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Growth differentiation factor-7

Growth differentiation factor-7 description/claims

This application is a continuation application of U.S. Ser. No. 11/481,654 filed Jul. 5, 2006, now pending; which is a continuation of U.S. application Ser. No. 10/758,210 filed Jan. 14, 2004, now issued as U.S. Pat. No. 7,074,574; which is a continuation application of U.S. application Ser. No. 09/412,791 filed Oct. 5, 1999, now issued as U.S. Pat. No. 6,680,372; which is a divisional application of 08/581,528 filed Jan. 9, 1996, now issued as U.S. Pat. No. 5,986,058; which is a 35 USC § 371 National Stage application of PCT Application No. PCT/US94/07799 filed Jul. 8, 1994; which is a continuation application of U.S. application Ser. No. 08/089,670 filed Jul. 9, 1993, now abandoned. The disclosure of each of the prior applications is considered part of and is incorporated by reference in the disclosure of this application.

1. Field of the Invention

The invention relates generally to growth factors and specifically to a new member of the transforming growth factor beta (TGF-β) superfamily, which is denoted, growth differentiation factor-7 (GDF-7).

2. Description of Related Art

The transforming growth factor β (TGF-β) superfamily encompasses a group of structurally-related proteins which affect a wide range of differentiation processes during embryonic development. The family includes, Mullerian inhibiting substance (MIS), which is required for normal male sex development (Behringer, et al., Nature, 345:167, 1990), Drosophila decapentaplegic (DPP) gene product, which is required for dorsal-ventral axis formation and morphogenesis of the imaginal disks (Padgett, et al., Nature, 325:81-84, 1987), the Xenopus Vg-1 gene product, which localizes to the vegetal pole of eggs ((Weeks, et al, Cell, 51:861-867, 1987), the activins (Mason, et al., Biochem, Biophys. Res. Commun., 135:957-964. 1986), which can induce the formation of mesoderm and anterior structures in Xenopus embryos (Thomsen, et al., Cell, 63:485, 1990), and the bone morphogenetic proteins (BMPs, osteogenin, OP-1) which can induce de novo cartilage and bone formation (Sampath, et al., J. Biol. Chem., 265:13198, 1990). The TGF-βs can influence a variety of differentiation processes, including adipogenesis, myogenesis, chondrogenesis, hematopoiesis, and epithelial cell differentiation (for review, see Massague, Cell 49:437, 1987).

The proteins of the TGF-β family are initially synthesized as a large precursor protein which subsequently undergoes proteolytic cleavage at a cluster of basic residues approximately 110-140 amino acids from the C-terminus. The C-terminal regions, or mature regions, of the proteins are all structurally related and the different family members can be classified into distinct subgroups based on the extent of their homology. Although the homologies within particular subgroups range from 70% to 90% amino acid sequence identity, the homologies between subgroups are significantly lower, generally ranging from only 20% to 50%. In each case, the active species appears to be a disulfide-linked dimer of C-terminal fragments. Studies have shown that when the pro-region of a member of the TGF-β family is coexpressed with a mature region of another member of the TGF-β family, intracellular dimerization and secretion of biologically active homodimers occur (Gray, A., and Maston, A., Science, 247:1328, 1990). Additional studies by Hammonds, et al., (Molec. Endocrin. 5:149, 1991) showed that the use of the BMP-2 pro-region combined with the BMP-4 mature region led to dramatically improved expression of mature BMP-4. For most of the family members that have been studied, the homodimeric species has been found to be biologically active, but for other family members, like the inhibins (Ling, et al., Nature, 321:779, 1986) and the TGF-βs (Chetfetz, et al., Cell, 48:409, 1987), heterodimers have also been detected, and these appear to have different biological properties than the respective homodimers.

Identification of new factors that are tissue-specific in their expression pattern will provide a greater understanding of that tissue's development and function.

The present invention provides a cell growth and differentiation factor, GDF-7, a polynucleotide sequence which encodes the factor, and antibodies which are immunoreactive with the factor. This factor appears to relate to various cell proliferative disorders, especially those involving neural tissue.

Thus, in one embodiment, the invention provides a method for detecting a cell proliferative disorder of neural origin and which is associated with GDF-7. In another embodiment, the invention provides a method for treating a cell proliferative disorder by suppressing or enhancing GDF-7 activity.

FIG. 1 shows RNase protection assays detecting expression of GDF-7 mRNA in neural tissue and cell lines. The arrow denotes the position of the protected species.

FIG. 2 shows nucleotide and predicted amino acid sequences of murine GDF-7. The putative pentabasic processing sites in the murine sequence is boxed.

FIG. 3 shows the alignment of the C-terminal sequences of GDF-7 with other members of the TGF-β superfamily. The conserved cysteine residues are boxed. Dashes denote gaps introduced in order to maximize alignment

FIG. 4 shows amino acid homologies among different members of the TGF-β superfamily. Numbers represent percent amino acid identities between each pair calculated from the first conserved cysteine to the C-terminus. Boxes represent homologies among highly-related members within particular subgroups.

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