Nucleic acid molecules that encodes human Zven1

Details Nucleic acid molecules that encodes human Zven1 Nucleic acid molecules that encodes human Zven1

2000-11-14

2002-11-26

Eyler, Yvonne (Department: 1646)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

C435S320100, C435S325000, C435S348000, C435S340000, C435S410000, C435S252100, C435S254110, C435S254200, C530S350000, C530S324000, C536S023500, C424S198100

Reexamination Certificate

active

06485938

ABSTRACT:

TECHNICAL FIELD
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
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.
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.
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).
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.
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&bgr; activity results in the degradation of the free cytosolic pool of &bgr;-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&bgr;. Consequently, the pool of intracellular &bgr;-catenin increases, and &bgr;-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.
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 &bgr;, 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)).
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)).
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
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
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.
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.
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 RKRKHIHTCPC 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

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