 Glu Pro Gly Leu Pro Ser Pro Ser Thr Leu Lys Lys Ser Glu Lys Ser 340 345 350 Gly Phe Ser Ser Pro Ser Pro Ser Gin Thr Ser Ser Leu Gly Thr Ala 355 360 365 Phe Thr Gin His His Arg Pro Val lie Thr Gly Pro Arg Ala Ser Pro 370 375 380 His Ala Thr Pro Ser Thr Leu His Phe Pro Thr Ser Pro lie lie Gin 385 390 395 400 Gin Pro Gly Pro Tyr Phe Ser His Pro Ala lie Arg Tyr His Pro Gin 405 410 415 Glu Thr Leu Lys Glu Phe Val Gin Leu Val Cys Pro Asp Ala Gly Gin 420 425 430 Gin Ala Gly Gin Val Gly Phe Leu Asn Pro Asn Gly Ser Ser Gin Gly 435 440 445 S Lys Val His Asn Pro Phe Leu Pro Thr Pro Met Leu Pro Pro Pro Pro 450 455 460 Pro Pro Pro Met Ala Arg Pro Val Pro Leu Pro Met Pro Asp Thr Lys 465 470 475 480 i Pro Pro Thr Thr Ser Thr Glu Gly Gly Ala Ala Ser Pro Thr Ser Pro 485 490 495 Thr Tyr Ser Thr Pro Ser Thr Ser Pro Ala Asn Arg Phe Val Ser Val 500 505 510 Gly Pro Arg Asp Pro Ser Phe Val Asn lie Pro Gin Gin Thr Gin Ser 515 520 525 Trp Tyr Leu Gly 530 <210> 48 <211> 433 <212> PRT <213> Homo sapiens <300> <301> Amemiy, K.

<302> Nuclear factor 1 <400> 48 Met Asp Glu Phe His Pro Phe lie Glu Ala Leu Leu Pro His Val Arg 1 5 10 Ala Phe Ser Tyr Thr Trp Phe Asn Leu Gin Ala Arg Lys Arg Lys Tyr 25 Phe Lys Lys His Glu Lys Arg Met Ser Lys Asp Glu Glu Arg Ala Val 40 Lys Asp Glu Leu Leu Gly Glu Lys Pro Glu lie Lys Gin Lys Trp Ala 55 Ser Arg Leu Leu Ala Lys Leu Arg Lys Asp lie Arg Pro Glu Phe Arg 70 75 Glu Asp Phe Val Leu Thr lie Thr Gly Lys Lys Pro Pro Cys Cys Val 90 Leu Ser Asn Pro Asp Gin Lys Gly Lys lie Arg Arg lie Asp Cys Leu 100 105 110 Arg Gin Ala Asp Lys Val Trp Arg Leu Asp Leu Val Met Val lie Leu 115 120 125 Phe Lys Gly lie Pro Leu Glu Ser Thr Asp Gly Glu Arg Leu Tyr Lys 130 135 140 Ser Pro Gin Cys Ser Asn Pro Gly Leu Cys Val Gin Pro His His lie S:145 150 155 160 Gly Val Thr lie Lys Glu Leu Asp Leu Tyr Leu Ala Tyr Phe Val His 165 170 175 Thr Pro Glu Ser Gly Gin Ser Asp Ser Ser Asn Gin Gin Gly Asp Ala 180 185 190 Asp lie Lys Pro Leu Pro Asn Gly His Leu Ser Phe Gin Asp Cys Phe 195 200 205 Val Thr Ser Gly Val Trp Asn Val Thr Glu Leu Val Arg Val Ser Gin 210 215 220 Thr Pro Val Ala Thr Ala Ser Gly Pro Asn Phe Ser Leu Ala Asp Leu 225 230 235 240 Glu Ser Pro Ser Tyr Tyr Asn lie Asn Gin Val Thr Leu Gly Arg Arg 245 250 255 Ser lie Thr Ser Pro Pro Ser Thr Ser Thr Thr Lys Arg Pro Lys Ser 260 265 270 lie Asp Asp Ser Glu Met Glu Ser Pro Val Asp Asp Val Phe Tyr Pro 275 280 285 Gly Thr Gly Arg Ser Pro Ala Ala Gly Ser Ser Gin Ser Ser Gly Trp 290 90295 300 Pro Asn Asp Val Asp Ala Gly Pro Ala Ser Leu Lys Lys Ser Gly Lys 305 310 315 320 Leu Asp Phe Cys Ser Ala Leu Ser Ser Gin Gly Ser Ser Pro Arg Met 325 330 335 Ala Phe Thr His His Pro Leu Pro Val Leu Ala Gly Val Arg Pro Gly 340 345 350 Ser Pro Arg Ala Thr Ala Ser Ala Leu His Phe Pro Ser Thr Ser Ilie 355 360 365 Ile Gin Gin Ser Ser Pro Tyr Phe Thr His Pro Thr Ilie Arg Tyr His 370 375 380 His His His Gly Gin Asp Ser Leu Lys Giu Phe Val Gin Phe Val Cys 385 390 395 400 Ser Asp Gly Ser Gly Gin Ala Thr Gly Gin His Ser Gin Arg GIn Ala 405 410 415 Pro Pro Leu Pro Thr Gly Leu Ser Ala Ser Asp Pro Gly Thr Ala Thr 420 425 430 Phe <210O> 49 <21 1 >829 <213> Mus musculus <400> 49 caattctcct acgggctcca gactoagact ggtggaccca aacgcactcc ccttactaag agggtcgcgg ccccacagga tggatcccct agagccccag aaacttctgg accacctcca 120 gtggatcatc cacctccttc aagtaaggct tccaggcctc cgcccatggg gagctgtcct 180 gctactggtg tggagccccc aagttcccca gtcattgagt ctgaaactct gatagaagac 240 gtgctgagac ctctggaaca ggcattggag gactgccatg gtcacacaaa gaaacaggta 300 tgtgatgata tcagccgacg cttggcgctg cttcaagaac agtgggctgg agggaagttg 360 tcaaaacctg taaaggaggg gatggcattg ctagtgcaag gaattttaan attcacccag 420 tgggatgcag cagatgacat tcaccgatca ttcatggttg accatgtgac tgaggtcagt 480 cagtggatgg tgggagtaaa aagattaatt gcagaaaagg aagagtctat cttcagagga 540 gaccaaagaa gagaaattta cagtggaacc tgagaaccag acaataccag gctccaaca 600 *:Soo gccatcataa tgcctgtggc tccccagact cacttcacct gacttcctat gccttagtgt 660 ggaaggcttc ttnttccttt ttaccaccag ggagactatt ggtcttgtgg gtctgacca 720 aagatcctat ntagaccact gcaagatcac ttgttatgta catttcaata. aacatctcaa 780 taaatcta aggtgga gtggtaga agagaaa aaaaaag 829 <210> <21 1> 875 <212> DNA <213> Homo sapiens <300> <301 Lanz, R. B.

<302> A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex <303> Cell <304> 1999 <305> 97 <306> 17-27 <313> 1 TO 875 <400> cgcttggcgg agctgtacgt gaagccgggc aacaaggaac gcggctggaa cgacccgccg cagttctcat acgggctgca gacccaggcc ggcggaccca ggcgctcgct gcttaccaag 120 agggtagccg caccccagga tggatccccc agagtccccg catcagagac ttctcctggg 180 cctcccccaa tggggcctcc acctccttca agtaaggctc ccaggtcccc acctgtgggg 240 agtggtcctg cctctggcgt ggagcccaca agtttcccag tcgagtctga ggctgtgatg 300 gaggatgtgc tgagaccttt ggaacaggca ttggaagact gccgtggcca cacaaggaag 360 caggtatgtg atgacatcag ccgacgcctg gcactgctgc aggaacagtg ggctggagga 420 aagttgtcaa tacctgtaaa gaagagaatg gctctactgg tgcaagagct ttcaagccac 480 cggtgggacg cagcagatga catccaccgc tccctcatgg ttgaccatgt gactgaggtc 540 agtcagtgga tggtaggagt taaaagatta attgcagaaa agaggagtct gftttcagag 600 gaggcagcca atgaagagaa atctgcagcc acagctgaga agaaccatac cataccaggc 660 ttccagcagg cttcataatc ctcggttccc cagactcacc ggacaccatc tcctatgcct 720 tggagacctt ctgtcacttg gctcccttct taccaccacc aagactgtcc cactgggcct 780 gacccaccta tgagggaaga agtcccacct gggccagagg gagttcatgt gttactcata 840 acatgcattt caataaaaac atctctgcgg tggtg 875 <210> 51 <211> 182 <212> PRT <213> Mus musculus <300> <301> Schleef, M.

<302> Subtractive cONA cloning as a tool to analyse secondary effects of a muscle disease. Characterisation of iaffected genes in the myotonic ADR mouse <303> Neuromuscul. Disord.

<304> 1994 <305> 4 <306> 205-217 <313>1 TO 182 <400> 51 Met Gin Asp Ile Met Asp Arg Pro Pro Arg Ser Pro Lys Glu Pro Leu 1 5 10 999999 Ile Ser Giy Trp Leu Phe Phe Arg Tyr Met Ala lie Gly Giy Tyr Val 25 Gly Ala Ala Thr Val Gly Ala Ala Aia Trp Trp Phe Leu Tyr Ala Glu 40 Asp Gly Pro His Val Ser Tyr His GIn Leu Thr His Phe Met GIn Cys 55 Thr Giu His Asn Pro Glu Phe Asp Gly Leu Asp Cys Glu Val Phe Glu 70 75 Ala Pro Glu Pro Met Thr Met Ala Leu Ser Glu Leu Val Thr lie Glu 90 Met Cys Asn Ala Leu Asn Ser Leu Ser Glu Asn Gin Ser Leu Leu Arg 100 105 110 Met Pro Pro Trp Val Asn lie Trp Leu Leu Gly Ser lie Cys Leu Ser 115 120 125 Met Ser Leu His Phe Leu lie Leu Tyr Val Asp Pro Leu Pro Met lie 130 135 140 Phe Lys Leu Arg Ala Leu Asp Phe Thr Gin Trp Leu Met Val Leu Lys 145 150 155 160 lie Ser Leu Pro Val lie Gly Leu Asp Glu Leu Leu Lys Phe lie Ala 165 170 175 Arg Asn Tyr Leu Glu Gly 180 <210> 52 <211> 1001 <212> PRT <213> Homo sapiens <400> 52 Met Glu Ala Ala His Ala Lys Thr Thr Glu Glu Cys Leu Ala Tyr Phe 1 5 10 Gly Val Ser Glu Thr Thr Gly Leu Thr Pro Asp Gin Val Lys Arg Asn 25 Leu Glu Lys Tyr Gly Leu Asn Glu Leu Pro Ala Glu Glu Gly Lys Thr 35 40 Leu Trp Glu Leu Val lie Glu Gin Phe Glu Asp Leu Leu Val Arg lie 55 Leu Leu Leu Ala Ala Cys lie Ser Phe Val Leu Ala Trp Phe Glu Glu 70 75 Gly Glu Glu Thr lie Thr Ala Phe Val Glu Pro Phe Val lie Leu Leu 85 90 lie Leu lie Ala Asn Ala lie Val Gly Val Trp Gin Glu Arg Asn Ala 100 105 110 Glu Asn Ala lie Glu Ala Leu Lys Glu Tyr Glu Pro Glu Met Gly Lys 115 120 125 Val Tyr Arg Ala Asp Arg Lys Ser Val Gin Arg lie Lys Ala Arg Asp 130 135 140 lie Val Pro Gly Asp lie Val Glu Val Ala Val Gly Asp Lys Val Pro 145 150 155 160 Ala Asp lie Arg lie Leu Ala lie Lys Ser Thr Thr Leu Arg Val Asp 165 170 175 Gin Ser lie Leu Thr Gly Glu Ser Val Ser Val lie Lys His Thr Glu 180 185 190 Pro Val Pro Asp Pro Arg Ala Val Asn Gin Asp Lys Lys Asn Met Leu 195 200 205 Phe Ser Gly Thr Asn lie Ala Ala Gly Lys Ala Leu Gly lie Val Ala 210 215 220 Thr Thr Gly Val Gly Thr Glu lie Gly Lys lie Arg Asp Gin Met Ala 225 230 235 240 Ala Thr Glu Gin Asp Lys Thr Pro Leu Gin Gin Lys Leu Asp Glu Phe 245 250 255 Gly Glu Gin Leu Ser Lys Val lie Ser Leu lie Cys Val Ala Val Trp 260 265 270 Leu lie Asn lie Gly His Phe Asn Asp Pro Val His Gly Gly Ser Trp 275 280 285 Phe Arg Gly Ala lie Tyr Tyr Phe Lys lie Ala Val Ala Leu Ala Val 290 295 300 Ala Ala lie Pro Glu Gly Leu Pro Ala Val lie Thr Thr Cys Leu Ala 305 310 315 320 Leu Gly Thr Arg Arg Met Ala Lys Lys Asn Ala lie Val Arg Ser Leu 325 330 335 *o Pro Ser Val Glu Thr Leu Gly Cys Thr Ser Val lie Cys Ser Asp Lys 340 345 350 Thr Gly Thr Leu Thr Thr Asn Gin Met Ser Val Cys Lys Met Phe lie 355 360 365 lie Asp Lys Val Asp Gly Asp lie Cys Leu Leu Asn Glu Phe Ser lie 370 375 380 Thr Gly Ser Thr Tyr Ala Pro Glu Gly Glu Val Leu Lys Asn Asp Lys 385 390 395 400 Pro Val Arg Pro Gly Gin Tyr Asp Gly Leu Val Glu Leu Ala Thr lie 405 410 415 0 Cys Ala Leu Cys Asn Asp Ser Ser Leu Asp Phe Asn Glu Ala Lys Gly 420 425 430 Val Tyr Glu Lys Val Gly Glu Ala Thr Glu Thr Ala Leu Thr Thr Leu 435 440 445 Val Glu Lys Met Asn Val Phe Asn Thr Asp Val Arg Ser Leu Ser Lys 450 455 460 Val Glu Arg Ala Asn Ala Cys Asn Ser Val lie Arg Gin Leu Met Lys 465 470 475 480 Lys Glu Phe Thr Leu Glu Phe Ser Arg Asp Arg Lys Ser Met Ser Val 485 490 495 Tyr Cys Ser Pro Ala Lys Ser Ser Arg Ala Ala Val Gly Asn Lys Met 500 505 510 Phe Val Lys Gly Ala Pro Glu Gly Val lie Asp Arg Cys Asn Tyr Val 515 520 525 Arg Val Gly Thr Thr Arg Val Pro Leu Thr Gly Pro Val Lys Glu Lys 530 535 540 lie Met Ala Val lie Lys Glu Trp Gly Thr Gly Arg Asp Thr Leu Arg 545 550 555 560 Cys Leu Ala Leu Ala Thr Arg Asp Thr Pro Pro Lys Arg Glu Glu Met 565 570 575 Val Leu Asp Asp Ser Ala Arg Phe Leu Glu Tyr Glu Thr Asp Leu Thr 580 585 590 Phe Val Gly Val Val Gly Met Leu Asp Pro Pro Arg Lys Glu Val Thr 595 600 605 Gly Ser lie Gin Leu Cys Arg Asp Ala Gly lie Arg Val lie Met lie 610 615 620 Thr Gly Asp Asn Lys Gly Thr Ala lie Ala lie Cys Arg Arg lie Gly 625 630 635 640 lie Phe Gly Glu Asn Glu Glu Val Ala Asp Arg Ala Tyr Thr Gly Arg 645 650 655 Glu Phe Asp Asp Leu Pro Leu Ala Glu Gin Arg Glu Ala Cys Arg Arg .660 665 670 Ala Cys Cys Phe Ala Arg Val Glu Pro Ser His Lys Ser Lys lie Val 675 680 685 Glu Tyr Leu Gin Ser Tyr Asp Glu lie Thr Ala Met Thr Gly Asp Gly 690 695 700 Val Asn Asp Ala Pro Ala Leu Lys Lys Ala Glu lie Gly lie Ala Met 705 710 715 720 Gly Ser Gly Thr Ala Val Ala Lys Thr Ala Ser Glu Met Val Leu Ala 725 730 735 Asp Asp Asn Phe Ser Thr lie Val Ala Ala Val Glu Glu Gly Arg Ala 740 745 750 lie Tyr Asn Asn Met Lys Gin Phe lie Arg Tyr Leu lie Ser Ser Asn 755 760 765 Val Gly Glu Val Val Cys lie Phe Leu Thr Ala Ala Leu Gly Leu Pro 770 775 780 Glu Ala Leu lie Pro Val Gin Leu Leu Trp Val Asn Leu Val Thr Asp 785 790 795 800 Gly Leu Pro Ala Thr Ala Leu Gly Phe Asn Pro Pro Asp Leu Asp lie 805 810 815 Met Asp Arg Pro Pro Arg Ser Pro Lys Glu Pro Leu lie Ser Gly Trp 820 825 830 Leu Phe Phe Arg Tyr Met Ala lie Gly Gly Tyr Val Gly Ala Ala Thr 835 840 845 Val Gly Ala Ala Ala Trp Trp Phe Leu Tyr Ala Glu Asp Gly Pro His 850 855 860 Val Asn Tyr Ser Gin Leu Thr His Phe Met Gin Cys Thr Glu Asp Asn 865 870 875 880 Thr His Phe Glu Gly lie Asp Cys Glu Val Phe Glu Ala Pro Glu Pro 885 890 895 Met Thr Met Ala Leu Ser Val Leu Val Thr lie Glu Met Cys Asn Ala 900 905 910 Leu Asn Ser Leu Ser Glu Asn Gin Ser Leu Leu Arg Met Pro Pro Trp 915 920 925 Val Asn lie Trp Leu Leu Gly Ser lie Cys Leu Ser Met Ser Leu His 930 935 940 Phe Leu lie Leu Tyr Val Asp Pro Leu Pro Met lie Phe Lys Leu Arg 945 950 955 960 Ala Leu Asp Leu Thr Gin Trp Leu Met Val Leu Lys lie Ser Leu Pro 965 970 975 Val lie Gly Leu Asp Glu lie Leu Lys Phe Val Ala Arg Asn Tyr Leu 980 985 990 Glu Asp Pro Glu Asp Glu Arg Arg Lys 995 1000 <210> 53 <211> 89 <212> PRT <213> Mus musculus <400> 53 Met Pro Ser Glu Leu Glu Lys Ala Leu Ser Asn Leu lie Asp Val Tyr 1 5 10 His Asn Tyr Ser Asn lie Gin Gly Asn His His Ala Leu Tyr Lys Asn 25 Asp Phe Lys Lys Met Val Thr Thr Glu Cys Pro Gin Phe Val Gin Asn 40 lie Asn lie Glu Asn Leu Phe Arg Glu Leu Asp lie Asn Ser Asp Asn 55 Ala lie Asn Phe Glu Glu Phe Leu Ala Met Val lie Lys Val Gly Val 70 75 Ala Ser His Lys Asp Ser His Lys Glu <210> 54 <211> 93 <212> PRT <213> Homo sapiens <300> <301> Dorin, J. R.

