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  Methods of using zven proteinsUSPTO Application #: 20070042960Title: Methods of using zven proteins Abstract: The present invention provides novel uses two members of a new family of human proteins, designated as “Zven,” as agents that stimulate gastrointestinal contractility, gastric emptying, intestinal transit, and treating gastroparesis The Zven1 gene, which resides in human chromosome 3p21.1-3p14.3, is expressed in testicular tissue and peripheral blood lymphocytes. The invention also provides methods for using the antibodies to detect the presence of the protein with antibodies and methods for using the polynucleotides to detect the presence of Zven RNA. (end of abstract) Agent: Zymogenetics, Inc. Intellectual Property Department - Seattle, WA, US Inventors: PAUL O. SHEPPARD, Paul D. Bishop, Theodore E. Whitmore, Penny P. Thompson USPTO Applicaton #: 20070042960 - Class: 514012000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 25 Or More Peptide Repeating Units In Known Peptide Chain Structure The Patent Description & Claims data below is from USPTO Patent Application 20070042960. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 10/990,246, filed Nov. 14, 2004, which is a divisional of U.S. application Ser. No. 10/212,355, filed Aug. 2, 2002, now U.S. Pat. No. 6,828,425, which is a divisional of U.S. application Ser. No. 09/712,529, filed Nov. 14, 2000, now U.S. Pat. No. 6,485,938, which claims the benefit of U.S. Provisional Application No. 60/165,905, filed Nov. 16, 1999, U.S. Provisional Application No. 60/184,875, filed Feb. 25, 2000, U.S. Provisional Application No. 60/197,750, filed Apr. 19, 2000, and U.S. Provisional Application No. 60/210,332, filed Jun. 7, 2000, all of which are herein incorporated by reference. TECHNICAL FIELD [0002] The present invention relates generally to new polypeptides having diagnostic and therapeutic uses. In particular, the present invention relates to polypeptides, designated "Zven1" and "Zven2," and to nucleic acid molecules encoding the Zven polypeptides. BACKGROUND OF THE INVENTION [0003] Cellular differentiation of multicellular organisms is controlled by hormones and polypeptide growth factors. These diffusable molecules allow cells to communicate with each other, to act in concert to form tissues and organs, and to repair and regenerate damaged tissue. Examples of hormones and growth factors include the steroid hormones, parathyroid hormone, follicle stimulating hormone, the interferons, the interleukins, platelet derived growth factor, epidermal growth factor, and granulocyte-macrophage colony stimulating factor, among others. [0004] Hormones and growth factors influence cellular metabolism by binding to receptor proteins. Certain receptors are integral membrane proteins that bind with the hormone or growth factor outside the cell, and that are linked to signaling pathways within the cell, such as second messenger systems. Other classes of receptors are soluble intracellular molecules. [0005] Wnt proteins are emerging as one of the pre-eminent families of signaling molecules in animal development. To date, murine Wnt genes include Wnt-1, Wnt-2, Wnt-2B/13, Wnt-3, Wnt-3A, Wnt-4, Wnt-5A, Wnt-5B, Wnt-6, Wnt-7A, Wnt-7B, Wnt-8A, Wnt-8B, Wnt-10A, Wnt-10B, Wnt-11, and Wnt-15, while the following human Wnt genes have been described: Wnt-1, Wnt-2, Wnt-2B/13, Wnt-3, Wnt-4, Wnt-5A, Wnt-7A, Wnt-8A, Wnt-8B, Wnt-10B, Wnt-11, Wnt-14, and Wnt-15 . See, for example, Nusse and Varmus, Cell 31:99 (1982), van Ooyen et al., EMBO J. 4:2905 (1985), Wainwright et al., EMBO J. 7:1743 (1988), McMahon and McMahon, Development 107:643 (1989), Gavin et al., Genes Dev. 4:2319 (1990), Roelink et al., Proc. Nat'l Acad. Sci. USA 87:4519 (1990), Roelink and Nusse, Genes Dev. 5:381 (1991), Clark et al., Genomics 18:249 (1993), Roelink et al., Genomics 17:790 (1993), Adamson et al., Genomics 24:9 (1994), Huguet et al., Cancer Res. 54:2615 (1994), Bouillet, Mech. Dev. 58:141 (1996), Ikegawa et al., Cytogenet. Cell Genet. 