Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1999-10-05
2004-01-20
Mertz, Prema (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S388100, C530S388230, C530S388240, C530S389100, C530S389200, C424S001490
Reexamination Certificate
active
06680372
ABSTRACT:
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-&bgr;) superfamily, which is denoted, growth differentiation factor-7 (GDF-7).
2. Description of Related Art
The transforming growth factor &bgr;(TGF-&bgr;) 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-&bgr;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-&bgr; 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-&bgr; family is coexpressed with a mature region of another member of the TGF-&bgr; 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-&bgr;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-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.
REFERENCES:
patent: WO/92/00382 (1992-01-01), None
patent: WO 92/07073 (1992-04-01), None
patent: WO 93/16099 (1993-08-01), None
patent: WO 94/15949 (1994-07-01), None
patent: WO 95/01801 (1995-01-01), None
patent: WO 95/16035 (1995-06-01), None
Doerks et al. TIG, vol. 14, No. 6., pp. 248-250, Jun. 1998.*
Mikayama et al. Proc. Natl. Acad. Sci. USA vol. 90, pp. 10056-10060, 1993.*
Voct et al. Biochemistry. John Wiley & Sons, Inc., pp. 126-128 and 228-234, 1990.*
Elaine E. Storm et al. “Mus Musculus Balb/c Putative Growth Factor GDF7 (Gdf7) Gene”.
Elaine E. Storm et al., “Limb Alterations in Brachypodism Mice Due to Mutations in a New Member of the TFG&bgr;-Superfamily”, Nature, 368:639-643 (Apr. 14, 1994).
Engin Ozkaynak et al., Osteogenic Protein-2,The Journal of Biological Chemistry, vol. 267, No. 9, Dec. 15, 1992, pps. 25220-25227.
Anthony J. Celeste, Identification of transforming growth factor &bgr; family members present in bone-inductive protein purified from bovine bone,Proc. Natl. Acad. Sci. USA, vol. 87, Dec. 1990, pps. 9843-9847.
Karen Lyons et al., Vgr-1, a mammalian gene related to Xenopus Vg-1, is a member of the transforming growth factor &bgr; gene superfamily,Proc. Natl. Acad. Sci. USA, vol. 86, Jun. 1989, pps. 4554-4558.
Se-Jin Lee, Expression of growth/differentiation factor 1 in the nervous system: Conservation of a bicistronic structure, Proc. Natl. Acad. Sci. USA., 88: pps. 4250-4254, May 1991.
GDF-3 and GDF-9: Two New Members of the Transforming Growth Factor-&bgr; Superfamily Containing a Novel Pattern of Cysteines* ,The Journal of Biological Chemistry, vol. 268, No. 5, Feb. 15, 1993, pps. 3444-3449.
Se-Jin Lee, Indentification of a Novel Member (GDF-1) of the Transforming Growth Factor-&bgr; Superfamily,Molecular Endocrinology, 1990, vol. 4, No. 7, pps. 1034-1039.
John M. Wozney et al., Novel Regulators of Bone Formation: Molecuar Clones and Activities,Science, vol. 242 (Research Articles) Dec. 15, 1988, pps. 1528-1534.
Engin Ozkaynak et al., OP-1 cDNA encodes an osteogenic protein in the TGF-B family,The EMBO Journal, vol. 9, No. 7, 1990, pps. 2085-2093.
Huynh Thanh
Lee Se-Jin
Gray Cary Ware & Freidenrich LLP
Haile Lisa A.
Imbra Richard J.
Mertz Prema
The Johns Hopkins University School of Medicine
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