<302> A clue to the basic defect in cystic fibrosis from cloning the CF antigen gene <303> Nature <304> 1987 <305> 326 <306> 614-617 <313> 1 TO 93 <400> 54 Met Leu Thr Glu Leu Glu Lys Ala Leu Asn Ser lie lie Asp Val Tyr 1 5 10 His Lys Tyr Ser Leu lie Lys Gly Asn Phe His Ala Val Tyr Arg Asp 25 Asp Leu Lys Lys Leu Leu Glu Thr Glu Cys Pro Gin Tyr lie Arg Lys 35 40 Lys Gly Ala Asp Val Trp Phe Lys Glu Leu Asp lie Asn Thr Asp Gly 55 Ala Val Asn Phe Gin Glu Phe Leu lie Leu Val lie Lys Met Gly Val 65 70 75 Ala Ala His Lys Lys Ser His Glu Glu Ser His Lys Glu 85 <210> <211> 134 <212> PRT <213> Homo sapiens <400> Met Ser Tyr Asn Cys Cys Ser Gly Asn Phe Ser Ser Arg Ser Cys Gly 1 5 10 Asp Tyr Leu Arg Tyr Pro Ala Ser Ser Arg Gly Phe Ser Tyr Pro Ser 25 Asn Leu Val Tyr Ser Thr Asp Leu Cys Ser Pro Ser Thr Cys Gin Leu 40 Gly Ser Ser Leu Tyr Arg Gly Cys Gin Glu lie Cys Trp Glu Pro Thr 55 Ser Cys Gin Thr Ser Tyr Val Glu Ser Ser Pro Cys Gin Thr Ser Cys 70 75 Tyr Arg Pro Arg Thr Ser Leu Leu Cys Ser Pro Cys Lys Thr Thr Tyr 90 Ser Gly Ser Leu Gly Phe Gly Ser Ser Ser Cys Arg Ser Leu Gly Tyr 100 105 110 Gly Ser Arg Ser Cys Tyr Ser Val Gly Cys Gly Ser Ser Gly Val Arg 115 120 125 Ser Leu Gly Tyr Gly Ser 130 <210> 56 <211> 306 <212> PRT <213> Mus musculus <400> 56 Met Ala Ser Ser Gly Ser Val Gin Gin Leu Pro Leu Val Leu Leu Met 1 5 10 Leu Leu Leu Ala Ser Ala Ala Arg Ala Arg Leu Tyr Phe Arg Ser Gly 25 Gin Thr Cys Tyr His Pro lie Arg Gly Asp Gin Leu Ala Leu Leu Gly 40 Arg Arg Thr Tyr Pro Arg Pro His Glu Tyr Leu Ser Pro Ala Asp Leu 55 Pro Lys Asn Trp Asp Trp Arg Asn Val Asn Gly Val Asn Tyr Ala Ser 70 75 Val Thr Arg Asn Gin His lie Pro Gin Tyr Cys Gly Ser Cys Trp Ala 90 His Gly Ser Thr Ser Ala Met Ala Asp Arg lie Asn lie Lys Arg Lys 100 105 110 Gly Ala Trp Pro Ser lie Leu Leu Ser Val Gin Asn Val lie Asp Cys 115 120 125 Gly Asn Ala Gly Ser Cys Glu Gly Gly Asn Asp Leu Pro Val Trp Glu 130 135 140 Tyr Ala His Lys His Gly lie Pro Asp Glu Thr Cys Asn Asn Tyr Gin 145 150 155 160 Ala Lys Asp Gin Asp Cys Asp Lys Phe Asn Gin Cys Gly Thr Cys Thr 165 170 175 Glu Phe Lys Glu Cys His Thr lie Gin Asn Tyr Thr Leu Trp Arg Val 180 185 190 Gly Asp Tyr Gly Ser Leu Ser Gly Arg Glu Lys Met Met Ala Glu lie 195 200 205 Tyr Ala Asn Gly Pro lie Ser Cys Gly lie Met Ala Thr Glu Met Met 210 215 220 Ser Asn Tyr Thr Gly Gly lie Tyr Ala Glu His Gin Asp Gin Ala Val 225 230 235 240 lie Asn His lie lie Ser Val Ala Gly Trp Gly Val Ser Asn Asp Gly 245 250 255 lie Glu Tyr Trp lie Val Arg Asn Ser Trp Gly Glu Pro Trp Gly Glu 260 265 270 Lys Gly Trp Met Arg lie Val Thr Ser Thr Tyr Lys Gly Gly Thr Gly 275 280 285 Asp Ser Tyr Asn Leu Ala lie Glu Ser Ala Cys Thr Phe Gly Asp Pro 290 295 300 lie Val 305 <210> 57 <211> 303 <212> PRT <213> Homo sapiens <400> 57 Met Ala Arg Arg Gly Pro Gly Trp Arg Pro Leu Leu Leu Leu Val Leu 1 5 10 4o Leu Ala Gly Ala Ala Gin Gly Gly Leu Tyr Phe Arg Arg Gly Gin Thr 20 25 Cys Tyr Arg Pro Leu Arg Gly Asp Gly Leu Ala Pro Leu Gly Arg Thr 40 Thr Tyr Pro Arg Pro His Glu Tyr Leu Ser Pro Ala Asp Leu Pro Lys 50 55 Ser Trp Asp Trp Arg Asn Val Asp Gly Val Asn Tyr Ala Ser lie Thr S 65 70 75 Arg Asn Gin His lie Pro Gin Tyr Cys Gly Ser Cys Trp Ala His Ala 90 Ser Thr Ser Ala Met Ala Asp Arg lie Asn lie Lys Arg Lys Gly Ala 100 105 110 Trp Pro Ser Thr Leu Leu Ser Val Gin Asn Val lie Asp Cys Gly Asn 115 120 125 Ala Gly Ser Cys Glu Gly Gly Asn Asp Leu Ser Val Trp Asp Tyr Ala 130 135 140 His Gin His Gly lie Pro Asp Glu Thr Cys Asn Asn Tyr Gin Ala Lys 145 150 155 160 Asp Gin Glu Cys Asp Lys Phe Asn Gin Cys Gly Thr Cys Asn Glu Phe 165 170 175 Lys Glu Cys His Ala lie Arg Asn Tyr Thr Leu Trp Arg Val Gly Asp 180 185 190 Tyr Gly Ser Leu Ser Gly Arg Glu Lys Met Met Ala Glu lie Tyr Ala 195 200 205 Asn Gly Pro lie Ser Cys Gly lie Met Ala Thr Glu Arg Leu Ala Asn 210 215 220 Tyr Thr Gly Gly lie Tyr Ala Glu Tyr Gin Asp Thr Thr Tyr lie Asn 225 230 235 240 His Val Val Ser Val Ala Gly Trp Gly lie Ser Asp Gly Thr Glu Tyr 245 250 255 Trp lie Val Arg Asn Ser Trp Gly Glu Pro Trp Gly Glu Arg Gly Trp 260 265 270 Leu Arg lie Val Thr Ser Thr Tyr Lys Asp Gly Lys Gly Ala Arg Tyr 275 280 285 Asn Leu Ala lie Glu Glu His Cys Thr Phe Gly Asp Pro lie Val 290 295 300 <210> 58 <211> 469 <212> PRT <213> Homo sapiens <400> 58 Met Asp lie Glu Asn Glu Gin Thr Leu Asn Val Asn Pro Thr Asp Pro S1 5 10 Asp Asn Leu Ser Asp Ser Leu Phe Ser Gly Asp Glu Glu Asn Ala Gly 20 25