74:149 (1996), Katoh et al., Oncogene 13:873 (1996), Lako et al., Genomics 35:386 (1996), Wang and Shackleford, Oncogene 13:1537 (1996), Bergstein, Genomics 46:450 (1997), Bui et al., Oncogene 14:1249 (1997), and Grove et al., Development 125:2315 (1998). [0006] Wnt genes typically encode secreted glycoproteins having 350-400 amino acids, and the proteins often include a conserved pattern of 23-24 cysteine residues in addition to other invariant residues (Cadigan and Nusse, Genes & Dev. 11:3286 (1997)). Following cellular secretion, Wnt proteins are believed to reside mainly in the extracellular matrix or to associated with the cellular surface. [0007] According to the classical Wnt signaling pathway model, Wnt proteins induce gene expression by de-repressing a signal pathway via a so-called "Frizzled" transmembrane receptor (see, for example, Brown and Moon, Curr. Opin. Cell Biol. 10:182 (1998)). In the absence of Wnt, glycogen synthase kinase-3.beta. activity results in the degradation of the free cytosolic pool of .beta.-catenin. The association of cognate Wnt proteins and Frizzled receptors leads to the activation of a signaling pathway. The most proximal intracellular component of this pathway is the Disheveled protein, which becomes phosphorylated and inhibits glycogen synthase kinase-3.beta.. Consequently, the pool of intracellular .beta.-catenin increases, and .beta.-catenin can interact with members of the lymphoid enhancer/T cell factor (LEF/TCF) family of architectural transcription factors in the nucleus. These complexes bind consensus LEF/TCF sites in promoters and induce transcription of Wnt-responsive genes. [0008] The Wnt proteins are multipotent, and the proteins are capable of inducing different biological responses in both embryonic and adult contexts (see, for example, Ingham, TIG 12:382 (1996)). This type of broad activity is shared with fibroblast growth factors, transforming growth factors .beta., and nerve growth factors (Nusse and Varmus, Cell 69:1073 (1992)). When over-expressed, Wnt proteins can promote tumor formation (Erdreich-Epstein and Shackleford, Growth Factors 15:149 (1998)). Knock-out mutations in mice have shown Wnt proteins to be essential for brain development, and the out growth of embryonic primordia for kidney, tail bud and limb bud (McMahon and Bradley, Cell 62:1073 (1990), Thomas and Capecchi, Nature 346:847 (1990), Stark et al., Nature 372:679 (1994), Takada et al., Genes Dev. 8:174 (1994), and Parr and McMahon, Nature 374:350 (1995)). [0009] Several secreted factors inhibit Wnt signaling (see, for example, Finch et al., Proc. Nat'l Acad. Sci. USA 94:6770 (1997); Moon et al., Cell 88:725 (1997); Luyten et al., WO 98/16641); Brown and Moon, Curr. Opin. Cell Biol. 10:182 (1998); Aikawa et al., J. Cell. Sci. 112:3815 (1999)). The Frzb proteins, for example, bind to secreted Wnt proteins and prevent productive interactions between Wnt and Frizzled proteins. These proteins contain a region that is homologous to a putative Wnt-binding domain of Frizzled proteins. Wnt-inhibitory factor-1 is another type of secreted protein, which binds to Wnt proteins and inhibits Wnt signaling (Hsieh et al., Nature 398:431 (1999)). Wnt-inhibitory factor-1 proteins are produced by fish, amphibia, and mammals, indicating the importance of these inhibitory proteins (Hsieh et al., Nature 398:431 (1999)). [0010] Inhibitors of Wnt signaling can be used to block the inducement of tumor formation by inappropriate Wnt expression. Accordingly, a need exists for the provision of new Wnt inhibitory proteins. BRIEF SUMMARY OF THE INVENTION [0011] The present invention provides members of a new human gene family, designated as "Zven," and, in particular, illustrative members of the gene family, designated "Zven1" and "Zven2." The present invention also provides Zven1 and Zven2 polypeptides and fusion proteins, nucleic acid molecules encoding such polypeptides and proteins, and methods for using these nucleotide and amino acid sequences. DESCRIPTION OF THE INVENTION 1. Overview [0012] The present invention provides