Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-03-12
2002-06-25
Campbell, Eggerton A. (Department: 1656)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C536S022100
Reexamination Certificate
active
06410232
ABSTRACT:
BACKGROUND OF THE INVENTION
Follistatin is a single-chain glycoprotein of 35 kDa which is composed of four cysteine-rich domains, three of which are homologous and highly conserved. (Lane et al. (1994)
The FASEB Journal
8:163-173; Esch et al. (1987)
Mol. Endo.
1:849-855; Sugano et al. (1994)
Frontiers in Endocrinology Vol.
3:
Inhibin and Inhibin
-
related Proteins,
Rome: Ares-Serono Symposia, 69-80). Follistatin domains have recently been described in several mosaic proteins, including agrin (Rupp et al. (1991)
Neuron
6:811-823), osteonectin/SPARC (Lankat-Buttgereit et al. (1988)
FEBS Lett.
236:352-356), and the brain-specific extracellular matrix glycoprotein, SC1 (Johnston et al. (1990)
Neuron
2: 165-176; see also, Patthy et al. (1993)
Trends Neurosci.
16:76-81). It has been proposed that modules donated to mosaic proteins retain the function they had in the donor protein. (Eib et al. (1996)
J. Neurochem.
67(3) 1047-1055).
Follistatin binds the transforming growth factor-&bgr; (TGF-&bgr;) family members activin-A and inhibin. (Michel et al. (1993)
Molecular and Cellular Endocrinology
91:1-11). The family of TGF-&bgr; proteins includes, among others, activin-A and inhibin. (Eib et al. (1996)
J. Neurochem.
67:1047-1055). Members of the TGF-&bgr; family are multifunctional cytokines with physiological effects on the growth and differentiation of a variety of normal and neoplastic cells (Sporn et al. (1992)
J. Cell. Biol.
119:1017-1021). It has been proposed that follistatin and other follistatin-related molecules act by regulating the availability of TGF-&bgr;-related and/or other growth factors thereby influencing cellular migration, proliferation, and differentiation (Amthor (1996)
Dev. Biol.
178:343-361).
Follistatin and follistatin-related molecules have been found to modulate a variety of biological processes. For example, follistatin has been identified as a regulator of pituitary follice stimulating hormone (FSH) secretion (Ueno et al. (1990)
Progress in Growth Factor Research
2:113-124; Besecke et al. (1997)
Endocrinology
138:2841-2848). Follistatins have also been characterized as growth factors (Vale et al. (1988)
Recent Progress in Hormone Research
44:1-34; Link et al. (1997)
Experimental Cell Research
233:350-362), and embryo modulators (Huylebroeck et al. (1994) Frontiers in Endocrinology, Vol. 3:
Inhibin and Inhibin
-
related Proteins,
Rome: Ares-Serono Symposia Publications, 271-288; Petraglia (1996)). Osteonectin, which contains a single. follistatin domain, binds the platelet-derived growth factor (PDGF), preventing PDGF receptor activation (Raines et al. (1992)
Proc. Natl. Acad. Sci.
89:1281-1304). Also, the follistatin domains in agrin have been reported to act in binding and thus creating local concentrations of TGF-&bgr; family members in motor neurons and muscle (Patthy et al. (1993)). In addition, follistatin has high affinity for heparin sulfate side chains of membrane proteoglycans. (Nakamura et al. (1991)
J. Biol. Chem.
266:19432-19437).
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery of novel molecules with a follistatin-like domain, referred to herein as “Follistatin-Module-Containing-Protein” (FMCP) and nucleic acid molecules. Thus, the presence of follistatin-related domains in a protein indicates a role in the binding of molecules structurally related to TGF-&bgr; family members (Eib et al. (1996)
J. Neurochem.
67:1047-1055). TGF-&bgr; superfamily members are multifunctional cytokines which modulate a number of functions. Therefore, the FMCP molecules of the present invention are useful as modulating agents in regulating a variety of cellular processes. Accordingly, in one aspect, this invention provides isolated nucleic acid molecules encoding FMCP proteins or biologically active portions thereof, as well as nucleic acid fragments suitable as primers or hybridization probes for the detection of FMCP-encoding nucleic acids. In one embodiment, an isolated nucleic acid molecule of the present invention encodes a FMCP protein which includes a follistatin cysteine-rich domain. In another embodiment, the FMCP nucleic acid molecule is a naturally occurring nucleotide sequence.