*SSS

Thr Glu Glu lie Lys Asn Glu lie Asn Gly Asn Trp lie Ser Ala Ser 40 Thr lie Asn Glu Ala Arg lie Asn Ala Lys Ala Lys Arg Arg Leu Arg 50 55 Lys Asn Ser Ser Arg Asp Ser Gly Arg Gly Asp Ser Val Ser Asp Asn 70 75 Gly Ser Glu Ala Val Arg Ser Gly Val Ala Val Pro Thr Ser Pro Lys 85 90 Gly Arg Leu Leu Asp Arg Arg Ser Arg Ser Gly Lys Gly Arg Gly Leu 100 105 110 Pro Lys Lys Gly Gly Ala Gly Gly Lys Gly Val Trp Gly Thr Pro Gly 115 120 125 Gin Val Tyr Asp Val Glu Glu Val Asp Val Lys Asp Pro Asn Tyr Asp 130 135 140 Asp Asp Gin Glu Asn Cys Val Tyr Glu Thr Val Val Leu Pro Leu Asp 145 150 155 160 Glu Thr Ala Phe Glu Lys Thr Leu Thr Pro lie lie Gin Glu Tyr Phe 165 170 175 Glu His Gly Asp Thr Asn Glu Val Ala Glu Met Leu Arg Asp Leu Asn 180 185 190 Leu Gly Glu Met Lys Ser Gly Val Pro Val Leu Ala Val Ser Leu Ala 195 200 205 Leu Glu Gly Lys Ala Ser His Arg Glu Met Thr Ser Lys Leu Leu Ser 210 215 220 Asp Leu Cys Gly Thr Val Met Ser Thr Asn Asp Val Glu Lys Ser Phe 225 230 235 240 Asp Lys Leu Leu Lys Asp Leu Pro Glu Leu Ala Leu Asp Thr Pro Arg 245 250 255 Ala Pro Gin Leu Val Gly Gin Phe lie Ala Arg Ala Val Gly Asp Gly 260 265 270 lie Leu Cys Asn Thr Tyr lie Asp Ser Tyr Lys Gly Thr Val Asp Cys 275 280 285 Val Gin Ala Arg Ala Ala Leu Asp Lys Ala Thr Val Leu Leu Ser Met 290 295 300 Ser Lys Gly Gly Lys Arg Lys Asp Ser Val Trp Gly Ser Gly Gly Gly 305 310 315 320 Gin Gin Pro Val Asn His Leu Val Lys Glu lie Asp Met Leu Leu Lys 325 330 335 Glu Tyr Leu Leu Ser Gly Asp lie Ser Glu Ala Glu His Cys Leu Lys 340 345 350 Glu Leu Glu Val Pro His Phe His His Glu Leu Val Tyr Glu Ala lie 355 360 365 Val Met Val Leu Glu Ser Thr Gly Glu Ser Ala Phe Lys Met lie Leu 370 375 380 Asp Leu Leu Lys Ser Leu Trp Lys Ser Ser Thr lie Thr lie Asp Gin 385 390 395 400 Met Lys Arg Gly Tyr Glu Arg lie Tyr Asn Glu lie Pro Asp lie Asn 405 410 415 Leu Asp Val Pro His Ser Tyr Ser Val Leu Glu Arg Phe Val Glu Glu 420 425 430 Cys Phe Gin Ala Gly lie lie Ser Lys Gin Leu Arg Asp Leu Cys Pro 435 440 445 Ser Arg Gly Arg Lys Arg Phe Val Ser Glu Gly Asp Gly Gly Arg Leu 450 455 460 Lys Pro Glu Ser Tyr 465 <210> 59 <211> 418 <212> PRT <213> Mus musculus <400> 59 Met Ala Phe lie Ala Ala Leu Gly Leu Leu Met Ala Arg lie Cys Pro 1 5 10 Ala Val Leu Ser Phe Pro Asp Gly Thr Leu Gly Met Asp Ala Ala Val 25 Gin Glu Asp His Asp Asn Gly Thr Gin Leu Asp Ser Leu Thr Leu Ala 40 Ser lie Asn Thr Asp Phe Ala Phe Ser Leu Tyr Lys Glu Leu Val Leu 55 Lys Asn Pro Asp Thr Asn lie Val Phe Ser Pro Leu Ser lie Ser Ala 70 75 Ala Leu Ala Leu Val Ser Leu Gly Ala Lys Gly Asn Thr Leu Glu Glu 90 lie Leu Glu Gly Leu Lys Phe Asn Leu Thr Glu Thr Ser Glu Ala Asp 100 105 110 lie His Gin Gly Phe Gly His Leu Leu Gin Arg Leu Asn Gin Pro Lys 115 120 125 Asp Gin Val Gin lie Ser Thr Gly Ser Ala Leu Phe lie Glu Lys Arg 130 135 140 Gin Gin lie Leu Thr Glu Phe Gin Glu Lys Ala Lys Thr Leu Tyr Gin 145 150 155 160 Ala Glu Ala Phe Thr Ala Asp Phe Gin Gin Pro Arg Gin Ala Lys Lys 165 170 175 SLeu lie Asn Asp Tyr Val Arg Lys Gin Thr Gin Gly Met lie Lys Glu 180 185 190 Leu Val Ser Asp Leu Asp Lys Arg Thr Leu Met Val Leu Val Asn Tyr 195 200 205 lie Tyr Phe Lys Ala Lys Trp Lys Val Pro Phe Asp Pro Leu Asp Thr 210 215 220 Phe Lys Ser Glu Phe Tyr Ala Gly Lys Arg Arg Pro Val lie Val Pro 225 230 235 240 Met Met Ser Met Glu Asp Leu Thr Thr Pro Tyr Phe Arg Asp Glu Glu 245 250 255 Leu Ser Cys Thr Val Val Glu Leu Lys Tyr Thr Gly Asn Ala Ser Ala 260 265 270 Leu Phe lie Leu Pro Asp Gin Gly Arg Met Gin Gin Val Glu Ala Ser 275 280 285 Leu Gin Pro Glu Thr Leu Arg Lys Trp Lys Asn Ser Leu Lys Pro Arg 290 295 300 Met lie Asp Glu Leu His Leu Pro Lys Phe Ser lie Ser Thr Asp Tyr 305 310 315 320 Ser Leu Glu Asp Val Leu Ser Lys Leu Gly lie Arg Glu Val Phe Ser 325 330 335 Thr Gin Ala Asp Leu Ser Ala lie Thr Gly Thr Lys Asp Leu Arg Val 340 345 350 Ser Gin Val Val His Lys Ala Val Leu Asp Val Ala Glu Thr Gly Thr 355 360 365 Glu Ala Ala Ala Ala Thr Gly Val Lys Phe Val Pro Met Ser Ala Lys 370 375 380 Leu Tyr Pro Leu Thr Val Tyr Phe Asn Arg Pro Phe Leu lie Met lie 385 390 395 400 Phe Asp Thr Glu Thr Glu lie Ala Pro Phe lie Ala Lys lie Ala Asn 405 410 415 Pro Lys <210> <211> 423 <212> PRT <213> Homo sapiens <400> Met Glu Arg Met Leu Pro Leu Leu Thr Leu Gly Leu Leu Ala Ala Gly 1 5 10 Phe Cys Pro Ala Val Leu Cys His Pro Asn Ser Pro Leu Asp Glu Glu 25 Asn Leu Thr Gin Glu Asn Gin Asp Arg Gly Thr His Val Asp Leu Gly 40 Leu Ala Ser Ala Asn Val Asp Phe Ala Phe Ser Leu Tyr Lys Gin Leu 55 Val Leu Lys Ala Pro Asp Lys Asn Val lie Phe Ser Pro Leu Ser lie 70 75 Ser Thr Ala Leu Ala Phe Leu Ser Leu Gly Ala His Asn Thr Thr Leu 90 Thr Glu lie Leu Lys Gly Leu Lys Phe Asn Leu Thr Glu Thr Ser Glu 100 105 110 Ala Glu lie His Gin Ser Phe Gin His Leu Leu Arg Thr Leu Asn Gin 115 120 125 Ser Ser Asp Glu Leu Gin Leu Ser Met Gly Asn Ala Met Phe Val Lys 130 135 140 Glu Gin Leu Ser Leu Leu Asp Arg Phe Thr Glu Asp Ala Lys Arg Leu 145 150 155 160 Tyr Gly Ser Glu Ala Phe Ala Thr Asp Phe Gin Asp Ser Ala Ala Ala 165 170 175 Lys Lys Leu lie Asn Asp Tyr Val Lys Asn Gly Thr Arg Gly Lys lie 180 185 190 Thr Asp Leu lie Lys Asp Leu Asp Ser Gin Thr Met Met Val Leu Val 195 200 205 Asn Tyr lie Phe Phe Lys Ala Lys Trp Glu Met Pro Phe Asp Pro Gin 210 215 220 Asp Thr His Gin Ser Arg Phe Tyr Leu Ser Lys Lys Lys Trp Val Met 225 230 235 240 Val Pro Met Met Ser Leu His His Leu Thr lie Pro Tyr Phe Arg Asp 245 250 255 Glu Glu Leu Ser Cys Thr Val Val Glu Leu Lys Tyr Thr Gly Asn Ala 260 265 270 Ser Ala Leu Phe lie Leu Pro Asp Gin Asp Lys Met Glu Glu Val Glu 275 280 285 i*ooo Ala Met Leu Leu Pro Glu Thr Leu Lys Arg Trp Arg Asp Ser Leu Glu 290 295 300 Phe Arg Glu lie Gly Glu Leu Tyr Leu Pro Lys Phe Ser lie Ser Arg 305 310 315 320 Asp Tyr Asn Leu Asn Asp lie Leu Leu Gin Leu Gly lie Glu Glu Ala 325 330 335 Phe Thr Ser Lys Ala Asp Leu Ser Gly lie Thr Gly Ala Arg Asn Leu 340 345 350 Ala Val Ser Gin Val Val His Lys Ala Val Leu Asp Val Phe Glu Glu 355 360 365 Gly Thr Glu Ala Ser Ala Ala Thr Ala Val Lys lie Thr Leu Leu Ser 370 375 380 Ala Leu Val Glu Thr Arg Thr lie Val Arg Phe Asn Arg Pro Phe Leu 385 390 395 400 Met lie lie Val Pro Thr Asp Thr Gin Asn lie Phe Phe Met Ser Lys 405 410 415 Val Thr Asn Pro Lys Gin Ala 420 <210> 61 <21 1 >542 <212> DNA <213> Mus musculus <400> 61 agcagktata tgtttattga tcctttgctc ctacctcttt attctggttg gtggtgttcc tcttttgtgt gaggttggtc agctgggaac taaaagaaag gctactttgt tctaagtagg 120 agtgccaggg gaaaggatct gctctgaccc acagaccoca tgcagctgca gaagtgaggg 180 ctctaactct gtgccagatg tggacaaagt gaggagatcc tgcagggggg cagtgcctgg 240 aggcaaagcc tggagaagtg aaagagtgag gcagactggg caccaagtag tcctagatgc 300 tgcggataga cacggggcag caagctttcc tcttggtcca tatgggttgg cctgtaaggt 360 tgcacagtcc catcaaraca gcaaggctga agggagacat aaccagagtc taaactggga 420 ctgagcttac ttgatggggc ccangctttt gggtggaggc asatacaggg agagagcagg 480 ggtgggggac aaaanaaatt tcangctcaa gaacatgggc tngtgctcca aaaaatcttg 540 ga 542 <210> 62 <21 1 >2035 <212> DNA <213> Mus musculus <400> 62 cacgagcaca gaggctggca gctggctggt ttcagctctg cagactgcag aacacagaag atggctttca ttgcagctct ggggctcttg atggctggga tctgccctgc tgtcctctgc 120 ttcccagatg gcacgttggg aatggatgct gcagtccaag aagaccatga caatgggaca 180 caactggaca gtctcacatt ggcctccatc aacactgact ttgcctcag cctctacaag 240 gag ctggtt tgaagaatcc agataaaaat attgtcttct ccccacttag caccgg30036 ctcaagttca atcttacaga gacctctgag gcagacatcc accagggctt tgggcacctc 420 ctacagaggc tcaaccagcc aaaggaccag gtacagatca gcacgggtag tgccctgttt 480 attgaaaagc gccagcagat cctgacagaa ttccaggaga aggcaaagac tctgtaccag 540 gctgaggcct tcacagcaga cttccagcag cctcgacagg ccaaaaagct catcaatgac 600 tatgtgagga aacagaccca ggggatgatc aaggaactgg tctcagacct ggataaaagg 660 acattgatgg tgctggtgaa ttatatctac tttaaagcca aatggaaggt gccctttgac 720 cctcttgaca cgttcaagtc tgagttctac tgcggcaaga ggaggcccgt gatagtgccc 780 atgatgagca tggaggacct gaccacaccc tacttccgag atgaggagct gtcctgcact 840 gtggtggagc tgaagtacac aggaaatgcc agcgccctgt tcatcctccc tgaccagggc 900 aggatgcagc aggtggaagc cagcttacaa ccagagaccc tgaggaagtg gaagaattct 960 ctgaaaccca ggatgataga tgagctccac ctgcccaagt tctccatctc caccgactac 1020 agcctggagg atgtcctttc aaagctgggc atcagggaag tcttctccac acaggctgac 1080 ctgtctgcaa tcacaggaac caaggatctg agagtgtctc aggtggtcca caaggctgtg 1140 ctggatgtgg ctgagacagg cacagaagca gctgctgcca ctggagtcaa atttgtccca 1200 atgtctgcga aactgtaccc tctgactgta tatttcaatc ggcctttcct gataatgatc 1260 tttgacacag aaactgaaat tgcccccttt atagccaaga tagccaaccc caaatgagac 1320 tagaactccc caagtgttga cgcttcttcc cgggagccag gcattgagcc tgtctgtggg 1380 tctccatgtg cattttggct tccatgctct gcttggcctt ggcatgcctg gattagatag 1440 tgactaactg tgttataacc tcatgtacag acatccctgt gggaagtcag tgccgtgctc 1500 coagactct tggtagcact agcccatgtt cctgagcctg aaatttgtct tgtcccctac 1560 ccctgctctc tccctgtatc tgcctccacc caaaagcctg ggccccatca agtaagctca 1620 gtcccagttt agactctggt tatgtctccc ttcagccttg ctgtcttgat gggactgtgc 1680 aaccttacag gccaacccat atggaccaag aggaaagctt ggctggcccg tgtctatccg 1740 cagcatctag gactacttgg tgcccagtct gcctcactct ttcatttctc caggctttgc 1800 ctccaggcac tgcccccctg caggatctcc tcactttgtc cacatctggc acagagttag 1860 agccctcact tctgcagctg catggggtct gtgggtcaga gcagatcctt tcccctggca 1920 ctcctactta gaacaaagta gcctttcttt tagttcccag ctgaccaacc tcacacaaaa 1980 gaggaacacc aaccagaata aagaggtagg agcaaaggat caataaacat gtaac 2035 <210> 63 <21 1> 120 <212> DNA <213> Mus musculus <400> 63 accacagtcc atgccatcac tgccacccag aagactgtgg atggcccctc tggaaagctg tggcgtgatg gccgtggggc tgcccagaac atcatccctg catccactgg tgctgccaag 120 <210> 64 <21 1> 1310 <212> DNA <213> Mus musculus <400> 64 actgcagaac acagaagatg gctttcattg cagctctggg gctcttgatg gctaggatct gccctgctgt cctctccttc ccagatggca cgttgggaat ggatgctgca gtccaagaag 120 accatgacaa tgggacacaa ctggacagtc tcacattggc ctccatcaac actgactttg 180 ccttcagcct ctacaaggag ctggttga agaatccaga tacaaatatt gtcttctccc 240 cacttagcat ctcagcggcc ttggccctcg tgtccctggg agcaaagggc aacaccctgg 300 aagagattct agaaggtctc aagttcaatc ttacagagac ctctgaggca gacatccacc 360 agggctttgg gcacctccta cagaggctca accagccaaa ggaccaggta cagatcagca 420 cgggtagtgc cctgtttatt gaaaagcgcc agcagatcct gacagaattc caggagaagg 480 caaagactct gtaccaggct gaggccttca cagcagactt ccagcagcct cgacaggcca 540 aaaagctcat caatgactat gtgaggaaac agacccaggg gatgatcaag gaactggtct 600 cagacctgga taaaaggaca ttgatggtgc tggtgaatta tatctacttt aaagccaaat 660 ggaaggtgcc ctttgaccct cttgacacgt tcaagtctga gttctacgcg ggcaagagga 720 ggcccgtgat agtgcccatg atgagcatgg aggacctgac cacacoctac ttccgagatg 780 aggagctgtc ctgcactgtg gtggagctga agtacacagg aaatgccagc gccctgttca 840 tcctccctga ccagggcagg atgcagcagg tggaagccag cttacaacca gagaccctga 900 ggaagtggaa gaattctctg aaacccagga tgatagatga gctccacctg cccaagttct 960 ccatctccac cgactacagc ctggaggatg tcctttcaaa gctgggcatc agggaagtct 1020 tctccacaca ggctgacctg tctgcaatca caggaaccaa ggatctgaga gtctctcagg 1080 tggtccacaa ggctgtgctg gatgtggctg agacaggcac agaagcagct gctgccactg 1140 gagtcaaatt tgtcccaatg tctgcgaaac tgtaccctct gactgtatat ttcaatcggc 1200 ctttcctgat aatgatcttt gacacagaaa ctgaaattgc cccctttata gccaagatag 1260 ccaaccccaa atgagactag aactccccaa gtgttgacgc ttcttcccgg 1310 <210O> 9 <21 1>20 <212> DNA <213> Artificial Sequence <220> <223> Beschreibung der k~instlichen Sequenz: Universal primer <220> <223> Description of Artificial Sequence: Universal Primer <400> agcgtggtcg cggccgaggt <210> 66 <21 1> 21 <212> DNA <213> Artificial Sequence <220> <223> Beschreibung der k~nstlichen Sequenz: Universai primer <220> <223> Description of Artificial Sequence: Universal Primer <400> 66 tccagftgtg tcccaftgtc a 21 <210> 67 <21 1> 21 <212> DNA <213> Mus musculus <400> 67 ctgtcctctg cttcccagat g 21 <210> 68 <21 1 >21 <212> DNA S. <213> Mus muscujus <400> 68 tccagttgtg tcccattgtc a 21 <210> 69 <211> 19 <212> DNA <213> Mus musculus <400> 69 atcaacggga agcccatca 19 <210> <21 1 <212> DNA <213> Mus musculus <400> gacatactca gcaccggcct <210> 71 <21 1> <212> DNA <213> Mus musculus <400> 71 actgcagaac acagaagatg gctttcattg <210> 72 <21 1> <212> DNA <213> Mus musculus <400> 72 ccgggaagaa gcgtcaacac ttggggagtt <210> 73 <21 1 <212> DNA <213> Homo sapiens <400> 73 aactcagctg aactcacatc tcccgtcaac <210> 74 <21 1> <212> DNA <213> Homo sapiens <400> 74 gtctgaaaga actagcctgl ccagccagta <210O> <21 1 >22 <212> DNA <213> Homo sapiens <400> catgggtgtg aaccatgaga ag 22 <210> 76 <21 1 >21 <212> DNA <213> Homo sapiens <400> 76 *ctaagcagtt ggtggtgcag g 21 <210> 77 <21 1 >19 <212> DNA <213> Homo sapiens <400> 77 gag gccattt ccagcgact 19 <210> 78 <211> <212> DNA <213> Homo sapiens <400> 78 gaataacccg acatggcgtc <210> 79 <211> 43 <212> DNA <213> Artificial Sequence <220> <223> Beschreibung der kOnstlichen Sequenz:Antisense primer that fuses the T7 RNA polymerase promoter with a region homologous to human MRP8 <220> <223> Description of Artificial Sequence: Antisense primer that fuses the T7 RNA polmerase promoter with a region horpolgous to human MRP8 <400> 79 taatacgact cactataggg cccacgccca tctttatcac cag 43 <210> <211>43 <212> DNA <213> Artificial Sequence <220> <223> Beschreibung der kOnstlichen Sequenz:Sense primer that fuses the T3 RNA polymerase promoter with a region homologous to human MRP8 <220> <223> Description of Artificial Sequence: Sense primer that fuses the T3 RNA polmerase promoter with a region homolgous to human MRP8 <400> aattaaccct cactaaaggg ggaatttcca tgccgtctac agg 43 <210> 81 <211> 42 <212> DNA <213> Artificial Sequence <220> <223> Beschreibung der kOnstlichen Sequenz:Antisense primer that fuses the T3 RNA polymerase promoter with a region homologous to human p68 helicase <220> <223> Description of Artificial Sequence: Antisense primer that fuses the T3 RNA polmerase promoter with a region homolgous to human p68 helicase <400> 81 aattaaccct cactaaaggg ggcaacatta cttccatatt gc 42 <210> 82 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> Beschreibung der kOnstlichen Sequenz:Sense primer that fuses the T7 RNA polymerase promoter with a region homologous to human p68 helicase <220> <223> Description of Artificial Sequence: Antisense primer that fuses the T7 RNA polmerase promoter with a region homolgous to human p68 helicase <400> 82 taatacgact cactataggg cgagacaggg aaaactatga c 41 <210> 83 <211> 22 <212> DNA <213> Mus musculus <400> 83 ccttatctct gtgcttcggg aa 22 <210> 84 <211>21 <212> DNA <213> Mus musculus *<400> 84 cgacctgaac ctctgtcttc g 21 <210> <211>15 <212> PRT <213> Homo sapiens <400> Arg Glu Phe Gin Arg Gly Thr Cys Ser Arg Pro Asp Thr Glu Cys 1 5 10 <210> 86 <211>16 <212> PRT <213> Homo sapiens <400> 86 Arg Glu Tyr Gin Arg Gly Asn Cys Asn Arg Gly Glu Asn Asp Cys Arg 1 5 10 <210> 87 <211> <212> PRT <213> Homo sapiens <400> 87 Cys Asp Glu Leu Thr Arg Lys Met Arg Arg Asp Gly Trp Pro Ala 1 5 10 <210> 88 <211>16 <212> PRT <213> Homo sapiens <400> 88 Asn Thr Phe Arg Asp Arg Glu Asn Tyr Asp Arg Gly Tyr Ser Ser Cys 1 5 10 <210> 89 <211> 175 <212> PRT <213> Homo sapiens <400> 89 Met Ser Tyr Asn Cys Cys Ser Gly Asn Phe Ser Ser Arg Ser Cys Gly S. 1 5 10 Asp Tyr Leu Arg Tyr Pro Ala Ser Ser Arg Gly Phe Ser Tyr Pro Ser 25 Asn Leu Val Tyr Ser Thr Asp Leu Cys Ser Pro Ser Thr Cys Gin Leu 40 Gly Ser Ser Leu Tyr Arg Gly Cys Gin Glu lie Cys Trp Glu Pro Thr 55 Ser Cys Gin Thr Ser Tyr Val Glu Ser Ser Pro Cys Gin Thr Ser Cys 70 75 Tyr Arg Pro Arg Thr Ser Leu Leu Cys Ser Pro Cys Lys Thr Thr Tyr 90 Ser Gly Ser Leu Gly Phe Gly Ser Ser Ser Cys Arg Ser Leu Gly Tyr 100 105 110 Gly Ser Arg Ser Cys Tyr Ser Val Gly Cys Gly Ser Ser Gly Val Arg 115 120 125 Ser Leu Gly Tyr Gly Ser Cys Gly Phe Pro Ser Leu Gly Tyr Gly Ser 130 135 140 Gly Phe Cys Arg Pro Thr Tyr Leu Ala Ser Arg Ser Cys Gin Ser Pro 145 150 155 160 Cys Tyr Arg Pro Ala Tyr Gly Ser Thr Phe Cys Arg Ser Thr Cys 165 170 175 <210> <211> 193 <212> PRT <213> Homo sapiens <400> Met Trp His Ala Asn Ser Glu Ser Ser Gin Cys Asn Ser Ala Glu Leu 1 5 10 Thr Ser Pro lie Asn Met Ser Tyr Asn Cys Cys Ser Gly Asn Phe Ser 25 Ser Arg Ser Cys Gly Gly Tyr Leu His Tyr Pro Ala Ser Ser Cys Gly 40 Phe Ser Tyr Pro Ser Asn Gin Val Tyr Ser Thr Asp Leu Cys Ser Pro 55 Ser Thr Cys Gin Leu Gly Ser Ser Leu Tyr Arg Gly Cys Gin Gin Thr 70 75 Cys Trp Glu Pro Thr Ser Cys Gin Thr Ser Tyr Val Glu Ser Ser Pro 90 Cys Gin Thr Ser Cys Tyr Arg Pro Arg Thr Ser Leu Leu Cys Ser Pro 100 105 110 Cys Gin Thr Thr Tyr Ser Gly Ser Leu Gly Phe Gly Ser Ser Ser Cys ***115 120 125 Arg Ser Leu Gly Tyr Gly Ser Arg Ser Cys Tyr Ser Val Gly Cys Gly 130 135 140 Ser Ser Gly Phe Arg Ser Leu Gly Tyr Gly Gly Cys Gly Phe Pro Ser 145 150 155 160 Leu Gly Tyr Gly Val Gly Phe Cys Arg Pro Thr Tyr Leu Ala Ser Arg 165 170 175 Ser Cys Gin Ser Ser Cys Tyr Arg Pro Thr Cys Gly Ser Gly Phe Tyr 180 185 190 Tyr <210> 91 <211> 172 <212> PRT <213> Homo sapiens <400> 91 Met Ser Tyr Asn Cys Cys Ser Arg Asn Phe Ser Ser Cys Ser His Gly 1 5 10 Gly Tyr Leu His Tyr Pro Gly Ser Ser Cys Gly Ser Ser Tyr Pro Ser 25 Asn Leu Val Tyr Ser Thr Asp Leu Cys Ser Pro Ser Thr Cys Gin Leu 40 Gly Ser Ser Leu Tyr Arg Gly Cys Gin Glu Thr Cys Trp Arg Pro Asn 55 Ser Cys Gin Thr Leu Cys Val Glu Ser Ser Pro Cys His Thr Ser Cys 70 75 Tyr Tyr Pro Arg Thr His Met Leu Cys Asn Ser Cys Leu Thr Met His 90 Val Gly Ser Arg Gly Phe Gly Ser Asn Ser Cys Cys Ser Leu Ser Cys 100 105 110 Gly Ser Arg Ser Cys Ser Ser Leu Gly Cys Gly Ser Asn Gly Phe Arg 115 120 125 Tyr Leu Asn Tyr Arg lie His Thr Ser Pro Ser Gin Ser Tyr Arg Ser 130 135 140 Arg Phe Cys His Pro lie Tyr Phe Pro Pro Arg Arg Trp Phe His Ser 145 150 155 160 Ser Cys Tyr Gin Pro Phe Cys Arg Ser Gly Phe Tyr 165 170 <210> 92 <211> 160 <212> PRT S<213> Homo sapiens <400> 92 Met Ser Tyr Asn Cys Cys Ser Arg Asn Phe Ser Ser Arg Ser Phe Gly 1 5 10 Gly Tyr Leu Tyr Tyr Pro Gly Ser Tyr Pro Ser Ser Leu Val Tyr Ser 20 25 Thr Ala Leu Cys Ser Pro Ser Thr Cys Gin Leu Arg Ser Ser Leu Tyr 40 Arg Asp Cys Gin Lys Thr Cys Trp Glu Pro Ala Ser Cys Gin Lys Ser 50 55 Cys Tyr Arg Pro Arg Thr Ser lie Leu Cys Cys Pro Cys Gin Thr Thr 70 75 Cys Ser Gly Ser Leu Gly Phe Arg Ser Ser Ser Cys Arg Ser Gin Gly 90 Tyr Gly Ser Arg Cys Cys Tyr Ser Leu Gly Asn Gly Ser Ser Gly Phe 100 105 110 Arg Phe Leu Lys Tyr Gly Gly Cys Gly Phe Pro Ser Leu Ser Tyr Gly 115 120 125 Ser Arg Phe Cys Tyr Pro Asn Tyr Leu Ala Ser Gly Ala Trp Gin Ser 130 135 140 Ser Cys Tyr Arg Pro Ilie Cys Giy Ser Arg Phe Tyr Gin Phe Thr Cys 145 150 155 160 <210> 93 <211> 137 <212> PRT <213> Homo sapiens <400> 93 Met Ser Tyr Asn Cys Ser Ser Giy Asn Phe Ser Ser Cys Cys Phe Giy 1 5 10 Ser Tyr Leu Arg Tyr Pro Vai Ser Thr Tyr Asn Leu Phe Tyr Pro Ser 25 Asn Ala Ilie Tyr Ser Pro Asn Thr Cys Gin Leu Giy Ser Ser Leu Tyr 40 Asn Gly Cys Gin Giu Thr Tyr Cys Giu Pro Thr Ser Cys Gin Thr Ser 55 .0 Cys Thr Leu Ala Arg Ser Tyr Gin Thr Ser Cys Tyr Cys Pro Lys Asn *65 70 75 Ser Ilie Phe Cys Ser Pro Arg Gin Thr Asn Tyr Ilie Arg Ser Leu Gly 90 Cys Giy Asn Thr Gly Leu Giy Ser Leu Gly Cys Gly Ser Thr Gly Phe *..100 105 110 Gin Ser Leu Asp Cys Gly Ser Ser Phe Tyr His Pro Thr