nucleic acid molecules that encode human Zven polypeptides. An illustrative nucleic acid molecule containing a sequence that encodes the Zven1 polypeptide has the nucleotide sequence of SEQ ID NO:1. The encoded polypeptide has the following amino acid sequence: MRSLCCAPLL LLLLLPPLLL TPRAGDAAVI TGACDKDSQC GGGMCCAVSI WVKSIRICTP MGKLGDSCHP LTRKVPFFGR RMHHTCPCLP GLACLRTSFN RFICLAQK (SEQ ID NO:2). Thus, the Zven1 nucleotide sequence described herein encodes a polypeptide of 108 amino acids. The putative signal sequences of Zven1 polypeptide reside at amino acid residues 1 to 20, 1 to 21, and 1 to 22 of SEQ ID NO:2. [0013] Zven1 is expressed in eosinophils, and northern analysis indicates Zven1 gene expression is present in human testicular tissue and peripheral blood lymphocytes. As described in Example 1, Zven1 is expressed in B cell, T cell, monocyte, and granulocyte cell lines. Moreover, Zven1 gene expression was detectable in unactivated monocytes, but not in activated monocytes. Thus, Zven1 gene expression can be used to differentiate between unactivated and activated monocytes. Example 2 describes studies, which indicate that Zven1 can inhibit the proliferation of lung tumor cells. The Zven1 gene resides in human chromosome 3p21.1-3p14.3. [0014] An illustrative nucleic acid molecule containing a sequence that encodes the Zven2 polypeptide has the nucleotide sequence of SEQ ID NO:4. The encoded polypeptide has the following amino acid sequence: MRGATRVSIM LLLVTVSDCA VITGACERDV QCGAGTCCAI SLWLRGLRMC TPLGREGEEC HPGSHKVPFF RKRKHHTCPC LPNLLCSRFP DGRYRCSMDL KNINF (SEQ ID NO:5). Thus, the Zven2 nucleotide sequence described herein encodes a polypeptide of 105 amino acids. The putative signal sequences of Zven2 polypeptide reside at amino acid residues 1 to 17, and 1 to 19 of SEQ ID NO:5. [0015] Northern analyses show that the Zven2 gene is highly expressed in human testicular and ovarian tissue. High levels of Zven2 gene expression were also detected in placenta, adrenal gland, and prostate. In contrast, little or no Zven2 gene expression was evident in heart, brain, lung, small intestine, liver, skeletal muscle, kidney, pancreas, spleen, thymus, colon, peripheral blood lymphocytes, stomach, thyroid, spinal cord, lymph node, trachea, and bone marrow. Accordingly, Zven2 nucleic acid probes and anti-Zven2 antibodies can be used to differentiate between various tissues. [0016] Sequence analysis revealed a homology relationship between Zven2 and dkk-1, a potent inhibitor of Wnt action reported in amphibians and humans (Glinka et al., Nature 391:357 (1998); Fedi et al., J. Biol. Chem. 274:19465 (1999)). Since the activation of Wnt signaling can contribute to the neoplastic process, a Wnt inhibitor can provide a useful therapeutic protein. [0017] As described below, the present invention provides isolated polypeptides comprising an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% identical to amino acid residues 23 to 108 of SEQ ID NO:2. Certain of such isolated polypeptides can specifically bind with an antibody that specifically binds with a polypeptide consisting of the amino acid sequence of SEQ ID NO:2. Particular polypeptides can inhibit the proliferation of lung tumor cells. An illustrative polypeptide is a polypeptide that comprises the amino acid sequence of SEQ ID NO:2. [0018] Similarly, the present invention includes provides isolated polypeptides comprising an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% identical to amino acid residues 20 to 105 of SEQ ID NO:5, wherein such isolated polypeptides can specifically bind with an antibody that specifically binds with a polypeptide consisting of the amino acid sequence of SEQ ID NO:5. An illustrative polypeptide is a polypeptide that comprises the amino acid sequence of SEQ ID NO:5. Continue reading... Full patent description for Methods of using zven proteins Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Methods of using zven proteins patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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