In another embodiment, a FMCP nucleic acid molecule is 45% homologous to the nucleotide sequence shown in SEQ ID NO:1, SEQ ID NO:3, or the nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 98546, or a complement thereof. In a preferred embodiment, an isolated FMCP nucleic acid molecule encodes the amino acid sequence of human FMCP.
In another embodiment, a FMCP nucleic acid includes a nucleotide sequence encoding a protein having an amino acid sequence sufficiently homologous to a follistatin cysteine-rich domain amino acid sequence of SEQ ID NO:2. In a preferred embodiment, a FMCP nucleic acid molecule has the nucleotide sequence shown SEQ ID NO:1, SEQ ID NO:3, or the nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 98546.
In yet another preferred embodiment, a FMCP nucleic acid molecule includes a nucleotide sequence encoding a protein having an amino acid sequence at least 45% homologous to the amino acid sequence of SEQ ID NO:2.
Another embodiment of the invention features isolated FMCP protein having an amino acid sequence 55% homologous to a follistatin cysteine-rich domain of SEQ ID NO:2 (e.g., about amino acid residues 97-243). Another embodiment of the invention features isolated FMCP protein having an amino acid sequence at least about 65%, prefereably 75%, 85%, or 95% homologous to a follistatin cysteine-rich domain of SEQ ID NO:2 (e.g., about amino acid residues 97-243). Yet another embodiment of the invention features isolated FMCP protein having an amino acid sequence at least about 55% homologous to the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:5. Another embodiment of the invention features isolated FMCP protein having an amino acid sequence at least about 65%, preferably 75%, 85%, or 95% homologous to the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:5.
Yet another embodiment of the invention features isolated FMCP protein which is encoded by a nucleic acid molecule having a nucleotide sequence at least about 55% homologous to a follistatin cysteine-rich domain of SEQ ID NO:2 (e.g., about nucleotides 311 to 751 of SEQ ID NO:1). Another embodiment of the invention features isolated FMCP protein which is encoded by a nucleic acid molecule having a nucleotide sequence at least about 65%, preferably 75%, 85%, or 95% homologous to a follistatin cysteine-rich domain of SEQ ID NO:2 (e.g., nucleotides 311 to 751 of SEQ ID NO:1). This invention further features isolated FMCP protein which is encoded by a nucleic acid molecule having a nucleotide sequence which hybridizes under stringent hybridization conditions to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1 (e.g., about nucleotides 311 to 751 of SEQ ID NO:1).
In another embodiment, an isolated nucleic acid molecule of the present invention encodes a FMCP protein which includes a signal sequence and is secreted. In another embodiment, an isolated nucleic acid molecule of the present invention encodes a FMCP protein which includes a signal sequence and is retained in an intracellular compartment. In another embodiment, the FMCP nucleic acid molecule encodes a FMCP protein and is a naturally occurring nucleotide sequence.
Another embodiment of the invention features FMCP nucleic acid molecules which specifically detect FMCP nucleic acid molecules relative to nucleic acid molecules encoding other molecules with follistatin-like domains. For example, in one embodiment, a FMCP nucleic acid molecule hybridizes under stringent conditions to a nucleic acid molecule comprising the nucleotide sequence of nucleotides 23 to 811 of SEQ ID NO:1 as shown in SEQ ID NO:3. In another embodiment, the FMCP nucleic acid molecule is at least 500 nucleotides in length and hybridizes under stringent conditions to a nucleic acid molecule co
Campbell Eggerton A.
Millennium Pharmaceuticals Inc.
Millennium Pharmaceuticals Inc.
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