Thr Phe Ser 115 120 125 Ser Arg Asn Phe Gin Ala Thr Cys Tyr 130 135 <210> 94 <21 1> 163 <212> PRT O 0 <213> Homo sapiens <400> 94 Met Ser Phe Asn Cys Ser Thr Arg Asn Cys Ser Ser Arg Pro Ilie Gly 1 5 10 Gly Arg Cys Ilie Vai Pro Val Ala Gin Vai Thr Thr Thr Ser Thr Thr 25 Asp Ala Asp Cys Leu Gly Gly Ilie Cys Leu Pro Ser Ser Phe Gin Thr 40 Gly Ser Trp Leu Leu Asp His Cys Gin Giu Thr Cys Cys Giu Pro Thr 55 Aia Cys Gin Pro Thr Cys Tyr Arg Arg Thr Ser Cys Val Ser Asn Pro 70 75 Cys Gin Vai Thr Cys Ser Arg Gin Thr Thr Cys Ilie Ser Asn Pro Cys 90 Ser Thr Thr Tyr Ser Arg Pro Leu Thr Phe Vai Ser Ser Giy Cys Gin 100 105 110 Pro Leu Gly Gly Ilie Ser Ser Val Cys Gin Pro Val Gly Gly Ile Ser 115 120 125 Thr Val Cys Gin Pro Vai Gly Gly Val Ser Thr Val Cys Gin Pro Aia 130 135 140 Cys Gly Val Ser Arg Thr Tyr Gin Gin Ser Cys Val Ser Ser Cys Arg 145 150 155 160 Arg Thr Cys <210> <21 1> 671 <212> DNA <213> Homo sapiens <400> aactcacatc tcccgtcaac atgtcctaca actgctgctc tggaaacttc tcctcccgct cctgtggtga ctacctgcgc tacccagcat cctcacgtgg cttttcctac cccagcaatc 120 tggtctacag cactgacctc tgctctccca gcacctgcca gctgggttcc tctctctata 180 ggggctgtca ggagatctgc tgggagccca ccagctgcca gacgtcctat gtggagtcca 240 gcccctgcca gacctcctgc taccgcccca gaacctcctt gctctgcagt ccttgcaaga 300 cgacttactc tgggtctcta ggctttggat ccagcagctg ccgctccctg ggctatggat 360 cgaggagctg ctactcagtg ggctgtgggt ccagtggtgt cagatccctg ggttatggaa 420 gctgtggctt cccttccctc ggctatggat ctggattctg ccgcccaacc tacttggctt 480 ctaggagctg ccagtctcct tgttacagac cagcctatgg atcaaccttc tgcagatcaa 540 cttgctgaat ttccagacct tttaagcaaa gtgtctcagt ctctacgtag agctgttatc 600 ataggcattt ccagcaatgt gagctaaccc ctcttactac tagctcttca tcctttctct 660 p..:ggcatcaagt a 671 <210> 96 <21 1 >697 <212> DNA <213> Homo sapiens <400> 96 atataaatgg tcctgtccag atgtggcatg caaactcaga atcttctcag tgtaactcag ctgaactcac atctcccatc aacatgtcct acaactgctg ctctggaaac ttctcctccc 120 gctcctgtgg tggctacctg cactacccag cctcctcctg tggcttttcc taccccagca 180 accaggtcta cagcactgac ctctgctctc ccagcacgtg ccagctgggt tcctctctct 240 ataggggctg tcagcagacc tgctgggagc ccaccagctg ocagacatoc tatgtggagt 300 ccagcccctg ccagacctcc tgctaccgtc ccagaacctc cttgctctgc agtccctgcc 360 agacaactta ctctgggtct ctaggctttg gatccagcag ctgccgctcc ctgggctatg 420 gatcgaggag ctgctactca gtgggctgtg ggtccagtgg cttcagatcc ctgggttatg 480 gaggctgtgg cttcccttcc ctgggctatg gcgttggatt ctgccgccca acctacttgg 540 cttctaggag ctgccagtct tcttgctaca gaccaacttg tggatcaggc ttctactatt 600 gatcatcttg ttaaattgct gattttgttg gctaatgcct tcaatgcctc tactcataac 660 ctttattgtc ttcatcatgt acagaaagaa ttagcct 697 <210> 97 <21 1> 637 <212> DNA <213> Homo sapiens <400> 97 ctcacatctt cccgtcaaca tgtcctacaa ctgttgctct agaaacttct cctcctgctc ccacgggggt tacttgcact acccaggctc ctcctgtggc tcttcctacc ccagcaacct 120 ggtctacagc actgacctct gctctcccag cacctgccag ctgggttcct ctctctatag 180 gggctgtcag gagacctgct ggaggcccaa cagctgtcag acattgtgtg ttgagtccag 240 cccctgccac acctcctgct actaccocag gactcacatg ctctgcaatt cttgcctgac 300 tatgcatgtt gggtctcggg gftttggatc caatagctgc tgctccctga gctgtggatc 360 caggagctgc tcctcactgg gctgtggatc caatggcttc agatatctga attatagaat 420 ccatacctcc ccttcccaga gttatagatc cagattctgc catccaatct attttccacc 480 tagaaggtgg ttccattcat cttgtatca gccattctgt agatctggtt tctactgact 540 aatgtggtga ctggtaaaac tcatttgaga aatgcatatt ctttagtaag gtcatctgtt 600 aatttcttcc tttgagaagt attctaatat tattgat 637 <210> 98 <21 1> 603 <212> DNA <213> Homo sapiens 98* tgaactccca tctctcatca gcatgtccta caactgctgc tctagaaact tctcctcccg ctcctttggg ggctacctgt actacccagg ctcctacccc agcagcctgg tctacagcac 120 tgccctctgc tctcccagca cctgccagct gcgttcctct ctctacaggg actgtcagaa 180 gacctgctgg gagcccgcca gctgccagaa atcctgctac cgccccagga cctccatcct 240 ctgctgtccc tgtcagacga cttgctctgg atctctaggc tttcggtcca gcagctgtcg 300 ctcccagggc tatggatcta ggtgctgcta ctcgctggga aatggatcca gtggcttcag 360 attcctgaaa tatggaggct gtggttttcc ttccctgagt tacggatcca gattctgcta 420 cccaaactac ttggcttctg gagcctggca gtcttcttgt tacagaccaa tctgtggatc 480 tcgcttctat caattcacct gctaaatttc tagatccttt tgagtattgg gatcaaagtc 540 tctactgaat gcagccatta ttttcattct tgccagatcc caatatcttt ttattcttcc 600 acc 603 <210O> 99 <21 1> 531 <212> DNA <213> Homo sapiens <400> 99 gagctcagaa ctcctgttaa catgtcttac aactgcagct ctggaaactt ctcctcctgc tgtttggaa gttacctgag gtatccagtt tccacttata atttgttcta ccccagcaat 120 gccatctatt ctccaaatac ctgccaactg ggctcctctc tctacaatgg ctgtcaggag 180 acctactgtg agcccaccag ctgccagaca tcctgcactt tggccagatc ctatcagaca 240 tcctgttact gcccaaagaa ttccatcftc tgcagtcccc gccagactaa ctacataaga. 300 tcccttggat gtggaaacac tggccttgga tctcttggft gtggaagcac tggcttccaa 360 tctctggact gtgggtccag cttctaccac ccaactacct tttcatccag gaatttccag 420 gcaacttgtt actaaccagc ctttgggtct cgcctttttg gatcatctta ctgaatattc 480 tccattctct catgattatt tctgtactct atggaactgc aacactcagc c 531 <210O> 100 <21 1> 609 <212> DNA <213> Homo sapiens <400> 100 gcagccctct gtctgacatc atgtccttca actgctccac aagaaattgc tctccaggc ccattggagg acgctgcatt gttccagtgg cccaagttac cacgacttcc accactgatg 120 ctgactgcct gggcggcatc tgtttgccca gttccttcca gactggctct tggctcctgg 180 accactgtca agagacctgc tgtgagccca ctgcttgcca gccaacctgt taccggcgaa 240 cttcatgtgt ctccaaccct tgccaggtga cttgctctcg acaaactacc tgtatttcca 300 acccctgctc aactacctac agccggccgc tcacctttgt ctctagtgga tgtcagcccc 360 tgggaggcat ctccagtgtc tgccaaccag tgggcggcat ctctactgtc tgccaaccag 420 tgggaggagt ctctactgtc tgccagccag cctgtggggt ctccaggacg tatcagcagt 480 cctgcgtgtc cagctgccga agaacctgct aagtgtgtag gagccagtga gcgaatcaag 540 actccacgac ctgccagctg tttccaggat cttccagcat gctgcttgtc cctgaatagc 600 tcttcatag 609 <210O> 101 <211> 113 <212> PRT <213> Mus musculus <400> 101 Met Ala Asn Lys Ala Pro Ser Gin Met Glu Arg Ser lie Thr Thr Ilie 1 5 10 Ilie Asp Thr Phe His Gin Tyr Ser Arg Lys Giu Giy His Pro Asp Thr *20 25 Leu Ser Lys Lys Glu Phe Arg Gin Met Vai Glu Aia GIn Leu Ala Thr 40 Phe Met Lys Lys Giu Lys Arg Asn Giu Ala Leu Ilie Asn Asp Ilie Met 55 Giu Asp Leu Asp Thr Asn GIn Asp Asn GIn Leu Ser Phe Glu Giu Cys 70 75 Met Met Leu Met Ala Lys Leu lie Phe Aia Cys His Glu Lys Leu His 90 Giu Asn Asn Pro Arg Giy His Giy His Ser His Gly Lys Giy Cys Gly 100 105 110 Lys <210O> 102 <211> 114 <212> PRT <213> Homo sapiens <400> 102 Met Thr Cys Lys Met Ser Gin Leu Glu Arg Asn lie Glu Thr lie lie 1 5 10 Asn Thr Phe His Gin Tyr Ser Val Lys Leu Gly His Pro Asp Thr Leu 25 Asn Gin Gly Glu Phe Lys Glu Leu Val Arg Lys Asp Leu Gin Asn Phe 40 Leu Lys Lys Glu Asn Lys Asn Glu Lys Val lie Glu His lie Met Glu 55 Asp Leu Asp Thr Asn Ala Asp Lys Gin Leu Ser Phe Glu Glu Phe lie 70 75 Met Leu Met Ala Arg Leu Thr Trp Ala Ser His Glu Lys Met His Glu 90 Gly Asp Glu Gly Pro Gly His His His Lys Pro Gly Leu Gly Glu Gly 100 105 110 Thr Pro <210> 103 <211> 341 <212> PRT <213> Mus musculus <400> 103 **Met Ala Val Ser Val Thr Pro lie Arg Asp Thr Lys Trp Leu Thr Leu 1 5 10 Glu Val Cys Arg Glu Phe Gin Arg Gly Thr Cys Ser Arg Pro Asp Thr 20 25 SGlu Cys Lys Phe Ala His Pro Ser Lys Ser Cys Gin Val Glu Asn Gly 40 Arg Val lie Ala Cys Phe Asp Ser Leu Lys Gly Arg Cys Ser Arg Glu 50 55 Asn Cys Lys Tyr Leu His Pro Pro Pro His Leu Lys Thr Gin Leu Glu 65 70 75 lie Asn Gly Arg Asn Asn Leu lie Gin Gin Lys Asn Met Ala Met Leu 90 Ala Gin Gin Met Gin Leu Ala Asn Ala Met Met Pro Gly Ala Pro Leu 100 105 110 Gin Pro Val Pro Met Phe Ser Val Ala Pro Ser Leu Ala Thr Ser Ala 115 120 125 Ser Ala Ala Phe Asn Pro Tyr Leu Gly Pro Val Ser Pro Ser Leu Val 130 135 140 Pro Ala Glu lie Leu Pro Thr Ala Pro Met Leu Val Thr Gly Asn Pro 145 150 155 160 Gly Val Pro Val Pro Ala Ala Ala Ala Ala Ala Ala Gin Lys Leu Met 165 170 175 Arg Thr Asp Arg Leu Glu Val Cys Arg Glu Tyr Gin Arg Gly Asn Cys 180 185 190 Asn Arg Gly Glu Asn Asp Cys Arg Phe Ala His Pro Ala Asp Ser Thr 195 200 205 Met lie Asp Thr Asn Asp Asn Thr Val Thr Val Cys Met Asp Tyr lie 210 215 220 Lys Gly Arg Cys Ser Arg Glu Lys Cys Lys Tyr Phe His Pro Pro Ala 225 230 235 240 His Leu Gin Ala Lys lie Lys Ala Ala Gin Tyr Gin Val Asn Gin Ala 245 250 255 Ala Ala Ala Gin Ala Ala Ala Thr Ala Ala Ala Met Gly lie Pro Gin 260 265 270 Ala Val Leu Pro Pro Leu Pro Lys Arg Pro Ala Leu Glu Lys Thr Asn 275 280 285 Gly Ala Thr Ala Val Phe Asn Thr Gly lie Phe Gin Tyr Gin Gin Ala 290 295 300 Leu Ala Asn Met Gin Leu Gin Gin His Thr Ala Phe Leu Pro Pro Gly 305 310 315 320 Ser lie Leu Cys Met Thr Pro Ala Thr Ser Val Asp Thr His Asn lie 325 330 335 Cys Arg Thr Ser Asp 340 <210> 104 <211> 370 <212> PRT <213> Homo sapiens <400> 104 Met Ala Val Ser Val Thr Pro lie Arg Asp Thr Lys Trp Leu Thr Leu S1 5 10 Glu Val Cys Arg Glu Phe Gin Arg Gly Thr Cys Ser Arg Pro Asp Thr 20 25 Glu Cys Lys Phe Ala His Pro Ser Lys Ser Cys Gin Val Glu Asn Gly 40 Arg Val lie Ala Cys Phe Asp Ser Leu Lys Gly Arg Cys Ser Arg Glu 55 Asn Cys Lys Tyr Leu His Pro Pro Pro His Leu Lys Thr Gin Leu Glu 70 75 lie Asn Gly Arg Asn Asn Leu lie Gin Gin Lys Asn Met Ala Met Leu 90 Ala Gin Gin Met Gin Leu Ala Asn Ala Met Met Pro Gly Ala Pro Leu 100 105 110 Gin Pro Val Pro Met Phe Ser Val Ala Pro Ser Leu Ala Thr Asn Ala 115 120 125 Ser Ala Ala Ala Phe Asn Pro Tyr Leu Gly Pro Val Ser Pro Ser Leu 130 135 140 Val Pro Ala Glu lie Leu Pro Thr Ala Pro Met Leu Val Thr Gly Asn 145 150 155 160 Pro Gly Val Pro Val Pro Ala Ala Ala Ala Ala Ala Ala Gin Lys Leu 165 170 175 Met Arg Thr Asp Arg Leu Glu Val Cys Arg Glu Tyr Gin Arg Gly Asn 180 185 190 Cys Asn Arg Gly Glu Asn Asp Cys Arg Phe Ala His Pro Ala Asp Ser 195 200 205 Thr Met lie Asp Thr Asn Asp Asn Thr Val Thr Val Cys Met Asp Tyr 210 215 220 lie Lys Gly Arg Cys Ser Arg Glu Lys Cys Lys Tyr Phe His Pro Pro 225 230 235 240 Ala His Leu Gin Ala Lys lie Lys Ala Ala Gin Tyr Gin Val Asn Gin 245 250 255 Ala Ala Ala Ala Gin Ala Ala Ala Thr Ala Ala Ala Met Gly lie Pro 260 265 270 Gin Ala Val Leu Pro Pro Leu Pro Lys Arg Pro Ala Leu Glu Lys Thr 275 280 285 Asn Gly Ala Thr Ala Val Phe Asn Thr Gly lie Phe Gin Tyr Gin Gin 290 295 300 Ala Leu Ala Asn Met Gin Leu Gin Gin His Thr Ala Phe Leu Pro Pro 305 310 315 320 Val Pro Met Val His Gly Ala Thr Pro Ala Thr Val Ser Ala Ala Thr 325 330 335 Thr Ser Ala Thr Ser Val Pro Phe Ala Ala Thr Ala Thr Ala Asn Gin 340 345 350 lie Pro lie lie Ser Ala Glu His Leu Thr Ser His Lys Tyr Val Thr 355 360 365 Gin Met 370 <210> 105 <211> 419 <212> PRT <213> Mus musculus <400> 105 Met Asn Lys His Gin Lys Pro Val Leu Thr Gly Gin Arg Phe Lys Thr 1 5 10 Arg Lys Arg Asp Glu Lys Glu Lys Phe Glu Pro Thr Val Phe Arg Asp 25 Thr Leu Val Gin Gly Leu Asn Glu Ala Gly Asp Asp Leu Glu Ala Val 40 Ala Lys Phe Leu Asp Ser Thr Gly Ser Arg Leu Asp Tyr Arg Arg Tyr 55 Ala Asp Thr Leu Phe Asp lie Leu Val Ala Gly Ser Met Leu Ala Pro 70 75 Gly Gly Thr Arg lie Asp Asp Gly Asp Lys Thr Lys Met Thr Asn His 90 Cys Val Phe Ser Ala Asn Glu Asp His Glu Thr lie Arg Asn Tyr Ala 100 105 110 Gin Val Phe Asn Lys Leu lie Arg Arg Tyr Lys Tyr Leu Glu Lys Ala 115 120 125 Phe Glu Asp Glu Met Lys Lys Leu Leu Leu Phe Leu Lys Ala Phe Ser "130 135 140 C* Glu Ala Glu Gin Thr Lys Leu Ala Met Leu Ser Gly lie Leu Leu Gly 145 150 155 160 Asn Gly Thr Leu Pro Ala Thr lie Leu Thr Ser Leu Phe Thr Asp Ser 165 170 175 Leu Val Lys Glu Gly lie Ala Ala Ser Phe Ala Val Lys Leu Phe Lys 180 185 190 Ala Trp Met Ala Glu Lys Asp Ala Asn Ser Val Thr Ser Ser Leu Arg 195 200 205 Lys Ala Asn Leu Asp Lys Arg Leu Leu Glu Leu Phe Pro Val Asn Arg 210 215 220 Gin Ser Val Asp His Phe Ala Lys Tyr Phe Thr Asp Ala Gly Leu Lys 225 230 235 240 Glu Leu Ser Asp Phe Leu Arg Val Gin Gin Ser Leu Gly Thr Arg Lys 245 250 255 Glu Leu Gin Lys Glu Leu Gin Glu Arg Leu Ser Gin Glu Cys Pro lie 260 265 270 Lys Glu Val Val Leu Tyr Val Lys Glu Glu Met Lys Arg Asn Asp Leu 275 280 285 Pro Glu Thr Ala Val lie Gly Leu Leu Trp Thr Cys lie Met Asn Ala 290 295 300 Val Glu Trp Asn Lys Lys Glu Glu Leu Val Ala Glu Gin Ala Leu Lys 305 310 315 320 His Leu Lys Gin Tyr Ala Pro Leu Leu Ala Val Phe Ser Ser Gin Gly 325 330 335 Gin Ser Glu Leu Val Leu Leu Gin Lys Val Gin Glu Tyr Cys Tyr Asp 340 345 350 Asn lie His Phe Met Lys Ala Phe Gin Lys lie Val Val Leu Phe Tyr 355 360 365 Lys Ala Asp Val Leu Ser Glu Glu Ala lie Leu Lys Trp Tyr Lys Glu 370 375 380 Ala His Ala Ala Lys Gly Lys Ser Val Phe Leu Asp Gin Met Lys Lys 385 390 395 400 Phe Val Glu Trp lie Gin Asn Ala Glu Glu Glu Ser Glu Ser Glu Gly 405 410 415 Glu Glu Ser <210> 106 <211> 2988 <212> PRT <213> Homo sapiens <400> 106 S Met Val Glu Gly Asp Thr Val Thr Phe Ser Phe Glu Met Arg Ser Gly 1 5 10 Arg Glu His Asn Thr Pro Asp Lys Ala Met Trp Gly Phe Ala Cys Thr 20 25 Val Arg Ala Gin Glu Ser Ser Glu Asp Val Ser Gly Gly Leu Pro Phe 35 40 Leu Val Asp Leu Ala Leu Gly Leu Ser Val Leu Ala Cys Ser Met Leu 55 Arg lie Leu Tyr Asn Gly Pro Glu lie Thr Lys Glu Glu Glu Ala Cys 65 70 75 Gin Glu Leu Leu Arg Ser Lys Leu Leu Gin Arg Glu Val lie Gin Pro 85 90 Asp Val Met Glu Glu Met Val Val Ser Cys Val lie Lys His Leu Asn 100 105 110 Leu Val Asp Ala Leu Gin Ser Leu lie Asn Phe Gin Tyr Gin Glu Glu 115 120 125 His Ala Glu Glu Tyr Asp Leu Leu Cys Lys lie Met Gly Glu Thr Phe 130 135 140 Lys Lys Leu Asn Ala Met Glu Arg Gin Leu Gin Asn Lys Met Lys Glu 145 150 155 160 Leu Glu Leu Leu Cys Ser Met Lys Glu Val Ser Phe Asp Gly Asn Asp 165 170 175 Leu Glu Asn Met Val Leu Ser Leu Arg Glu Lys Phe Leu Gin Glu Val 180 185 190 Asn Ser Leu lie Gin Lys Pro Ser His Pro Leu Ala Lys Thr Lys Thr 195 200 205 Leu Val Lys Ser Leu Met Asn Arg Ala Glu Leu Leu Leu His Val Thr 210 215 220 lie Ala Ala Gin Ser Gly Leu Thr Arg Ser lie Ser Gly Thr Pro Ala 225 230 235 240 Glu Thr Pro Ala Cys Lys Ser Ala Ser Glu Thr Lys Val lie Ser His 245 250 255 Ala Val Arg Gin Pro Val Phe Leu Arg Ser Met Ser Ala Pro Ser Asp 260 265 270 Leu Glu Met lie Gly Asn Glu Asp Leu Glu Phe Thr Arg Ala Asn Gin 275 280 285 Arg Arg Arg His Val Thr Ser His Arg Ser Ser Ser Phe Thr Leu Leu 290 295 300 Gin Ser Leu Ala lie Glu Asp Ser Arg Asp Lys Pro Thr Tyr Ser Val 305 310 315 320 Leu Leu Gly Gin Leu Phe Ala Phe lie Gly Thr Asn Pro Asp Gin Ala :325 330 335 Val Ser Ser Ser Ser Phe Leu Leu Ala Ala Gin Thr Arg Trp Arg Arg 340 345 350 Gly Asn Thr Arg Lys Gin Ala Leu Val His Met Arg Glu Leu Leu Thr 355 360 365 Ala Ala Val Arg Val Gly Gly Val Thr His Leu Val Gly Pro Val Thr 370 375 380 Met Val Leu Gin Gly Gly Pro Arg lie Glu Glu Leu Thr Cys Gly Gly 385 390 395 400 Met Val Glu Gin Val Gin Glu Ala Phe Gly Glu Thr Met Thr Ser Val :405 410 415 Val Ser Leu Cys Ala Arg Tyr Pro lie Ala Cys Ala Asn Ser lie Gly 420 425 430 Leu Leu Cys Thr lie Pro Tyr Thr Arg Ser Glu Glu Lys Cys Leu Val 435 440 445 Arg Ser Gly Leu Val Gin Leu Met Asp Arg Leu Cys Ser Leu Ser Asn 450 455 460 Gin Thr Glu Ser Ser Ser Ser Glu Lys Gin Thr Lys Lys Gin Lys Val 465 470 475 480 Ala Thr Met Ala Trp Ala Ala Phe Gin Val Leu Ala Asn Arg Cys Val 485 490 495 Glu Trp Glu Lys Glu Glu Glu Thr Gly Ser Tyr Tyr Val Ala Gin Leu 500 505 510 Cys Arg Ala Ala Leu Pro Leu Met Ser Val Glu Asp Cys Gly Asn Val 515 520 525 Glu Leu Pro Pro Trp Ser Tyr Ser Val Pro Ser Leu Asn Ser Glu Gin 530 535 540 Glu Asp Pro Ser Asp Pro Ala Ser Lys lie Ala Ser Leu Leu Leu Ala 545 550 555 560 Lys Leu Ala Asp Tyr Val Val Pro Gly Cys Gin Thr Val Leu Ser Pro 565 570 575 Thr Ala Ser Glu Pro Asp Thr Thr Leu Thr Lys Thr Ser Pro Lys Asn 580 585 590 Ser Leu Lys Gly Asp Lys Asp Pro Gly Glu Glu Ser Glu Ala Val Asp 595 600 605 Gly Lys Leu Ser lie Phe lie His Lys Arg Glu Asp Gin Ser Ser His 610 615 620 Glu Val Leu Gin Pro Leu Leu Ser Ser Ser Glu Gly Arg Pro Phe Arg 625 630 635 640 Leu Gly Thr Gly Ala Asn Met Glu Lys Val Val Lys Met Asp Arg Asp 645 650 655 Met Thr Lys Gly Gly Cys Cys Glu Val lie Thr Glu Glu Ala Ala Ala 660 665 670 Ala Leu Arg Lys Ala Thr Lys Trp Ala Gin Ser Gly Leu lie Val Ser 675 680 685 lie Gly Pro Pro Val Glu Ser lie Asn Pro Glu Thr Val Ser Gly Leu 690 695 700 Ser Thr Gly Asp Lys Lys Lys Thr Ala Gin Thr Ser lie Cys Arg Glu 705 710 715 720 Arg Asn Ser Glu Leu Ala Arg Thr Asp Pro Val Arg Pro Phe lie Ser 725 730 735 Gly His Val Ala Asn Ser Met Ala Ala Glu Val lie Ala Leu Leu His 740 745 750 Ser Leu Leu Met Ala Pro Glu Ser Asn Ala Ala Gin lie Trp Thr Thr 755 760 765 Thr Ala Glu Lys Val Leu Ser Arg Ala Leu Met Tyr lie Pro Gin Leu 770 775 780 Gly Lys Tyr Ala Glu Ser lie Leu Glu Asn Gly Ser Ser Ser Gly Arg 785 790 795 800 Lys Leu Ala Lys Leu Gin Arg lie Ala Arg Gin Ala Val Ala Ala Leu 805 810 815 Cys Ala Leu Gly Gly Phe Lys Glu Thr lie Lys lie Gly Ser Glu Val 820 825 830 Gin Ala Leu Pro Leu His Lys Leu Ser lie Thr Glu Lys Val Val Gin 835 840 845 Ala Val Gin Ser Met Leu Leu Pro Gin Glu Gly Ser Leu Ser lie His 850 855 860 Thr Ser Leu Pro Ala Thr Gly Asp Gly Ser Ala Pro Val Met Ala Val 865 870 875 880 Val Arg Leu Leu Ala Glu lie Arg Thr Arg Ala Cys Leu Val Met Ala 885 890 895 Gin Leu Leu Glu Asp Ser Leu Phe Cys Glu Glu Phe lie Gin Gin Cys 900 905 910 Pro Ala Ala Val Glu Val Leu Asn Leu Val Ala Gin Glu Cys Ser Ala 915 920 925 Gly Glu Arg Leu Ala Val Val Glu Val Gin Cys Glu Arg Leu Arg Met 930 935 940 Leu Tyr Arg Asp Cys Ala Arg Pro Pro Pro Pro Pro Leu Gin Ala Asp 945 950 955 960 Arg Arg Gin Ala Pro Ser Phe Tyr Trp Glu lie Glu lie Val Ser Tyr 965 970 975 Gly Asp Thr Asp Asp Asp Thr Gly Pro lie Val Ser Phe Gly Phe Thr 980 985 990 Thr Glu Ala Glu Lys Arg Asp Gly Ala Trp Thr Asn Pro Val Gly Thr 995 1000 1005 Cys Leu Phe His Asn Asn Gly Arg Ala Val His Tyr Asn Gly Ser Ser 1010 1015 1020 Leu Leu Gin Trp Lys Ser Val Arg Leu Asp Val Thr Leu Ser Pro Gly 1025 1030 1035 1040 Asp Val Ala Gly lie Gly Trp Glu Arg Thr Glu Gly Thr Pro Pro Pro 1045 1050 1055 Pro Gly Gin Pro Ala Lys Gly Arg Val Tyr Phe Thr Tyr Cys Gly Gin 1060 1065 1070 Arg Leu Ser Pro Tyr Leu Glu Asp Val Ser Gly Gly Met Trp Pro Val 1075 1080 1085 Val His lie Gin Lys Lys Ala Glu lie Lys lie Asn Val Ser Leu Ser 1090 1095 1100 Lys Ser Phe lie Trp Ser Pro Phe Gin Asn Thr Lys Thr Arg Ala Asn 1105 1110 1115 1120 Phe Gly Ser Arg Pro Phe Ala Tyr Ala Glu Gly Gin Ala His Arg Asn 1125 1130 1135 Ala Ala Asp Leu Cys Thr Asp Leu Ala Glu Glu lie Ser Ala Asn Phe 1140 1145 1150 Glu Ala Leu Pro Phe Ala Met Ala Ser Asp Ser Asp Asn Asp Ala Gly 1155 1160 1165 Thr Ser lie Ala Ser Asp Pro Gly Thr His Gly Pro Pro Cys Arg lie 1170 1175 1180 Ala Ala Val Ala Thr Ala Gin Gin Gin Tyr Asp Ser Asp Thr Ser Cys 1185 1190 1195 1200 His Tyr Lys Val Glu Leu Ser Tyr Glu Asn Phe lie Thr Ser Gly Pro 1205 1210 1215 Asp Pro His Pro Pro Pro lie Ala Asp Asp Glu Ser Asp Asp Asp Asp 1220 1225 1230 Asp Asp Asp lie Pro Gin Glu Asp His Tyr Ala Leu Leu Val Lys Ala 1235 1240 1245 Trp Glu Thr Lys Val Phe Pro Thr lie Arg Arg Arg Phe Arg Asn Glu 1250 1255 1260 Ala Glu Arg Lys Ser Gly Leu Asp Gin lie Lys Gly Ala Leu Gin Leu 1265 1270 1275 1280 Gly Met Val Asp lie Ala Arg Gin Thr Val Glu Phe Leu Tyr Glu Glu 1285 1290 1295 Asn Gly Gly lie Pro Arg Asp Leu Tyr Leu Pro Thr lie Glu Asp lie 1300 1305 1310 Lys Asp Glu Ala Asn Lys Phe Thr lie Asp Lys Val Arg Lys Gly Leu 1315 1320 1325 Thr Val Val Thr Arg Ser Pro Asp Ser Asn Asn Val Ala Ser