Growth differentiation factor-8 (GDF-8) and polynucleotides enco

Details Growth differentiation factor-8 (GDF-8) and polynucleotides enco Growth differentiation factor-8 (GDF-8) and polynucleotides enco

1995-10-29

1998-10-27

Kemmerer, Elizabeth C.

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

435 691, 435 694, 4353201, 4351723, 4352523, 530350, 530397, 530399, 536 231, 536 235, 536 2351, 536 2433, C07K 14475, C12N 121, C12N 510, C12N 1512

Patent

active

058277331

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

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-.beta.) superfamily, which is denoted, growth differentiation factor-8 (GDF-8).
2. Description of Related Art
The transforming growth factor .beta. (TGF-.beta.) 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-.beta.s 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-.beta. 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-.beta. family is coexpressed with a mature region of another member of the TGF-.beta. 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-.beta.s (Cheifetz, 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.


SUMMARY OF THE INVENTION

-The present invention provides a cell growth and differentiation factor, GDF-8, 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 those involving muscle, nerve, and adipose tissue.
Thus, in one embodiment, the invention provides a method for detecting a cell proliferative disorder of muscle, nerve, or fat origin and which is associated with GDF-8. In another embodiment, the invention provides a method for treating a cell proliferative disorder by suppressing or enhancing GDF-8 activity.


BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a Northern blot showing e

REFERENCES:
Bowie et al. Science 247:1307-1310, 1990.
Rudinger. Peptide Hormones, Parsons, ed., University Park Press, Baltimore, pp. 1-7, 1976.
Wells. Biochemistry 29:8507-17, 1990.
Ngo et al. The Protein Folding Problem and Tertiary Structure Prediction. Merz et al., eds., Birkhauser, Boston, pp. 491-495, 1994.
Massague. Cell 49:437-438, 1987.
Callard et al. The Cytokine FactsBook, Academic Press, London, pp. 31-32, 1994.

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