Ser Ala 1330 1335 1340 Val Gly Thr Ala Leu Pro Lys Phe Ala lie Arg Gly Met Leu Lys Thr 1345 1350 1355 1360 Phe Gly Leu His Gly Val Val Leu Asp Val Asp Ser Val Asn Glu Leu 1365 1370 1375 Val Gin Val Glu Thr Tyr Leu Arg Ser Glu Gly Val Leu Val Arg Tyr 1380 1385 1390 Trp Tyr Pro lie Asp Met Leu Glu Arg Pro Pro Ala Gly Tyr Arg Arg 1395 1400 1405 Thr Ala Thr Asn Gly Leu Val Thr Leu Asp Asn Thr Asn Leu Gin lie 1410 1415 1420 His Arg Glu Leu Leu Arg Cys Glu Ala Ala Leu Ala Arg Leu Tyr Cys 1425 1430 1435 1440 Arg Met Ala Leu Leu Asn lie Phe Ala Pro Lys Leu Pro His Leu Phe 1445 1450 1455 Thr Arg Leu Phe His lie Pro Ala lie Arg Asp lie Thr Leu Glu His 1460 1465 1470 Leu Gin Leu Leu Ser Asn Gin Leu Leu Ala Pro Pro Leu Pro Asp Gly 1475 1480 1485 Thr lie Ser Ser Ser Ser lie Leu Leu Ala Gin Ser Leu Gin His Cys 1490 1495 1500 lie His Ser Gin Asn Cys Ser Ala Thr Asp Leu Phe Tyr Gin Gly Asn 1505 1510 1515 1520 Ser Gin Thr Val Arg Glu Trp Leu Asn Val Ala lie Thr Arg Thr Leu 1525 1530 1535 His Gin Gly Glu Glu Ser Leu Leu Glu Leu Thr Lys Gin lie Cys Ser 1540 1545 1550 Phe Leu Gin Thr Ala Pro Glu Gin Phe Pro Ser Glu Glu Phe Pro lie 1555 1560 1565 Ser Glu Ser Lys Val Asn Met Asp Val Asn Phe Pro Gly Ala Ala Phe 1570 1575 1580 t* i, Val Val Val Ser Cys Lys Glu Ser Gin Ser Gly Phe Arg Lys Asp Ser S* 1585 1590 1595 1600 Ser Leu Tyr Lys Ala Pro Trp Ala Arg Val Leu Val Tyr Gly Leu Gly 1605 1610 1615 His Lys Val Lys Arg Asn Gly Gin Leu Asn Leu lie Glu Ala Ala Cys g 1620 1625 1630 Tyr Pro Arg Asp Ala Ser Pro Ala Asn Thr Gly Leu Ala Pro Pro Pro *1635 1640 1645 Thr Ala Asp Gin Tyr Pro Ser Val Val Leu Ser Thr Asp Arg Val His 1650 1655 1660 lie Lys Leu Gly Val Ser Pro Pro Pro Gly Ala Val Leu Val Leu His 1665 1670 1675 1680 Ser Leu Pro Leu Glu Phe Pro Leu Ala Met Ala Phe Ala Glu Gin Leu 1685 1690 1695 Leu Ser Trp Lys Ser Glu Asp Ser Glu Gly Lys Ser Glu Asp Glu Pro 1700 1705 1710 Asp Thr lie Pro Thr Ser Val Leu Leu Gin Val Val Glu Leu Leu Gly 1715 1720 1725 Asn Phe Leu Trp Thr Thr Asp Met Ala Ala Cys Val Lys Glu Leu Val 1730 1735 1740 Phe His Leu Leu Ala Glu Leu Leu Arg Thr Val His Thr Leu Glu Gin 1745 1750 1755 1760 Arg Arg His Pro Ala Gly Leu Ser Ser Ser lie Ala Leu Gin Leu Asn 1765 1770 1775 Pro Cys Leu Ala Met Leu Met Ala Leu Gin Ser Glu Leu His Lys Leu 1780 1785 1790 Tyr Asp Glu Glu Thr Gin Asn Trp Val Ser Gly Gly Ala Cys Gly Gly 1795 1800 1805 Ser Gly Gly Ala Ala Ala Gly Asp Gin Gly Arg Phe Ser Thr Tyr Phe 1810 1815 1820 His Ala Leu Met Glu Gly Cys Leu Ala Val Ala Glu Val Thr Leu Pro 1825 1830 1835 1840 Thr Asn Met Ser Val Thr Ala Ser Gly Val Thr Ser Ala Thr Ala Pro 1845 1850 1855 Asn Leu Ser Asp Ser Ser Ser Ser Ser Ser Ser Ser Pro Gly Gin Thr 1860 1865 1870 Pro Gin Ser Pro Ser Leu Leu Ser Lys Arg Lys Lys Val Lys Met Lys 1875 1880 1885 Arg Glu Lys Ala Ser Ser Ser Gly Lys Arg Gin Ser Ser Arg Thr Val 1890 1895 1900 Asp Ser Asp Pro Thr Val Leu Ser lie Gly Gly Ser Lys Pro Glu Asp 1905 1910 1915 1920 Met Leu Trp Phe His Arg Ala Leu Thr Leu Leu lie lie Leu Arg His 1925 1930 1935 Leu Thr Arg Lys Asp Pro Gin Gly Leu Gly Val Thr Ser Asp Ala lie 1940 1945 1950 Ala Asp Ala Cys Gin Ala Leu Val Gly Pro Thr Ala His Ser Arg Leu 1955 1960 1965 Leu Val lie Ser Gly lie Pro Thr His Leu Asp Glu Gly Val Val Arg 1970 1975 1980 Gly Ala lie Arg Lys Ala Cys Asn Ala His Gly Gly Val Phe Lys Asp 1985 1990 1995 2000 Glu lie Tyr lie Pro Leu Gin Glu Glu Asp Thr Lys Lys Pro Lys Asp 2005 2010 2015 Lys Ala Glu Gly Gly Asp Gly Lys Val Glu Pro Glu Lys Thr Leu Ala 2020 2025 2030 Phe Pro Gly Thr Asp Ser Met Glu Val Ser Thr Ser Ser Ser Leu Thr 2035 2040 2045 Pro Ala Met Ser lie Ser Ala Ser Ala Ser Thr Ser Gin Ala Ser lie 2050 2055 2060 Cys Ser Ser Gin Gly lie Ser Gin Thr Val Ser Asp Leu Ser Val Asp 2065 2070 2075 2080 Pro Leu Pro Ala Gly Leu Glu Leu Pro lie Pro Pro Gly Leu Leu Glu 2085 2090 2095 Pro His Ala Val Ser Ser Gin Glu Ser Leu Asp lie Ser Leu Cys Ser 2100 2105 2110 Thr Gly Ser Leu Gly Ser Leu Gly Ser Leu Gly Glu Pro Leu Asp Asn 2115 2120 2125 Ala Glu Thr Ala Ser Val Ser Asp Met Gly Ser Met Tyr Thr Val Thr 2130 2135 2140 Ser Leu Asp Asn Gin Pro Leu Ala Ala Arg Pro lie Lys Gly Phe Ala 2145 2150 2155 2160 Val Val Glu lie Arg Ser Arg Ala Lys lie Glu Lys lie Arg Ala Ser 2165 2170 2175 Leu Phe Asn Asn Asn Asp Leu lie Gly Leu Ser Ser Leu Asp Gly Glu 2180 2185 2190 Asp Glu Leu Met Glu Met Ser Thr Glu Glu lie Leu Thr Val Ser Val 2195 2200 2205 Val Asn Gin Ser Leu Phe Asp Thr Gin Gly Ser Pro Gly Leu Glu Asp 2210 2215 2220 Tyr Phe Asn Asp Lys Ser lie Lys Gly Glu Lys Leu Val Pro Gly Ala S 2225 2230 2235 2240 Arg Glu Val Leu Thr Glu lie Phe Lys Ser Cys Ala His Ser Glu Gin 2245 2250 2255 Thr Leu Ser Leu Thr Pro Ala Lys Pro lie Arg Val Ser Asp lie Tyr 2260 2265 2270 Leu Ser Lys Glu Gin lie Asn Ser Gin Thr Pro Gly Asn Leu Leu His 2275 2280 2285 Leu Phe Phe Thr Asn Val Arg Pro Pro Lys Lys Val Leu Glu Asp Gin 2290 2295 2300 Leu Thr Gin lie Leu Arg Lys Tyr Gly Val Pro Lys Pro Lys Phe Asp 2305 2310 2315 2320 Lys Ser Lys Tyr Ser Lys Ala Gly Lys Glu Gin His Pro Val Lys Val 2325 2330 2335 Val Ser Thr Lys Arg Pro lie Thr Lys Pro Pro Ala Lys Asp Lys Ala 2340 2345 2350 Val Leu Asn Ser Val Ser Arg Thr Ala Leu Ser Glu Lys Lys Pro Thr 2355 2360 2365 Val Lys Pro Lys Ser Pro Glu Lys Ser Lys Pro Asp Glu Lys Asp Pro 2370 2375 2380 Glu Lys Ser Pro Thr Lys Lys Gin Glu Val Pro Glu Glu Lys Tyr Leu 2385 2390 2395 2400 Thr Leu Glu Gly Phe His Lys Phe Val lie Asp Arg Ala Arg Gin Asp 2405 2410 2415 lie Arg Ser Val Trp Arg Ala lie Leu Ser Cys Gly Tyr Asp Leu His 2420 2425 2430 Phe Glu Arg Cys Ala Cys lie Asp Val Arg His Ala Gin Lys Ala Ser 2435 2440 2445 Arg Lys Trp Thr Leu Glu Met Asp Val Ala Leu Val Gin Tyr lie Asn 2450 2455 2460 Gin Leu Cys Arg His Leu Ala lie Thr Pro Ala Arg Leu His Pro His 2465 2470 2475 2480 Glu Val Tyr Leu Asp Pro Ala Asp Ala Ala Asp Pro Arg Val Ala Cys 2485 2490 2495 Leu Leu Asn Val Pro lie Glu Ser Leu Arg Leu Arg Phe Ala Leu Leu 2500 2505 2510 Gin Ser Leu Asn Thr Thr Leu Glu Thr Phe Phe Leu Pro Leu Val Glu 2515 2520 2525 Leu Arg Gin Thr Pro Met Tyr Thr His Ser lie Ala Ala Leu Leu Lys 2530 2535 2540 Glu Ala Lys Gly Leu lie Phe Tyr Asp Thr Lys Val Thr Val Met Asn S 2545 2550 2555 2560 Arg Val Leu Asn Ala Thr Val Gin Arg Thr Ala Asp His Ala Ala Pro 2565 2570 2575 Glu lie Thr Leu Asp Pro Leu Glu lie Val Gly Gly Glu lie Arg Ala 2580 2585 2590 Ser Glu Asn Ser Tyr Phe Cys Gin Ala Ala Arg Gin Leu Ala Ser Val 2595 2600 2605 Pro Ser Ser Gin Leu Cys Val Lys Leu Ala Ser Gly Gly Asp Pro Thr 2610 2615 2620 Tyr Ala Phe Asn lie Arg Phe Thr Gly Glu Glu Val His Gly Thr Ser S* 2625 2630 2635 2640 Gly Ser Phe Arg His Phe Leu Trp Gin Val Cys Lys Glu Leu Gin Ser 2645 2650 2655 Ser Ser Leu Ser Leu Leu Leu Leu Cys Pro Ser Ser Ala Val Asn Lys 2660 2665 2670 Asn Lys Gly Lys Tyr lie Leu Thr Pro Ser Pro lie Thr Tyr Gly Glu 2675 2680 2685 Glu Gin Leu Leu His Phe Leu Gly Gin Leu Leu Gly lie Ala lie Arg 2690 2695 2700 Ala Asp Val Pro Leu Pro Leu Asp Leu Leu Pro Ser Phe Trp Lys Thr 2705 2710 2715 2720 Leu Val Gly Glu Pro Leu Asp Pro Glu Gin Asp Leu Gin Glu Ala Asp 2725 2730 2735 lie Leu Thr Tyr Asn Tyr Val Lys Lys Phe Glu Ser lie Asn Asp Glu 2740 2745 2750 Thr Glu Leu Glu Ala Leu Cys Ala Glu lie Ala Ser Gin His Leu Ala 2755 2760 2765 Thr Glu Ser Pro Asp Ser Pro Asn Lys Pro Cys Cys Arg Phe Thr Tyr 2770 2775 2780 Leu Thr Met Thr Gly Glu Glu Val Glu Leu Cys Ser Arg Gly Arg His 2785 2790 2795 2800 lie Leu Val Ala Trp Glu Asn Lys Asp lie Tyr Ala Ala Ala lie Arg 2805 2810 2815 Ser Leu Arg Leu Arg Glu Leu Gin Asn Val Glu Cys Val Thr Ala Val 2820 2825 2830 Arg Ala Gly Leu Gly Ser lie lie Pro Leu Gin Leu Leu Thr Met Leu 2835 2840 2845 Ser Pro Leu Glu Met Glu Leu Arg Thr Cys Gly Leu Pro Tyr lie Asn 2850 2855 2860 Leu Glu Phe Leu Lys Ala His Thr Met Tyr Gin Val Gly Leu Met Glu 2865 2870 2875 2880 Thr Asp Gin His lie Glu Phe Phe Trp Gly Ala Leu Glu Met Phe Thr 2885 2890 2895 Gin Glu Glu Leu Cys Lys Phe lie Lys Phe Ala Cys Asn Gin Glu Arg 2900 2905 2910 lie Pro Phe Thr Cys Pro Cys Lys Asp Gly Gly Pro Asp Thr Ala His 2915 2920 2925 Val Pro Pro Tyr Pro Met Lys lie Ala Pro Pro Asp Gly Thr Ala Gly 2930 2935 2940 Ser Pro Asp Ser Arg Tyr lie Arg Val Glu Thr Cys Met Phe Met lie 2945 2950 2955 2960 Lys Leu Pro Gin Tyr Ser Ser Leu Glu lie Met Leu Glu Lys Leu Arg 2965 2970 2975 Cys Ala lie His Tyr Arg Glu Asp Pro Leu Ser Gly 2980 2985 <210O> 107 <21 1> 1801 <212> DNA <213> Mus musculus <400> 107 cattgtctgc ctcagccact gccgccgcca ctgctgctgc aggatccgcc gcagccacca gtctcgcgcg tcgtcgctcc ctccttggac agtaatttta tgaataagca tcagaagcca 120 gtactaacag gccagcggtt caaaacccgg aaaagggatg aaaaagagaa attcgaaccc 180 acagttttca gggatacact tgtccagggg ctaatgaag ctggtgatga ccttgaagct 240 gtagccaaat ttttggattc tactggctca cgattagatt accgtcgcta tgcagacaca 300 ctctttgata tcctggtggc tggcagtatg cttgcccctg gaggaacacg catagacgat 360 ggtgacaaga ccaagatgac caaccactgt gtgttttcag caaatgaaga tcatgaaacc 420 atccgaaact atgctcaggt cttcaataaa ctcatcagga gatacaagta tttggaaaag 480 gcatttgaag atgaaatgaa aaagcttctc ctcttcctta aagcattttc tgaagcagag 540 cagacaaagt tggcaatgct gtctgggatc ctgctgggca atgggaccct cccagccacc 600 atcctcacca gtctcttcac agacagctta gtcaaagaag gcatcgcagc ctcattcgct 660 gtcaagcttt tcaaagcctg gatggcagag aaagatgcca attctgttac ctcttcactg 720 agaaaagcca acttagacaa gaggctgctt gaactcttcc cagtgaacag acagagtgtg 780 gatcatttcg ctaagtactt cactgacgcg gggctgaagg agctgtcgga ctttctccga 840 gtccagcagt cgctgggcac caggaaagaa ctgcagaagg agctgcaaga gcgactgtct 900 caggaatgcc ccatcaagga ggtggtgctt tacgtcaaag aggaaatgaa aaggaacgac 960 cttccggaaa cagctgtgat cgggctgctg tggacctgca tcatgaatgc ggtggaatgg 1020 aacaagaagg aggagctggt tgcggagcag gcactgaagc acctaaagca atacgctccg 1080 ctgctggccg tgttcagttc ccaaggccag tccgagctcg tcctcctgca gaaggttcag 1140 gaatactgct acgacaacat ccacttcatg aaggccttcc agaagatcgt ggttctcttt 1200 tataaagccg acgttctgag cgaagaggcg atactgaagt ggtataaaga agcacacgcc 1260 gccaaaggca agagcgtctt tcttgaccag atgaagaaat ttgtggagtg gatacaaaat 1320 gcagaagaag aatctgaatc agaaggcgaa gaaagctaaa tgtctscrgc acwctgcmta 1380 aaaaaggaaa raaawaaytm awrsgccaca ctttgtcgcg yygscgmnatg ctgrwgcgkt 1440 kggggrgggr rrcttggctt ctgtttgcac caaggaaata aatgataggc gaggcctccc 1500 ccgctccccg gggaaggcat ttttttcatt tctgttttgt ttcaatggag ccctgaggcg 1560 tcggctacta cacttgggac tctacctctc actgtacgct aactaaagcc attcaacaag 1620 ggggtcaggt aggaacctga agctcaaaac tcagtacacc ccttttttta gctgtatttt 1680 caggtactgt gtgaacgccc cactggtgtc tatgttacag ggccacttca atagttgtgt 1740 ttcttctgct cgtgtatgtg atttgacaaa ccagtttttt taaaataaac ggctttttaa 1800 a 1801 <210O> 108 <21 1 >11157 <212> DNA <213> Homo sapiens <400> 108 atggtggaag gagatacagt caccttctcc tttgaaatga gaagtggccg tgaacacaac actcctgata aagccatgtg gggctttgct tgcacagttc gcgctcagga gtcttcggag 120 gatgtctcag gaggcttgcc ctttctggta gacctggctt taggtctgtc tgtgttagct 180 tgftccatgt taagaatcct gtacaatgga ccagaaafta ccaaagaaga aagcg 4 gaaatggtgg tatcttgtgt tattaagcac ttgaacttgg ttgatgcact gcagtctcta 360 ataaatttcc aatatcaaga agaacatgct gaagaatatg atttattatg taaaattatg 420 ggagagacct ttaagaaact caatgccatg gagagacagc tgcagaacaa aatgaaagaa 480 ctagaacttt tatgttcaat gaaggaagtc tcctttgatg ggaatgatct tgaaaacatg 540 gtcctatcac tgagggagaa gttcctacaa gaagtgaatt ctcttattca gaaaccctca 600 cacccactgg ctaaaacaaa gacgttagtg aagagtttaa tgaaccgagc cgagctgttg 660 ctgcatgtca ccatcgcagc ccagtcgggc ctcacgagaa gcatctctgg gacccctgct 720 gaaacaccag cttgtaaatc agcttctgaa acaaaagtga tatctcacgc tgtcaggcag 780 cctgtttc ttcgcagcat gtcagctcct tctgacctgg aaatgattgg taatgaagat 840 ttggaattta ctagagcaaa tcagaggcgt cgccacgtga ccagccaccg cagcagctcc 900 tttacactcc tgcagtcgct ggccattgag gacagcaggg acaagcccac ctacagtgtc 960 ctgctagggc agctgtttgc tttcatcggc accaaccctg accaagctgt gtccagcagc 1020 agtttccttt tggctgcaca gacaaggtgg cggcggggaa acactcgcaa gcaggcactg 1080 gtgcacatgc gggaattgct gacagctgcc gtacgagtcg ggggagtgac gcatcttgtg 1140 ggtccagtga cgatggtcct tcagggagga cccagaattg aagaactcac atgtggtggg 1200 atggtcgagc aggtccagga agcctttggc gagaccatga cctctgttgt gtctctgtgt 1260 gctcgttacc ctatcgcttg cgcaaatagc attggactct tatgtaccat accttacacc 1320 aggagcgaag agaagtgcct ggtacgcagt ggccttgtgc agctcatgga tcgactgtgt 1380 agcftgagca atcagaccga gtccagctcc agtgagaaac agaccaagaa gcagaaggtg 1440 gccaccatgg cctgggctgc cttccaggtg cttgccaacc gctgtgttga gtgggaaaaa 1500 gaggaagaga caggatctta ctatgttgcc cagctgtgcc gggcggcgct gcccctgatg 1560 agcgtagaag actgtggaaa cgtggagctc ccaccctgga gctactctgt cccctcctta 1620 aacagtgagc aggaggatcc cagcgaccca gcttccaaga tcgcctccct gctcttagca 1680 aagctggcag attatgtggt tccaggatgt cagacagttc tttctccaac cgcttctgaa 1740 cctgacacca cattgacaaa aaccagtccc aagaattcct tgaaaggaga taaagatcct 1800 ggagaagaga gtgaggctgt ggatggcaag ctctcgatat ttatccacaa gcgggaagac 1860 cagtcatccc atgaagtcct ccagccattg ctaagtagtt cagaaggacg gcccttccga 1920 cttggtactg gcgccaacat ggagaaagtt gtgaagatgg atcgagacat gaccaagggt 1980 ggctgttgcg aagtgattac agaagaggct gcagccgccc tgcggaaagc caccaagtgg 2040 gcacagtcag gcctcatcgt cagcattggg ccacctgtag agtctatcaa cccagagact 2100 gtgagtggac tatccacagg cgacaaaaag aaaactgccc aaacttccat ttgccgagag 2160 aggaactcgg agcttgcaag gactgatcct gtgcgtccct tcatcagtgg gcatgtggca 2220 aacagcatgg ctgcagaagt gatcgccttg ctacatagct tgctcatggc acctgaatca 2280 aatgctgctc aaatatggac cacaacagca gagaaggttc tgtctagagc actgatgtac 2340 attccacaat tggggaaata cgcagaaagc attctggaaa atggcagcag cagtggcagg 2400 aaacttgcca aacttcagag aattgcacgc caggccgttg ccgcactgtg tgcacttgga 2460 ggcttcaaag agacaatcaa gataggatcc gaggttcagg cattgcctct tcataaactg 2520 tccattactg agaaggtagt acaggcagtc cagtccatgt tgcttcctca ggagggaagt 2580 ctctctattc acacctcact tcctgcaaca ggagatgggt cagctcctgt gatggcagtc 2640 gttcggctcc ttgctgaaat aaggacaaga gcatgcctgg tcatggccca gcttttagaa 2700 gacagottat tttgtgaaga attcatacaa caatgtccag cagctgttga agttcttaac 2760 ctagtagccc aggaatgtag tgctggagag cgacttgcag ttgtggaggt acagtgtgaa 2820 cggctgagga tgctctaccg ggactgtgct cggcccccac cacctcctft gcaggctgac 2880 gatgacaccg gacccatagt ftcctttggc ttcactacag aagcagagaa gcgagatggg 3000 gcttggacta atccagtggg cacttgtctt ttccataaca acggccgagc cgtgcactat 3060 aatggctcca gtttgttaca gtggaagagc gttcgcttag acgtgactct ctcccccggt 3120 gacgtggcag gaattggctg ggagagaact gaggggactc cacctcctcc gggacagcca 3180 gccaagggcc gggtgtactt cacatactgc gggcagcgcc tctcaccata tcttgaagac 3240 gtctctggtg gcatgtggcc agtggttcac attcagaaaa aggcagaaat aaaaataaac 3300 gtaagtcttt ccaaatcctt catttggtct cctttccaga acaccaaaac ccgagctaac 3360 tttggctccc ggccgtttgc ctacgcggaa gggcaggccc accgcaatgc tgctgacctg 3420 tgcactgacc tagcagaaga gatcagcgct aactttgagg ccctgccttt cgccatggca 3480 tctgacagtg acaatgatgc tggcaccagt attgcatcag acccaggcac tcatgggcca 3540 ccatgccgga ttgctgccgt ggccaccgct cagcaacaat atgatagtga cacctcctgt 3600 cattataaag tcgagctcag ctatgagaat ttcatcacct ctggcccaga ccctcacccg 3660 cctcccattg cagatgatga aagcgatgat gatgacgatg atgacatccc tcaggaggac 3720 cactacgccc tgctggtgaa agcatgggag accaaggttt ttcctaccat ccgaagacgc 3780 ttccgcaatg aagcagagcg gaaatcgggc ctggaccaga taaagggggc cttacaacta 3840 ggtatggtgg atattgcccg acagacggtt gaatttctct acgaagagaa tggtggcatc 3900 ccaagagacc tttatcttcc caccattgaa gacattaaag acgaagcaaa caagttcaca 3960 attgataaag ttcgaaaagg tctcacagta gtaacccgct ciccagacag caataatgta 4020 gccagcagtg ctgttggaac tgctctgcca aaatttgcca tccgagggat gctgaaaacc 4080 tttgggcttc atggagtcgt cttagatgtt gattcagtga atgaactggt gcaggtagaa 4140 acgtacctcc gcagtgaagg tgtgctggtg cgatactggt atcctattga catgttggaa 4200 aggcccccag caggctaccg aaggactgcc accaatgggc tggtcacact ggacaatacc 4260 aaccttcaaa ttcacaggga gctgctgcgc tgcgaggctg cgctggccag gctgtactgc 4320 cgcatggccc tgctcaatat cttcgccccg aagttgcctc acttgttcac tcgcctcttc 4380 cacatccctg ccatccggga cattaccctg gagcacctgc aactgctgtc caatcagctc 4440 ctcgcacctc ctctcccaga cggcaccatc agctccagct cgatcctcct ggcgcagtct 4500 ftacagcatt gcatccattc ccagaactgc tccgccacgg acctctta ccagggcaac 4560 tcccagacag tgagagagtg gctcaacgtg gccatcaccc ggaccctgca ccagggcgag 4620 gagagccttt tagagctgac gaaacagatc tgctctttcc tgcagacagc accagagcag 4680 ttcccctccg aagagttccc aatttccgaa tccaaagtca acatggacgt gaatttcccc 4740 ggggcagctt ttgttgttgt gtcttgtaaa gaaagtcaat ctggattccg caaagactcc 4800 tctctgtaca aggcaccgtg ggcacgggtg ctcgtatatg gcctcggcca caaagtgaag 4860 cgaaatggcc agctgaacct catcgaggcc gcctgttacc cgcgggacgc gtccccagcc 4920 aacactgggc ttgcacctcc ccccaccgct gaccagtacc cctctgtggt cctctccaca 4980 gacagggtcc acatcaaact gggggtgtct ccacctcctg gagcagtcct ggtgttacat 5040 tccctgcccc tggagttccc actggctatg gccttcgcag agcagctgct gtcctggaaa 5100 toagaggaca gtgaagggaa gtccgaagat gagcctgaca ccattccgac atccgtcctc 5160 ctgcaggtgg tggagctgct aggaaacttc ttgtggacca cggacatggc agcctgcgtg 5220 aaggagcttg tttccatct cctggcagag ctcctgcgca cggtgcacac cctggagcag 5280 aggcggcacc ccgctggcct gtcctcctca atcgccctcc agctgaaccc ctgcctggcc 5340 atgctgatgg ccttgcagtc ggagctccac aagctgtacg acgaggagac gcagaactgg 5400 gtctcaggcg gcgcctgcgg gggctccggg ggggcggcgg ccggtgacca gggcaggttc 5460 tctacgtatt ttcatgcact catggaaggg tgcctggctg tggccgaagt gaccctgcct 5520 actaacatga gtgtcacagc cagtggggtg acctcagcga ccgccccaaa tctcagtgac 5580 tcgtcctcct cctcctcgtc ctccccagga cagacoccac agagtcccag cctcctctcc 5640 aagaggaaaa aagtcaagat gaagcgggaa aaggcctcct cgtcgggcaa gcgccagtct 5700 tcccgcaccg tggactcgga ccccaccgtg ctcagcatcg gaggcagcaa gcccgaggac 5760 atgctgtggt tccaccgcgc actcaccctg ctcatcatcc tccgccacct caccaggaag 5820 gacccacagg ggctgggcgt gacgagtgac gccatcgccg atgcctgcca ggccctggtg 5880 ggccccaccg cccacagccg cttgctggtg atctccggga tccccaccca cctggacgag 5940 ggcgtagtca gaggcgccat ccgcaaggcc tgcaacgccc acggcggggt ctcaaagac 6000 gagatctaca tcccgctgca ggaagaagac accaagaagc caaaagacaa ggccgagggc 6060 ggggacggga aagttgagcc cgagaagaca ctggccttcc ccggcacaga cagcatggag 6120 gtcagcacgt ccagcagcct gacccccgcc atgagcatca gcgcctccgc ctccaccagc 6180 caggcctcca tctgcagctc gcagggcatc tcccaaaccg tcagcgacct ctctgtggat 6240 ccgctgcctg ccggcctcga gctgcccatc cctccgggcc tgttggagco ccacgcggtg 6300 tccagccagg aaagcctgga catttccctg tgcagcaccg gcagcctggg cagcctgggc 6360 agcctggggg agcccctgga caatgcagag acggcctcgg tgtcggacat gggctccatg 6420 taccagca ftcctga caccgcc ctgcccccgccccatcaa aggcttcgca 6480 gtcgtggaga taagatcccg agccaaaatt gagaaaattc gagcaagttt atttaacaat 6540 :9 aatgacttga ttggtttgtc aagtttggat ggtgaagatg aattgatgga aatgtcaaca 6600 gaagagattc taaccgtgtc tgtagtaaat cagagtctct ttgatactca agggagccca 6660 gggttagaag attatttcaa tgataagtca attaaagggg agaagctggt gcccggagcc 6720 agagaggttc tgacggagat atttaagagt tgtgcccatt cagagcagac gctgagcctg 6780 acaccagoga agcccatcag agtctctgac atttatctta gcaaagagca gatcaactcc 6840 cagaccccag gcaacctcct ccacctcttc ttcaccaatg tccggccgcc aaaaaaggtg 6900 ctggaggatc agctcaccca gatcctgagg aagtatggcg tgccaaagcc caagtttgac 6960 aagagcaagt acagcaaggc cgggaaggag cagcaccccg tgaaggtggt gagcaccaag 7020 cggcctatca ccaagccgcc cgccaaggac aaggctgtgc tcaacagcgt cagcaggact 7080 gccttaagtg agaagaagcc aactgtgaag ccaaaatcac cagaaaagag caaaccagat 7140 gaaaaggacc cagaaaagtc acctaccaaa aaacaagaag tccctgagga aaaatacctg 7200 acgctggaag gatttcacaa atttgttaft gaccgagcca ggcaagatat ccgtagcgtc 7260 :tggagggcga tcttgtcctg tggttacgat cttcactttg agaggtgcgc atgcatcgat 7320 cagtacatca accagctatg ccgccacctc gccatcacac ccgcacggct ccatccccat 7440 gaggtgtacc tggaccccgc ggatgctgct gaccccagag tggcctgtct cctgaacgtg 7500 cccatcgaga gcctgcgcct gcgcttcgcc ttgctgcagt ccctcaacac cacactggag 7560 accttcttcc tgcccctggt ggagctgcgc cagacaccca tgtataccca cagcatcgcc 7620 gccctgctga aggaggccaa agggctgatc ttctatgaca cgaaggtgac cgtgatgaat 7680 cgagtgctga atgccactgt gcagaggaca gcggaccacg cggcccctga gatcaccttg 7740 gacccactgg aaattgtggg aggggaaatc agagcttctg aaaactccta cttctgtcag 7800 gctgccaggc agctggcctc agtgccgtcg tctcagctct gcgtcaagct ggccagtggc 7860 ggtgacccca catatgcctt caacatccgc ttcactggcg aggaggtcca tggcaccagc 7920 ggctctttcc gccacttcct gtggcaggtg tgtaaggagc tgcagagttc ctcgctgtcg 7980 ctgctgctgc tgtgccccag ctcagctgtc aataagaaca agggcaagta tatcctgacc 8040 ccgagcccca tcacctacgg ggaggagcag ctgctgcact tcctggggca gctgctgggg 8100 attgcaattc gggcagacgt cccgctgccc ctggacctcc tgccctcctt ctggaagacg 8160 ctggtgggcg agcccttgga ccctgagcaa gacctgcagg aagcggatat cctcacctac 8220 aattacgtca agaagtttga gagcatcaat gatgagaccg agctggaggc cctgtgcgct 8280 gagatcgcct cccagcacct ggccacggag agccctgaca gccccaacaa gccctgctgc 8340 aggttcacct acctgaccat gacgggcgag gaggtggagc tgtgcagccg gggccggcac 8400 atccttgtgg cgtgggagaa caaggacatc tacgcggcag ccatccggag cctgcggctg 8460 cgggagctgc agaatgtgga gtgcgtgacg gccgtgcggg ccggcctggg ctccatcatc 8520 cccctgcagc tgctgaccat gctcagccca ctggagatgg agctgcgcac ctgcggcctc 8580 ccctacatca acctcgagtt cctcaaggcc cacaccatgt accaagtggg gctgatggag 8640 acggaccagc acatcgagtt cttctggggg gccctggaga tgttcaccca ggaggagctg 8700 tgcaagttca tcaagtttgc ctgcaaccag gagcgcatcc cgttcacctg cccctgcaaa 8760 gatgggggtc ccgacactgc ccatgtgccc ccgtacccca tgaagatcgc ccccccagat 8820 ggcacagcag gttccccaga ctctcgctac atccgcgtgg agacctgcat gtcatgatc 8880 aagcttcccc agtactcctc tctggaaatc atgctggaga aacttcgttg tgccattcac 8940 taccgtgaag accccctcag tggctgatgg gagggagccc cagaattagg ctgtcactga 9000 ggcacccact ctgctggctt gggaagccac cactgcggcc cgtccctcca gggccctgcg 9060 tgaggagttg gcaacatttt gcttttccaa actttcgtcc acattccagg gcctcctgga 9120 agacttaacc ttttgtcttt gtacgtttcg tgatgggttg gttcttttgc tgcctgtttg 9180 tggtctattt gtaggatagt tagttccca gacagtttgt gtctaatttg atcttcttgg 9240 acattgtccc tcatggccac cagattctaa tgccataagg ccccagctgg ttccccatca 9300 cagaaccacc cagcaggaag ccgggggtac aatgacctcg gccacacaga gcgctcgtgc 9360 tttcagcaga gcgcctccac agacaagcct gtggccagcc ctgccctcca gcotcgagct 9420 ggagttgctc cagaggcagc cccagcaggc ctccctccac atagaggtgg ctgggccaat 9480 tgcccaaaca cgtgagacac acagggagct ttatgtgttc atcttcctgc tttagaactt 9540 gctcccggtc ttggtttttc tgaggaaaag cccacagtgg ttcccctgcc cctcccatac 9600 ctccctatct gccgtctgtc tctttgggcc ctggtctgac agttttcatc tgaggcctcc 9660 tcgggagcag gagacttaag ggttcatccc gaccttagtt cacagagcct agctgggtgc 9720 atcccagccg cagggggtga gaagacaccc agagatgggg gacaatgctc aggtgggggc 9780 ctcctccgag actctggttg agaggaaagc acatgattca agcctacccc acaaaaaagg 9840 agcacaaaat gctcagaaat ggcccttcct ccctgcagtg acgtaggaca agggaaaggg 9900 ccacacccat tttcaaaaga gtggactgag gtgctctgct caatttgggg tctgctttag 9960 tgacccagac actcaagtcc agatggagac tccagggggg tccttctgcc cctctggcca 10020 gccccaccca gcactcccca tcaccccatg taagtgtgta tgccagggct gag~tgcctc 10080 caggctcacc cactgcatct ttgccccaaa taggtctttg tccagtggta ctttgttcat 10140 gagcagcaca ggccatcttg ttggacactg tcactttggg ccttgccagg tctcacagaa 10200 tcacatcgct gtatttattg tataatattg tgaatattgg aagttttgag tgagtgctgt 10260 ctagaaggtt ttggagtgtg gatgctggtc caagaaagaa gatgtgccct ggcctgctgg 10320 aaagattgtg aattctagag atagagccgt tagcatccat ctcctccctg taactcttag 10380 gaaatgcatc aaggaccatt atagaaagga tcccctgacc taaggatgaa atcgacctag 10440 ggttaatcat gacagctgca tcagttgtat tggatgcaag tcaactctgg aggtgagtgc 10500 ccgcaagcag ttcccctgct ttgaaagaag atggtcagcc cgctgcctcc ccagcggcca 10560 cagctccttt gagtgtgggg ggtcacagcc aggatgtatt cctgacaata aggatccttt 10620 tattcatt tctgcataat gaaagagcct ttcgatttat tagaagtggt ttttcctccc 10680 tacatcttta aattcttggt tctctttagt cctcatccct tgaatggact tgtcagctac 10740 ctccccagga ggagftcaga agcttctgtt ggccatcact tgagtagatg acaagctgta 10800 aggtatctgc tgctaacgtg gctgcttctc cgagagcaca ttgaggtcca gacagatcca 10860 aacttgccctaaaat ttgtgta gfacfgatgatatt fatattt 0920 ttatggttgc atttaacaaa cttttcattc aatctgatgc tatttacacc atgctgtgta 10980 aaggaagctc actaaaggaa aaaagtcaca ccaataaata accttcatct aattttgatt 11040 taccttaaga gttgtgtgat catctactct tgctgagcaa gttcaaaggc tggcatgctt 11100 ggatggctct gatatttaag tgctgccaag tggctaggaa ttaaagtgtt tctaatt 11157 <210O> 109 <21 1> 324 <212> PRT <213> Mus musculus <400> 109 Met Asp Gin Ser Asn Met Thr Ser Leu Ala Glu Glu Lys Ala Met Asn 1 5 10 Thr Ser Ser Arg Asn Ala Ser Leu Gly Ser Ser His Pro Pro lie Pro 25 lie Val His Trp Val lie Met Ser lie Ser Pro Leu Gly Phe Val Glu 40 Asn Gly lie Leu Leu Trp Phe Leu Cys Phe Arg Met Arg Arg Asn Pro 55 Phe Thr Val Tyr lie Thr His Leu Ser lie Ala Asp lie Ser Leu Leu 70 75 Phe Cys lie Phe lie Leu Ser lie Asp Tyr Ala Leu Asp Tyr Glu Leu 90 Ser Ser Gly His His Tyr Thr lie Val Thr Leu Ser Val Thr Phe Leu 100 105 110 Phe Gly Tyr Asn Thr Gly Leu Tyr Leu Leu Thr Ala lie Ser Val Glu 115 120 125 Arg Cys Leu Ser Val Leu Tyr Pro lie Trp Tyr Arg Cys His Arg Pro 130 135 140 Lys His Gin Ser Ala Phe Val Cys Ala Leu Leu Trp Ala Leu Ser Cys 145 150 155 160 Leu Val Thr Thr Met Glu Tyr Val Met Cys lie Asp Ser Gly Glu Glu 165 170 175 Ser His Ser Arg Ser Asp Cys Arg Ala Val lie lie Phe lie Ala lie 180 185 190 Leu Ser Phe Leu Val Phe Thr Pro Leu Met Leu Val Ser Ser Thr lie 195 200 205 o Leu Val Val Lys lie Arg Lys Asn Thr Trp Ala Ser His Ser Ser Lys 210 215 220 Leu Tyr lie Val lie Met Val Thr lie lie lie Phe Leu lie Phe Ala 225 230 235 240 Met Pro Met Arg Val Leu Tyr Leu Leu Tyr Tyr Glu Tyr Trp Ser Ala 245 250 255 Phe Gly Asn Leu His Asn lie Ser Leu Leu Phe Ser Thr lie Asn Ser 260 265 270 Ser Ala Asn Pro Phe lie Tyr Phe Phe Val Gly Ser Ser Lys Lys Lys 275 280 285 Arg Phe Arg Glu Ser Leu Lys Val Val Leu Thr Arg Ala Phe Lys Asp 290 295 300 Glu Met Gin Pro Arg Arg Gin Glu Gly Asn Gly Asn Thr Val Ser lie 305 310 315 320 Glu Thr Val Val <210> 110 <211> 267 <212> PRT <213> Homo sapiens <400> 110 Met Thr Thr Lys Asn Leu Glu Thr Lys Val Thr Val Thr Ser Ser Pro 1 5 10 Thr Arg Gly Ala Gly Asp Gly Met Glu Thr Glu Glu Pro Pro Lys Ser 25 Val Glu Val Thr Ser Gly Val Gin Ser Arg Lys His His Ser Leu Gin 40 Ser Pro Trp Lys Lys Ala Val Pro Ser Glu Ser Pro Gly Val Leu Gin 55 Leu Gly Lys Met Leu Thr Glu Lys Ala Met Glu Val Lys Ala Val Arg 70 75 lie Leu Val Pro Lys Ala Ala lie Thr His Asp lie Pro Asn Lys Asn 85 90 Thr Lys Val Lys Ser Leu Gly His His Lys Gly Glu Phe Leu Gly Gin 100 105 110 Ser Glu Gly Val lie Glu Pro Asn Lys Glu Leu Ser Glu Val Lys Asn 115 120 125 Val Leu Glu Lys Leu Lys Asn Ser Glu Arg Arg Leu Leu Gin Asp Lys 130 135 140 Glu Gly Leu Ser Asn Gin Leu Arg Val Gin Thr Glu Val Asn Arg Glu 145 150 155 160 Leu Lys Lys Leu Leu Val Ala Ser Val Gly Asp Asp Leu Gin Tyr His 165 170 175 Phe Glu Arg Leu Ala Arg Glu Lys Asn Gin Leu lie Leu Glu Asn Glu 180 185 190 Ala Leu Gly Arg Asn Thr Ala Gin Leu Ser Glu Gin Leu Glu Arg Met 195 200 205 Ser lie Gin Cys Asp Val Trp Arg Ser Lys Phe Leu Ala Ser Arg Val 210 215 220 Met Ala Asp Glu Leu Thr Asn Ser Arg Ala Ala Leu Gin Arg Gin Asn 225 230 235 240 Arg Asp Aia His Giy Ala Ilie GIn Asp Leu Leu Ser Giu Arg Glu Gin 245 250 255 Phe Arg GIn Glu Met Ile Ala Thr GIn Lys Phe 260 265 <210> 111 <21 1> 403 <212> PRT <213> Mus musculus <400> 111 Met Glu Lys Met Thr Thr Leu Lys Ser Ser Giu Asn Lys Gly Ilie Leu 1 5 10 Thr Ser Thr Pro Ilie Arg Gly Ala Gly Asp Giy Met Giu Thr Glu Glu 25 Pro Pro Lys Ser Val Glu Val Thr His Gly Val Gin Pro Iie Asn GIn 40 His Val Leu Pro Ser Pro Arg Lys Lys Vai Ser Ser Asp Ser Pro Gly 55 Val Leu GIn Leu Gly Lys Iie Leu Asn Glu Arg Thr Val Glu Val Giu 70 75 Ala Val Arg Ile Phe Val Pro Lys Aia Aia Ile Thr His Asp Ile Pro 90 Thr Lys Asn Thr Lys Vai Lys Ser Leu Giy His His Arg Glu Giu Leu 100 105 110 His Asn Gin Aia Glu Val Vai Thr Asp Pro Arg Lys Glu Leu Ser Glu 115 120 125 Vai Lys Lys Vai Leu Giu Lys Leu Lys Asn Ser Glu Arg Arg Leu Leu *130 135 140 GIn Asp Lys Giu Gly Leu Ser Asn GIn Leu Arg Val GIn Thr Giu Ile 145 150 155 160 Asn Arg Glu Leu Lys Lys Leu Leu Val Ala Ser Val Gly Asp Asp Pro 165 170 175 GIn Tyr His Phe Glu Arg Leu Aia Arg Giu Lys Asn GIn Leu Ile Leu 180 185 190 Giu Asn Giu Ala Leu Gly Arg Asn Thr Ala GIn Leu Ser Glu GIn Leu *195 200 205 Giu Arg Met Ser Ilie Gin Cys Asp Val Trp Arg Ser Lys Phe Leu Ala 210 215 220 Ser Arg Val Met Ala Asp Giu Leu Thr Asn Phe Arg Val Val Leu Gin 225 230 235 240 Arg GIn Asn Arg Asp Ala Gin Ser Ala Ilie Gin Asp Leu Leu Ser Glu 245 250 255 Arg Glu Gin Phe Arg Gin Giu Met Thr Ser Thr Gin Lys Phe Leu Giu 260 265 270 Glu Leu Leu Val Ser Leu Gin Trp Gly Arg Giu Gin Thr Tyr Ser Pro 275 280 285 Asn Thr Gin Pro His Ser Thr Ala Asp Leu Ala Leu Thr Asn His Gly 290 295 300 Leu Ala Gin Ala Ilie His Ala His Leu Leu Gly Asn Val Gly Ilie Ser 305 310 315 320 His Gin Lys Lys Ilie Pro Thr Thr Val Giu Phe Cys Ser Thr Pro Ala 325 330 335 Giu Lys Met Ala Giu Lys Val Leu Arg Ilie Leu Asp Pro Val Ala Cys 340 345 350 Thr Giu Ser Ser Pro Asp Asn Gin Phe Ala Glu Ser Ser Pro Thr Thr 355 360 365 Leu Leu Thr Thr Lys Lys Asn Ilie Gly Arg Phe His Pro Tyr Thr Arg 370 375 380 Tyr Giu Asn Ilie Thr Phe Asn Cys Cys Asn His Cys Gin Gly Giu Leu 385 390 395 400 Ilie Ala Leu 0 so <21 0> 112 *000 <21 1>35 <213> Mu msclu *0 <400> 112 Met Glu Lys Met Thr Thr Leu Lys Ser Ser Giu Asn Lys Gly Lys Gin *1 5 10 Giu Met Met Lys Gly Lys Lys Met Gin Ser Pro Ser Pro Ala Cys Ser 25 *sees: Pro Ala Arg *0 <210> 113 <21 1 >319 <212> PRT <213> Mus musculus <400> 113 Met Met Val Leu Arg Val Giu Giu Leu Val Thr Gly Lys Lys Asn Ser 1 5 10 Asn Gly Ala Ala Gly Giu Phe Leu Pro Gly Giu Phe Arg Asn Gly Glu 25 Tyr Glu Ala Ala Val Ala Leu Glu Lys Gin Glu Asp Leu Lys Thr Leu 40 Pro Ala Asn Ser Val Lys Gin Gly Glu Glu Gin Arg Lys Ser Glu Lys 55 Leu Arg Glu Ala Glu Leu Lys Lys Lys Lys Leu Glu Gin Arg Ser Lys 70 75 Leu Glu Asn Leu Glu Asp Leu Glu lie lie Val Gin Leu Lys Lys Arg 90 Lys Lys Tyr Lys Lys Thr Lys Val Pro Val Val Lys Glu Pro Glu Pro 100 105 110 Glu lie Met Thr Glu Pro Val Asp Val Pro Arg Phe Leu Lys Ala Ala 115 120 125 Leu Glu Asn Lys Leu Pro Val Val Glu Lys Phe Leu Ser Asp Lys Asn 130 135 140 Ser Pro Asp Val Cys Asp Glu Tyr Lys Arg Thr Ala Leu His Arg Ala 145 150 155 160 Cys Leu Glu Gly His Leu Ala lie Val Glu Lys Leu Met Glu Ala Gly 165 170 175 Ala Gin lie Glu Phe Arg Asp Met Leu Glu Ser Thr Ala lie His Trp 180 185 190 Ala Cys Arg Gly Gly Asn Ala Asp Val Leu Lys Leu Leu Leu Asn Lys 195 200 205 S* Gly Ala Lys lie Ser Ala Arg Asp Lys Leu Leu Ser Thr Ala Leu His 210 215 220 Val Ala Val Arg Thr Gly His Tyr Glu Cys Ala Glu His Leu lie Ala 225 230 235 240 Cys Glu Ala Asp Leu Asn Ala Lys Asp Arg Glu Gly Asp Thr Pro Leu 245 250 255 His Asp Ala Val Arg Leu Asn Arg Tyr Lys Met lie Arg Leu Leu Met 260 265 270 Thr Phe Gly Ala Asp Leu Lys Val Lys Asn Cys Ala Gly Lys Thr Pro 275 280 285 Met Asp Leu Val Leu His Trp Gin Ser Gly Thr Lys Ala lie Phe Asp 290 295 300 Ser Leu Lys Glu Asn Ala Tyr Lys Asn Ser Arg lie Ala Thr Phe 305 310 315 <210> 114 <211> 509 <212> PRT <213> Homo sapiens <400> 114 Met Tyr Ser Pro Leu Cys Leu Thr Gin Asp Glu Phe His Pro Phe lie 1 5 10 Glu Ala Leu Leu Pro His Val Arg Ala Phe Ala Tyr Thr Trp Phe Asn 25 Leu Gin Ala Arg Lys Arg Lys Tyr Phe Lys Lys His Glu Lys Arg Met 40 Ser Lys Glu Glu Glu Arg Ala Val Lys Asp Glu Leu Leu Ser Glu Lys 55 Pro Glu Val Lys Gin Lys Trp Ala Ser Arg Leu Leu Ala Lys Leu Arg 70 75 Lys Asp lie Arg Pro Glu Tyr Arg Glu Asp Phe Val Leu Thr Val Thr 90 Gly Lys Lys Pro Pro Cys Cys Val Leu Ser Asn Pro Asp Gin Lys Gly 100 105 110 Lys Met Arg Arg lie Asp Cys Leu Arg Gin Ala Asp Lys Val Trp Arg 115 120 125 Leu Asp Leu Val Met Val lie Leu Phe Lys Gly lie Pro Leu Glu Ser 130 135 140 o Thr Asp Gly Glu Arg Leu Val Lys Ser Pro Gin Cys Ser Asn Pro Gly 145 150 155 160 Leu Cys Val Gin Pro His His lie Gly Val Ser Val Lys Glu Leu Asp 165 170 175 Leu Tyr Leu Ala Tyr Phe Val His Ala Ala Asp Ser Ser Gin Ser Glu 180 185 190 Ser Pro Ser Gin Pro Ser Asp Ala Asp lie Lys Asp Gin Pro Glu Asn 195 200 205 Gly His Leu Gly Phe Gin Asp Ser Phe Val Thr Ser Gly Val Phe Ser 210 215 220 Val Thr Glu Leu Val Arg Val Ser Gin Thr Pro lie Ala Ala Gly Thr 225 230 235 240 Gly Pro Asn Phe Ser Leu Ser Asp Leu Glu Ser Ser Ser Tyr Tyr Ser 245 250 255 Met Ser Pro Gly Ala Met Arg Arg Ser Leu Pro Ser Thr Ser Ser Thr 260 265 270 Ser Ser Thr Lys Arg Leu Lys Ser Val Glu Asp Glu Met Asp Ser Pro 275 280 285 Gly Glu Glu Pro Phe Tyr Thr Gly Gin Gly Arg Ser Pro Gly Ser Gly 290 295 300 Ser Gin Ser Ser Gly Trp His Glu Val Glu Pro Gly Met Pro Ser Pro 305 310 315 320 Thr Thr Leu Lys Lys Ser Glu Lys Ser Gly Phe Ser Ser Pro Ser Pro 325 330 335 Ser Gin Thr Ser Ser Leu Gly Thr Ala Phe Thr Gin His His Arg Pro 340 345 350 Val Ilie Thr Gly Pro Arg Ala Ser Pro His Ala Thr Pro Ser Thr Leu 355 360 365 His Phe Pro Thr Ser Pro Ilie Ile Gin Gin Pro Gly Pro Tyr Phe Ser 370 375 380 His Pro Aia Ilie Arg Tyr His Pro Gin Giu Thr Leu Lys Giu Phe Vai 385 390 395 400 Gin Leu Val Cys Pro Asp Ala Gly Gin Gin Aia Gly Gin Val Giy Phe 405 410 415 Leu Asn Pro Asn Giy Ser Ser Gin Giy Lys Val His Asn Pro Phe Leu 420 425 430 Pro Thr Pro Met Leu Pro Pro Pro Pro Pro Pro Pro Met Aia Arg Pro 435 440 445 Val Pro Leu Pro Val Pro Asp Thr Lys Pro Pro Thr Thr Ser Thr Giu 450 455 460 Gly Giy Aia Aia Ser Pro Thr Ser Pro Thr Tyr Ser Thr Pro Ser Thr 465 470 475 480 Ser Pro Aia Asn Arg Phe Vai Ser Val Gly Pro Arg Asp Pro Ser Phe 485 490 495 Vai Asn Ilie Pro Gin Gin Thr GIn Ser Trip Tyr Leu Gly .500 505 <210> 115 <400> 115 000 <210> 116 <21 1> 1625 <212> DNA <213> Homo sapiens <400> 116 agcagcggcg ggggcccgag ggattctgaa ggaagatttc cattaggtaa tttgtttaat cagtgcaagc gaaattaagg gaaaatggat gtagaaaatg agcagatact gaatgtaaac 120 cctgcagatc ctgataactt aagtgactct ctcttttccg gtgatgaaga aaatgctggg 180 actgaggaag taaagaatga aataaatgga aattggattt cagcatcctc cattaacgaa 240 gctagaatta atgccaaggc aaaaaggcga ctaaggaaaa actcatcccg ggactctggc 300 agaggcgatt cggtcagcga cagtgggagt gacgccctta gaagtggatt aactgtgcca 360 accagtccaa agggaaggtt gctggatagg cgatccagat ctgggaaagg aaggggacta 420 ccaaagaaag gtggtgcagg aggcaaaggt gtctggggta cacctggaca ggtgtatgat 480 gtggaggagg tggatgtgaa agatcctaac tatgatgatg accaggagaa ctgtgtttat 540 gaaactgtag ttttgccttt ggatgaaagg gcatttgaga agactttaac accaatcata 600 caggaatatt ttgagcatgg agatactaat gaagttgcgg aaatgttaag agatttaaat 660 cttggtgaaa tgaaaagtgg agtaccagtg ttggcagtat ccttagcatt ggaggggaag 720 gctagtcata gagagatgac atctaagctt ctttctgacc tttgtgggac agtaatgagc 780 acaactgatg tggaaaaatc atttgataaa ttgttgaaag atctacctga attagcactg 840 gatactocta gagcaccaca gttggtgggc cagtttattg ctagagctgt tggagatgga 900 attttatgta atacctatat tgatagttac aaaggaactg tagattgtgt gcaggctaga 960 gctgctctgg ataaggctac cgtgcttctg agtatgtcta aaggtggaaa gcgtaaagat 1020 agtgtgtggg gctctggagg tgggcagcaa tctgtcaatc accttgttaa agagattgat 1080 atgctgctga aagaatattt actctctgga gacatatctg aagctgaaca ttgccttaag 1140 gaactggaag tacctcattt tcaccatgag cttgtatatg aagctattat aatggtttta 1200 gagtcaactg gag aaagtac atttaagatg attggatt tattaaagtc cctttggaag 1260 tcttctacca ttactgtaga ccaaatgaaa agaggttatg agagaattta caatgaaatt 1320 ccggacatta atctggatgt cccacattca tactctgtgc tggagcggtt tgtagaagaa 1380 tgttttcagg ctggaataat ttccaaacaa ctcagagatc tttgtccttc aaggggcaga 1440 aagcgttg taagcgaagg agatggaggt cgtcttaaac cagagagcta ctgaatataa 1500 gaactcttgc agtcttagat gtataaaaa tatatatctg aattgtaaga gttgttagca 1560 caagtttttt tttttttttt ttaagcactt gttttgggta caaggcattt ctgacatttt 1620 gggta 1625 <210> 117 <21 1> 3510 <212> DNA <213> Mus musculus <400> 117 gaattcggca cgaggtgtgc taagacctga cggctagcgc tgctttggct actgcacgcc ccgctgtaag gggcccgctg tctccagaag aactggatat tctttgttac aattatggca 120 gacaaattaa caagaattgc tattgtcaac cacgacaaat gcaaacctaa gaaatgtcga 180 ccccagagca aaatagcatg gatttctgaa actctctgta ttggttgtgg tatttgtatt 300 aagaaatgtc cctttggcgc cttatcaatt gtcaatttgc caagcaactt ggaaaaagaa 360 acaacacatc gctactgtgc caatgccttc aagcttcaca ggttgcctat ccctcgtcca 420 ggtgaagttt tgggattagt tggaactaat ggtattggaa agtcaactgc actaaaaatt 480 ttagcaggaa aacaaaagcc aaaccttgga aagtatgatg atccacctga ttggcaagag 540 attttgactt atttccgtgg atctgaatta caaaattact ttaccaagat tctcgaagat 600 .*gacctaaaag ccattatcaa acctcaatat gtagaccaaa ttcccaaggc tgcaaagggg 660 acagtgggct ctattctgga ccgaaaagat gaaacaaaga cacaggcaat tgtatgtcag 720 cagcttgatt taactcacct taaagaacga aatgtcgaag atctttcagg aggagagttg 780 cagagatttg cttgtgctgt cgtttgcata caaaaggctg atatttttat gtttgatgaa 840 ccttctagtt acctcgatgt caagcaacgt ttaaaggctg ccattacgat tcgatctcta 900 5: ataaatccag atagatatat cattgtggtg gagcatgatc taagtgtatt agactatctc 960 tctgacttca tctgctgtct atatggggta ccgagtgctt atggtgttgt cacgatgcct 1020 tttagtgtaa gagaaggcat aaatatattt ttggatggct atgttccaac agagaacctg 1080 aggttcaggg atgcgtcgct tgtttttaag gtagctgaga cagcaaatga agaagaagtt 1140 aaaaagatgt gcatgtataa atatcccggg atgaagaaaa agatgggaga gttcgagcta 1200 gcaattgtag ctggagagtt cacggactct gagatcatgg tgatgctggg ggagaatggt 1260 acaggtaaaa ctacatttat cagaatgctt gctggaaggc ttaaaccaga tgaaggagga 1320 gaagtgccag ttctaaatgt cagttataag ccacagaaaa tcagtcccaa atcaacagga 1380 agtgttcgcc agttactgca tgaaaagatc agagatgctt acacgcatcc gcagtttgtg 1440 actgatgtaa tgaagcccct acagattgaa aacatcattg accaagaggt acagacattg 1500 tctggtggtg aacttcagcg agtagcttta gctctttgtt tgggcaaacc tgctgacgtc 1560 tatttgattg atgaaccttc tgcatatttg gattctgagc aaagattaat ggcagctcgg 1620 gtcgtcaaac gtttcattct ccatgcaaag aagacagctt ttgttgtaga acatgacttc 1680 atcatggcca cctatctagc agatcgcgtc atcgtttttg atggtgttcc atcaaagaac 1740 acagttgcaa acagtcctca gactcttttg gctggcatga acaaattttt gtctcagctc 1800 gaaattacat tcagaagaga ccccaacaac tacaggccac gaataaataa gctcaattca 1860 atcaaggatg tagaacaaaa gaagagtgga aactactttt tcttggatga ttagattgag 1920 tctgaactta taagccattt acttactggg attttatca tataaaactt taatcaggtt 1980 ttatggcccc acatactctg gagcttgaag tatgattc ttaatgtgac atcaaaaagc 2040 cagttgtctt gtaaattgtt gtttaagaac tattgttc taagattaa acctctgtgc 2100 atactacatg aacatggaga catttcagat tatcagttac ctccagattt tcacaatcta 2160 cggggagatt tcagttgta tattatattc atgtaccaaa tgcttcctgg tgttgcccat 2220 ctttaaaatc tggataaaa tctgtactta cctgtttgct aagtgtacca gtataacaga 2280 actgccccct tctaaaaagc cagicacaga cttgctgcca aagtctgata cataagcatc 2340 agggctatat ttgctacttg tgttcagtgt gtgcttccaa ggaacagtgt ctgctacaaa 2400 caccattgtt ggaagatgtt gatgaccaac ttatgcattg tttttaatga gtftttggtg 2460 ctttgaaca tctgtcaaaa ttatttcag tgccctaatt taactttttt ttttagttct 2520 tacattctat aacaacattc acagtaatgt tactitata aatatataat cactgatcaa 2580 gattagggag gaggcatttc tgaagactat ttgcttcctg cagaactata ggcttgggct 2640 ggggagatgg ttcagtcagt aagtacaagc tgcacgctca tgaggaccat atttgagact 2700 ttagtagaag tgaagtccag cagatcccta aagcccactg gcctgccagc ctaacacagt 2760 ctatgagcac atcagtaga aggtcctgtc taaaagcta agtggacagt aattgaggaa 2820 gacactctgg caccaacaca cacacacaaa acccaaccga tacagtcttt atagttggtg 2880 cctaagtatc tggattttag ggtttcggtt taattgt tttgagacag cttgtcgtcc 2940 tatagcccaa gctggcctca aattatgtat ccaaggacaa ccttgaattt ctcagcccac 3000 tacctaggct tggattacac agtgctgaag atcaaaccca gggctttgtg ttgtgctatg 3060 caacactcta acaactgagc tacatcccca gccctacata ttttagactc cagagtcttc 3120 tgttgagcaa ccaagggaca acctaaaaca acttctccag tgagtgcagg gaaatagcaa 3180 tacaaagtgt ccattgctgc agtgcaatcc tatttgttgg aatcaaagga cattatccag 3240 attttacaat atgccaaact ggaattatga ggaaggtgga ttataatgaa cagggcaggc 3300 agaacaggaa aaattagaag tatttgataa gactttagaa ctttaaataa taggtctgat 3360 taatttgcag acaatgatag aaagtttgtt ttgactgata cccattaggc tttctaaaaa 3420 tgaatttata tatccataaa tatgtttctg ttgttaagga accaagtata tggaataaaa 3480 0*0 tctccctta tcagttaaaa aaaaaaaaaa 3510 0: <210> 118 o~o. <21 1> 3566 0:00.: <212> DNA <213> Homo sapiens 0 n <400> 118 ccggtcctga gacacgctgt gtggctgaaa agtgaaggca agagctcatt tggcctctgt gctcccctcc gcaagggatc gtttctccag aagagctgga tattctttcg cccagttatg 120 gcagacaagt taacgagaat tgctattgtc aaccatgaca aatgtaaacc taagaaatgt 180 cgacaggaat gcaaaaagag ttgtcctgta gttcgaatgg gaaaattatg catagaggtt 240 acaccccaga gcaaaatagc atggatttcc gaaactcttt gtattggttg tggtatctgt 300 0.0e.: attaagaaat gcccctttgg cgccttatca attgtcaatc taccaagcaa ctggaaaaa 360 0 gaaaccacac atcgatattg tgccaatgcc ttcaaacttc acaggttgcc tatccctcgt 420 ccaggtgaag ttttgggatt agttggaact aatggtattg gaaagtcaac tgctttaaaa 480 attttagcag gaaaacaaaa gccaaacctt ggaaagtacg atgatcctcc tgactggcag 540 gagattttga cttattccg tggatctgaa ttacaaaatt actttacaaa gattctagaa 600 :,00 gatgacctaa aagccatcat caaacctcaa tatgtagacc agattcctaa ggctgcaaag 660 0 gggacagtgg gatctatttt ggaccgaaaa gatgaaacaa agacacaggc aattgtatgt 720 cagcagcttg atttaaccca cctaaaagaa cgaaatgttg aagatcttc aggaggagag 780 ttgcagagat ftgcttgtgc tgtcgtttgc atacagaaag ctgatatttt catgtttgat 840 gagccttcta gttacctaga tgtcaagcag cgtttaaagg ctgctattac tatacgatct 900 ctaataaatc cagatagata tatcattgtg gtggaacatg atctaagtgt attagactat 960 ctctccgact tcatctgctg ttatatggt gtaccaagcg cctatggagt tgtcactatg 1020 ccttttagtg taagagaagg cataaacatt tttttggatg gctatgtc aacagaaaac 1080 ttgagattca gagatgcatc acttgttttt aaagtggctg agacagcaaa tgaagaagaa 1140 gttaaaaaga tgtgtatgta taaatatcca ggaatgaaga aaaaaatggg agaatttgag 1200 ctagcaattg tagctggaga gttacagat tctgaaatta tggtgatgct gggggaaaat 1260 ggaacgggta aaacgacatt tatcagaatg cttgctggaa gacttaaacc tgatgaagga 1320 ggagaagtac cagttctaaa tgtcagttat aagccacaga aaattagtcc caaatcaact 1380 ggaagtgttc gccagttact acatgaaaag ataagagatg cttatactca cccacaattt 1440 gtgaccgatg taatgaagcc tctgcaaatt gaaaacatca ttgatcaaga ggtgcagaca 1500 ttatctggtg gtgaactaca gcgagtagct ttagcccttt gcttgggcaa acctgctgat 1560 gtctatttaa ttgatgaacc atctgcatat ttggattctg agcaaagact gatggcagct 1620 cgagttgtca aacgtttcat actccatgca aaaaagacag cctttgttgt ggaacatgac 1680 ttcatcatgg ccacctatct agcggatcgc gtcatcgttt ttgatggtgt tccatctaag 1740 aacacagttg caaacagtcc tcaaaccctt ttggctggca tgaataaatt tttgtctcag 1800 cttgaaatta cattcagaag agatccaaac aactataggc cacgaataaa caaacttaat 1860 tcaattaagg atgtagaaca aaagaagagt ggaaactact ttttcttgga tgattagact 1920 gactctgaga atattgataa gccatttatt aaaaggagta tttactagaa ttttttgtca 1980 tataaaactt gaatcaggat tttatgcccc acatactctg gaacttgaag tataatatac 2040 ttaatataac ataaaaagcc agttgggttc taaattgtag ttgaaacaca gaaaatgcca 2100 cttttctgtt cctgaagagg ctcttttgtg cataatattc taaaatgaag acatttcaag 2160 ctatacaaat tacttccaag ttttcatgat gtatgggaag attttcagta ggtgtattat 2220 attcacggta ccaaatgctg accagtgttg ctccattttt taaatcttga aaagggtttc 2280 tgtacttacc tggtttgcca agtatgccag tgtaatgaaa ctgcccftat tttaaaagcc 2340 agtcaaagat tccactgatt gacatttgat aaataaacat caggattatg tttattgttt 2400 gttttcagtc tttgcactat attaccagta tatggtttcc gaggaagatt atctactgca 2460 aaacaccact gttggaaaaa taggtatttt taaattgttt ttaatctttt ttggtgcttt 2520 taaacatgtt tagcaaaaac caattcagtc cattccccgc aaaaaacccc taactttact 2580 ctgaactt tttgtttttg cattccatga ggttctgtat tcagtcattc tctaggtaat 2640 gtcatttttg tacacatata tttatataat cactgattga gatttaggaa aaagcatttc 2700 taaagaatat ttgcttccct tagaactaca gactcgaaat ctttaaagat ggtgcctaag 2760 catctatgta ttttttttaa gttccacaga tttttctgtt gggcaggcca aggattataa 2820 accacttccc taaaggcaac attaatgcaa aagtccccag atggcaatac aaagtatccc 2880 ctggtaccac atatattcat ttgtgagttt ggatatagag cacattatct aaaccatttt 2940 gtagttccaa aaacccatct aaatttcttg agttcctgaa ttttgaacag gattacctgg 3000 agcctggagc cactttaagt tgtacttctg actaaactgg aattatgagt gaggaagagt 3060 gtttactaaa taaatgactg gggcaagcaa aattgaggag gaaattagaa actgtttgac 3120 aaactttaag agctacttga aataacagaa gtcttgatta atatgcaaat aatggctaga 3180 aagtatggtt taactggacc ctatatgcc ttttaaaaat aatttcagta acccataaat 3240 acatttgt aaaattaa tataagaatggataaa aatgactccctttattac cctcccaaag gttaccagcg tttgaattta ataatgtata ttctttcatg ctttttctg 3360 tgcacttacc taagtgtgaa tatgtaaagg gtttgttttg tatacaaatg ggattatact 3420 aaaataagta atgcctattt ttaaggatag gttaaatttg tgaatgatca tttcaaatat 3480 attgaataaa ataagcaaaa gctattgtta tttactgatc ctgaaaaaaa aaaaaaaaaa 3540 aaaaaaaaaa aaaaaaaaaa aaaaaa 3566 <210> 119 <21 1> 2321 <212> DNA <213> Mus musculus <400> 119 ggtccttgcc ctcgcagctc cggccctcga caccaccggc ccctccgctg gtgacgcccc cgcagaggct tcgccgtcgc cgaggccttc tctccgcgac tcgtcgccgc aggattotac 120 tttcactggg ttccgcccgc acaccgccac cattgacgcc atgtcgagtt attctagtga 180 ccgagaccgc ggccgggatc gagggtttgg tgcacctcga tttggaggga gtagaacagg 240 acccctctct ggaaagaagt ttggaaatcc tggggagaaa ctagtaaaa agaagtggaa 300 tcttgatgag ctgcccaaat ttgagaagaa tttttatcaa gaacaccctg atttggcaag 360 gcgcaccgca caagaggtag atacatacag aagaagcaag gaaattacag ttagaggtca 420 caactgtcca aaacctgttc tgaattttta tgaagcaaac tttcctgcga atgtcatgga 480 tgtgattgca aggcagaact ttactgaacc cactgctatt caagctcagg gctggccagt 540 tgctctcagt ggattggata tggttggagt agctcagact ggatctggga aaacattatc 600 ttatttgctg cctgccattg tacacataaa ccaccagcca ttcctagaga gaggtgatgg 660 gcctatttgc ttggtgctgg caccaactcg agaactggca cagcaggtgc agcaagtggc 720 tgctgaatat tgtcgagctt gtcgcttgaa gtctacttgc atctatggtg gtgctcccaa 780 aggaccacag aftcgtgatt tggaaagagg tgtggaaatc tgtattgcaa cacctggaag 840 actgattgac tttttagagt gtgggaaaac caatctgaga agaacaactt accttgtcct 900 tgatgaagct gataggatgc ttgatatggg atttgaaccc cagataagga aaattgtgga 960 tcaaataaga cctgataggc aaacactaat gtggagtgca acttggccaa aagaagtaag 1020 acagcttgct gaagatttcc tgaaagacta tattcatatc aatattggtg cactggaact 1080 gagtgcaaac cataacattc ttcagattgt ggatgtatgt catgatgtcg aaaaggatga 1140 aaagcttatt cgtctgatgg aagaaatcat gagtgagaag gagaataaaa ctattgtttt 1200 tgttgaaacc aaaagaagat gtgatgaact taccagaaaa atgaggagag atgggtggcc 1260 tgccatgggc atccatggtg acaagagtca gcaggaacgt gactgggttc taaatgaatt 1320 caaacatgga aaagctccta ttctgattgc taccgatgtg goctocagag ggctagatgt 1380 ggaagatgtg aaatttgtca tcaattatga ctaccctaac tcctcagagg attatattca 1440 tcgaattgga agaactgctc gcagtaccaa aacaggcaca gcatacactt tctttacacc 1500 taataacata aagcaagtga gcgaccftat ctctgtgctt cgggaagcta atcaagcaat 1560 taatcccaag ttgcttcagt tggtcgaaga cagaggttca ggtcgttcca ggggtagagg 1620 aggcatgaag gacgatcgtc gtgacagata ctctgcaggc aaaaggggtg gatttaatac 1680 ctttagagac agggaaaact atgacagagg ctactctaat ctgcttaaga gagattttgg 1740 ggctaaaact cagaatggtg tttacagtgc tgcaaattac accaatggga gctttggaag 1800 taattttgta tctgctggca tacagaccag ftttaggact ggtaatccaa cagggactta 1860 ccagaacggt tatgatagca ctcagcaata tggaagtaat gtgcaaata tgcacaatgg 1920 tatgaaccaa caggcatatg catatcctgc taccgcagct gctgcgccta tgattggcta 1980 tcccatgcca acagggtatt ctcaataaga ctttagaagt atatgtaaat gtctgttttt 2040 cataattgct ctttatattg tgtgttatca gacaagatag ttatttaaga aacatgggaa 2100 atgcagaaat gactgcagtg cagcagtaat tatggtgcac tttttcgct atttaagttg 2160 gatatttctc tacattcctg aaacaatttt taggtttttt ftttgtactag aaaatgcagg 2220 cagtgttttc acaaaagcaa ctgtacagtg atttcaaata caataaatga aggcaatgca 2280 tggccttcca ataaaagata tttgaagact gaaaaaaaaa a 2321 <210O> 120 <21 1> 1217 <212> DNA <213> Mus musculus <400> 120 tgcttgcaaa gatcacactt tcctaactga gccaccctca cccctcagct gtctctttca tttcaattct tgaaactttc atacatcttg tttgtttgat ttatctacag aaaatgacct 120 gaagtgaccc agggcaagaa ctcctcatgg accagtcaaa tatgacatcc cttgctgaag 180 agaaagccat gaatacctcc agcagaaatg cctccctggg gagctcacac ccacccattc 240 ccatagtgca ctgggtcatc atgagcatct cccctctggg ctttgtggag aatgggatcc 300 tcctctggtt cctctgcttc cggatgagga gaaatccctt cacggtctac attacocact 360 tgtccattgc tgatatctct cttctgttct gtattttat cctgtccatt gactatgctt 420 tagactatga actctcttct ggccatcact acacaatcgt gacattatcg gtgacttc 480 tatttggcta caacacgggc ctctatctgc tgacagccat cagtgtggag aggtgcctat 540 cggtcctcta ccccatatgg tacagatgcc accgccccaa gcaccagtca gcattcgtct 600 gtgcccttct gtgggcactt tcgtgcttgg tgaccaccat ggagtatgtc atgtgtattg 660 acagcggaga agagagtcat tctcggagtg actgccgggc ggtcatcatc ttcatagcca 720 tcctcagctt cttggtcttc actccgctca tgttagtgtc cagcaccatc ttggtggtga 780 agatcgga gacactgggcctccat cfcgagctgtacattgtc atcatggtca 840 agtactggtc agcctttggg aacctgcata acatctcctt gcttttctccaccatcaaca 960 gcagcgccaa ccctttcatc tacttttttg tgggcagcag taagaagaag cgcttcaggg 1020 agtccftaaa agtcgtcctg accagggctt tcaaagatga aatgcaaccc aggcgccagg 1080 agggcaacgg caacactgta tccaftgaga ctgtggtctg aggacagcag gggaaattgt 1140 ggacagaaac agtggaatgc tggaggcttt tagcttgtgc ttggaatgca atttaagcac 1200 atttaaatct cctaact 1217 <210O> 121 <211> 1144 <212> DNA <213> Homo sapiens <400> 121 agccccctga aatacggaga ataagaatct tagaggttgt tcagcagaag tcttggagtg cattttcagt ggttaaggtg aaaaaatgac tactaaaaat ttagaaacca aagtcaccgt 120 tacttcatcc ccaacccgag gagcaggaga tggaatggaa actgaggaac cacctaaatc 180 tgttgaagtt acctccggag tccaatctag aaagcatcat agtcttcaga gtccatggaa 240 gaaagcagtt ccatcagaga gcccaggagt tcttcagcta gggaaaatgc tcactgaaaa 300 agcaatggaa gttaaagctg taagaatatt agttcccaaa gctgctataa ctcatgatat 360 ccccaacaaa aatacaaagg ttaagtctct gggacatcat aaaggagaat tccttggtca 420 gtcagaggga gttatagaac ctaataagga actctcagag gtaaagaatg tattggaaaa 480 gctcaagaat tctgaaagaa ggttactaca ggacaaagaa ggtctttcaa accagctccg 540 tgtacagaca gaggtaaatc gtgagttaaa aaagttactg gtggcttctg ttggggatga 600 tcftcagtat cactttgaac gtctagcccg tgagaaaaat cagcttattt tagaaaatga 660 agccctaggt cgaaacacag ctcagctttc tgaacagfta gaacgtatgt caatacagtg 720 tgatgtatgg cgaagtaaat tccttgcaag cagggtaatg gcagatgagt taaccaactc 780 aagagcagct ttacagcgtc aaaaccgtga tgcacacggg gctatacaag atctcctaag 840 tgaacgggaa cagtttcgtc aagaaatgat agctacccag aagttctaag aattagat 900 ccagttacct gcaaagagag ttcacctgat aatccatttt ttgagtcttc accaaccacc 960 ttacttgcta caaagaaaaa tattggacga tttcatccct atactagata. tgaaaatata 1020 actttcaatt gctgcaatca ctgccgggga gaactgattg ccctttaaca gtcaatatgt 1080 tggaggcatg ctaaggtact Icottattac ccaagagtca ttattatttg ggagctgggg 1140 ttct 1144 <210O> 122 <21 1> 1812 <212> DNA <213> Mus musculus <400> 122 aattcgtcga caaggggcgg gttggcttca gagtgcsagg ggagtttaca agtcagccgg ctgctgagcg agtgaagagc ctgagcggtg gacattgaag taaggatatc acaggtcttc 120 ggtgaaagtc ttggattgta ttctcattag ttatggaaaa aatgactacc cttaaaagtt 180 cggaaaacaa aggcatcctt acttcgaccc caatccgagg agcaggagat ggaatggaaa 240 cggaggagcc ccctaagtct gttgaagtca cccacggagt ccaacccata aatcaacatg 300 tccttccaag tccacggaag aaagtgtcct cagacagccc gggcgttctt cagctgggga 360 9. agattcttaa tgaaagaaca gtggaagttg aagctgtcag aatatttgtt cccaaagctg 420 ctatcactca cgacatcccc accaagaaca caaaggttaa gtccctagga catcacagag 480 aagaactcca caatcaggca gaagtggtca cagacccaag gaaggaactc tcagaggtaa 540 agaaggtttt ggaaaagctc aagaattctg aaaggaggct acttcaggac aaagaaggcc 600 tttccaatca gctccgagta cagacagaga taaatcgtga gttaaagaag ttactcgtgg 660 cttctgttgg ggatgacccg cagtatcact ttgaacgtct agcccgggag aagaaccagc 720 tcatcttaga aaatgaagca ctaggtcgga acacagccca gctttctgaa cagctggaac 780 ggatgtcaat acagtgcgat gtctggagaa gtaaattcct tgcaagcagg gtaatggcag 840 atgagttaac aaacttcaga gtggttttac agcgtcagaa ccgagatgcc cagagcgcta 900 tccaggatct cctgagtgaa cgagagcagt ttcgtcagga aatgacctct acccaaaaat 960 ttttggaaga actcttggtc tccttacagt gggggagaga goagacatac tcccctaaca 1020 cacagcccca tagcacggca gacttagcac tcacgaacca tggactggca caagcaatac 1080 atgcccatct gttggggaat gttggcatta gccatcaaaa gaagattcca acaacagtcg 1140 aattctgcag taccccagct gagaaaatgg ctgaaaaggt tctgcggaft ttggatccag 1200 ttgcctgtac agagagctct ccggacaacc aatttgctga atcttcacca accacattac 1260 tcactacaaa gaaaaatatt ggacgtttcc atccctatac cagatatgaa aatataactt 1320 tcaattgctg caatcactgc cagggggagc tcattgctct ttagtgtgta. gtctgttgga 1380 gccatgctca gtacccagag tcattatttg ggagcccgga ttagtaagtt gctagaaata 1440 aaatcaattc atcgtgatat aatacatacc catgaagcta tttcatgtac tggattccag 1500 attattttt aacaaatatc tcagggtaag aaagtgaagc tttgtagata tatttaaaga 1560 acagaatact tcccagtaca tagtatttat gctaaaaaac taaaaagatt ttataacttt 1620 cttttaggcc ctatattatt attctgttat atatttatat aaactataag caggtttcat 1680 tttggtgcat aaagcaaaac caggcaaact ccaaccatgc attgtaaagg ggtgtggcca 1740 tatccatcct ttaccgctgt ctggctgctt tactgtaggg cagcagagtc ggtgtgtggc 1800 tagcaaagtc ca 1812 <210O> 123 <21 1> 1889 <212> DNA <213> Mus musculus <400> 123 aattcgtcga caaggggcgg gttggcttca gagtgcsagg ggagtttaca agtcagccgg ctgctgagcg agtgaagagc ctgagcggtg gacattgaag taaggatatc acaggtcttc 120 ggtgaaagtc ttggattgta ttctcattag ttatggaaaa aatgactacc cttaaaagtt 180 cggaaaacaa agggaaacaa gaaatgatga aaggtaagaa aatgcaaagc cctagccctg 240 cctgctcacc cgcgcgttag ccagagctgg catccttact tcgaccccaa tccgaggagc 300 aggagatgga atggaaacgg aggagccccc taagtctgtt gaagtcaccc acggagtcca 360 acccataaat caacatgtcc ttccaagtcc acggaagaaa gtgtcctcag acagcccggg 420 cgttcttcag ctggggaaga ttcttaatga aagaacagtg gaagttgaag ctgtcagaat 480 atttgttccc aaagctgcta tcactcacga catccccacc aagaacacaa aggttaagtc 540 cctaggacat cacagagaag aactccacaa tcaggcagaa gtggtcacag acccaaggaa 600 ggaactctca gaggtaaaga aggttttgga aaagctcaag aattctgaaa ggaggctact 660 tcaggacaaa gaaggccttt ccaatcagct ccgagtacag acagagataa atcgtgagtt 720 aaagaagtta ctcgtggctt ctgttgggga tgacccgcag tatcactttg aacgtctagc 780 ccgggagaag aaccagctca tcttagaaaa tgaagcacta ggtcggaaca cagcccagct 840 ttctgaacag ctggaacgga tgtcaataca gtgcgatgtc tggagaagta aattccttgc 900 aagcagggta atggcagatg agttaacaaa cttcagagtg gttttacagc gtcagaaccg 960 agatgcccag agcgctatcc aggatctcct gagtgaacga gagcagtttc gtcaggaaat 1020 gacctctacc caaaaatttt tggaagaact cttggtctcc ttacagtggg ggagagagca 1080 gacatactcc cctaacacac agccccatag cacggcagac ttagcactca cgaaccatgg 1140 actggcacaa gcaatacatg cccatctgtt ggggaatgtt ggcattagcc atcaaaagaa 1200 gattccaaca acagtcgaat tctgcagtac cccagctgag aaaatggctg aaaaggttct 1260 gcggattttg gatccagttg cctgtacaga gagctctccg gacaaccaat ttgctgaatc 1320 ttcaccaacc acattacica ctacaaagaa aaatattgga cgtttccatc cctataccag 1380 atatgaaaat ataactttca attgctgcaa tcactgccag ggggagctca ttgctcttta 1440 gtgtgtagtc tgttggagcc atgctcagta cccagagtca ttatttggga gcccggatta 1500 gtaagttgct agaaataaaa tcaattcatc gtgatataat acatacccat gaagctattt 1560 catgtactgg attccagatt attttttaac aaatatctca gggtaagaaa gtgaagcttt 1620 glagatatat ttaaagaaca gaatacttcc cagtacatag tatttatgct aaaaaactaa 1680 aaagatttta taactttctt ttaggcccta tattattatt ctgtatata tttatataaa 1740 ctataagcag gtttcatttt ggtgcataaa gcaaaaccag gcaaactcca accatgcatt 1800 gtaaaggggt gtggccatat ccatccttta ccgctgtctg gctgctttac tgtagggcag 1860 cagagtcggt gtgtggctag caaagtcca 1889 <210O> 124 <21 1> 1758 <212> DNA <213> Mus musculus <400> 124 gttccagggg ttmattcsrc aagagagaaa aacatagact cacggctgcc aacatgatgg tactgagagt agaggagctg gtaacaggca aaaagaacag caatggggcc gcaggggaat 120 tccttcctgg ggagttcaga aatggagaat atgaagctgc tgttgctttg gagaagcaag 180 aggacctgaa gacacttccg gccaacagcg tgaagcaggg ggaggaacaa cggaaaagcg 240 agaaactgcg agaggcagag ctcaaaaaga aaaaactaga acaaagatca aagcttgaaa 300 acttagaaga ccttgaaata attgttcaac tgaagaaaag gaaaaaatac aagaaaacca 360 aagttccagt tgtgaaggag ccagaacctg aaattatgac tgaacctgtg gatgtgccga 420 ggtttctgaa agctgcgctg gagaacaaac tgccagttgt agagaaattc ctgtcagaca 480 agaacagccc cgacgtctgc gatgagtata aacggacggc actccaccga gcatgcttag 540 aaggacactt ggcgatcgtg gagaagttaa tggaggctgg agcccagatt gaattccgag 600 atatgcttga atccacagcc atccactggg catgtcgtgg aggaaacgca gatgtcctga 660 aactgttgct gaacaaagga gccaaaatca gtgccagaga caagcttctc agcacagcgc 720 tgcatgtggc ggtgaggact ggtcattacg agtgcgctga gcacctcatc gcctgcgagg 780 ctgatctcaa tgccaaggac agagaaggag acaccocact gcatgatgct gtgaggctga 840 accgctataa gatgattcga ctcttgatga ccttcggtgc ggacctcaag gtcaagaact 900 gtgctgggaa gacccccatg gatctggtgt tgcactggca gagtggaacc aaagcaatat 960 tcgacagcct caaggagaat gcctacaaga actctcgcat agctacattc tgagaaaaga 1020 gactcaacag gagctgttcg caggcatttt ttaaagcatt tcccaacaga agagcaacta 1080 gcaataaaat ccagcttttg tttgccagcc aaatagggag agatgctcaa agaagcttca 1140 agaaagcact gggttgtagg tgttaaaata tcctctagtg atgttcacca cttttattta 1200 ttcctaccta tttatttatt tcatagcacc agtattcagg ctttcatgaa catcattttg 1260 ggggagcaag acttcatctg tatgtacatt cagagtcttc ccatagctct taaaccgtgt 1320 gggtgaatgg tgtctaattg cacccctttg tgttctcact tgcataaagc tattcaaggt 1380 actttttaaa aggcaagggt tgatccccgc agcccttctc tgaattctca ctgctgatat 1440 ctgaatgaag caacagaagg cacgcagtaa cgcagacggg aacggaagca gttccgcagg 1500 actggcgcgr aggctcgcca cccacccaca gatttggttc ggtttggttg tttaccarat 1560 cacatgatkt cgatktccca aggtgaaggc aacgtcagga gtsccgcatg tagggagatg 1620 gagggagtag gcaatggggc caaggaaaac tgagttcgat gaaagaagaa atcaaaagga 1680 cacgcgctgt aaatgtataa atgtatattg tgttgtatgt atattttata tttataataa 1740 atgcaaacta attcccgg 1758 <210> 125 <211> 43 <212> DNA <213> Artificial Sequence <220> <223> Beschreibung der kinstlichen Sequenz:Antisense primer that links the Sp6 promoter with a sequence homologous to human MRP-14 <220> <223> Description of Artificial Sequence: Antisense primer that links the Sp6 promoter with a sequence homologous to human MRP-14 <400> 125 atttaggtga cactatagaa taccccgagg cctggcttat ggt 43 <210> 126 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> Beschreibung der kinstlichen Sequenz:Sense primer that links the T3 promoter with a sequence homologous to human MRP-14 <220> <223> Description of Artificial Sequence: Antisense primer that links the T3 promoter with a sequence homologous to human MRP-1 <400> 126 aattaaccct cactaaaggg ggtggctcct cggctttgac a 41 <210O> 127 <21 1> <212> DNA <213> Homo sapiens <400> 127 gagagaggta ccatgccgtc tgaactggag <210> 128 <21 1> 36 <212> DNA <213> Homo sapiens <400> 128 gagagagaca cgtgctactc cttgtggctg tctttg 36

Claims (23)

1. Use of at least one polypeptide or variants thereof according to one of SEQ ID No. 1 to SEQ ID Nr. 4, SEQ ID No. 7 to SEQ ID No. 9, SEQ ID No. 103 to SEQ ID No. 104 or SEQ ID No. 106 or nucleic acids encoding this or variants thereof for the diagnosis and/or prevention and/or treatment of disorders or for the identification of pharmacologically active substances.

2. Use of at least one polypeptide or variants thereof according to one of SEQ ID No. 5 to SEQ ID No. 6 or SEQ ID No. 10 to SEQ ID No. 48, SEQ ID No. to SEQ ID No. 58, SEQ ID No. 89 to SEQ ID No. 94, SEQ ID No. 105 or SEQ ID No. 109 to SEQ ID No. 114 or nucleic acids encoding this or variants thereof for the diagnosis and/or prevention and/or treatment of skin disorders and/or treatment in wound healing or for the identification of pharmacologically active substances. g* 20 3. Use of at least one polypeptide or variants thereof according to one of SEQ ID No. 51 to SEQ ID No. 54 or SEQ ID No. 101 to SEQ ID No. 102 or nucleic acids encoding this or variants thereof, for the diagnosis and/or prevention and/or treatment in wound healing or for the identification of pharmacologically active substances.

4. Use of at least one nucleic acid or variants thereof according to one of SEQ ID No. 49 or SEQ ID No. 50, for the diagnosis and/or prevention and/or treatment of skin diseases and/or treatment in wound healing or for the identification of pharmacologically active substances. 81 Use of a nucleic acid according to one of Claims 1 to 4, characterized in that the nucleic acid is a DNA or RNA, preferably a DNA, in particular a double-stranded DNA.

6. Use of a nucleic acid according to one of Claims 1 to 5, characterized in that the sequence of the nucleic acid has at least one intron and/or a polyA sequence.

7. Use of a nucleic acid according to one of Claims 1 to 6 in the form of its antisense sequence.

8. Use of a nucleic acid according to one of Claims 1 to 7, characterized in that the nucleic acid has been prepared synthetically.

9. Use of a polypeptide according to one of Claims 1 to 3, characterized in that the polypeptide has been prepared synthetically. Use of a polypeptide according to one of Claims 1 to 3, characterized in that the 20 polypeptide is a fusion protein.

11. Use of a nucleic acid according to one of Claims 1 to 8 for the preparation of a vector, preferably in the form of a plasmid, shuttle vector, phagemid, cosmid, expression vector or 0 25 vector having gene therapy activity. *o o

12. Use of a nucleic acid according to one of Claims 1 to 8 for the preparation of a knock-out gene construct or an expression cassette.

13. Host cell, transformed using a vector or a knock-out gene construct according to one of Claims 11 or 12. 82

14. Host cell according to Claim 13, characterized in that it is a skin cell. Transgenic embryonic non-human stem cell, characterized in that it contains a knock-out gene construct or an expression cassette according to Claim 12.

16. Process for the production of a transgenic non-human mammal, characterized in that an embryonic non-human stem cell according to Claim is regenerated to give a transgenic non-human mammal.

17. Transgenic non-human mammal, characterized in that its genome contains a knock-out gene construct or an expression cassette according to Claim 12.

18. Process for preparing a polypeptide for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the ore• identification of pharmacologically active substances in a suitable host cell, characterized in that a nucleic acid according to one of Claims 1 to 8 is expressed.

19. Process for preparing a fusion protein for 25 the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances in a suitable host cell, characterized in that a nucleic acid according to one of Claims 1 to 8 is expressed. 83 Process for producing an antibody, preferably a polyclonal or monoclonal antibody, for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances, characterized in that an antibody- producing organism is immunized with a polypeptide or functional equivalents thereof or parts thereof having at least 6 amino acids, preferably having at least 8 amino acids, in particular having at least 12 amino acids according to one of Claims 1 to 3 and 9 or

21. Antibody for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances, characterized in that it is directed against a polypeptide according to one of Claims 1 to 3 and 9 or

22. Use of an antibody according to Claim 21 for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or oo o oo*o treatment in wound healing or for the identification of pharmacologically active substances.

23. Process for preparing a diagnostic for the diagnosis of disorders, in particular skin disorders and/or disorders in wound healing, characterized in that at least one nucleic acid, at least one polypeptide or at least one antibody according to one of the aforementioned claims is combined with suitable additives and auxiliaries. 84

24. Diagnostic for the diagnosis of disorders, in particular skin disorders and/or disorders in wound healing, characterized in that it contains at least one nucleic acid, at least one polypeptide or at least one antibody according to one of the aforementioned claims, if appropriate together with suitable additives and auxiliaries. Diagnostic according to Claim 24, characterized in that it contains a probe, preferably a DNA probe.

26. Process for producing a medicament for the treatment of disorders, in particular skin disorders and/or disorders in wound healing, characterized in that at least one nucleic acid, at least one polypeptide or at least one antibody according to one of the aforementioned claims is combined with suitable additives and auxiliaries.

27. Medicament for the treatment of disorders, SOS. in particular skin disorders and/or disorders in wound healing, characterized in that it contains at @55545 least one nucleic acid, at least one polypeptide or at least one antibody according to one of the aforementioned claims, if appropriate together with -suitable additives and auxiliaries. 25 28. Use of a medicament according to Claim 27 oeooe for the treatment of disorders, in particular skin disorders and/or disorders in wound healing.

29. Process for preparing a test for the S 0 discovery of functional interactors in connection with disorders, in particular skin disorders and/or disorders in wound healing, characterized in that at least one nucleic acid, at least one polypeptide 85 or at least one antibody according to one of the aforementioned claims is combined with suitable additives and auxiliaries. Test for the identification of functional interactors in connection with disorders, in particular skin disorders and/or disorders in wound healing, characterized in that it contains at least one nucleic acid, at least one polypeptide or at least one antibody according to one of the aforementioned claims, if appropriate together with suitable additives and auxiliaries.

31. Process for preparing an array immobilized on a support material for analysis in connection with disorders, in particular skin disorders or disorders in wound healing, characterized in that at least one nucleic acid, at least one polypeptide or at least one antibody according to one of the Saforementioned claims is immobilized on a support material. 20 32. Array immobilized on a support material for analysis in connection with disorders, in particular skin disorders or disorders in wound healing, characterized in that it contains at least one nucleic acid and/or at least one polypeptide and/or at least one antibody according to one of the aforementioned claims. DATED this 16th day of NOvember 2000. SWITCH BIOTECH AG WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN. VIC. 3122.