MARTINE F. ROUSSEL
ASSOCIATE PROFESSOR

EDUCATION:
B.S. 1971, Universite de Tours, France (Biology)
M.S. 1974, Universite des Sciences, Paris 7, France (Biochemistry)
Ph.D. 1978, Universite de Lille, France (Biochemistry)
These d'Etat 1982, Universite de Lille, France (Molecular Biology)

RESEARCH INTERESTS: Our interests have focused on the mechanisms by which growth-factor receptors with intrinsic tyrosine kinase activity relay proliferative signals that directly affect progression through the first gap phase (G1) of the cell cycle and the cell's subsequent commitment to initiate DNA synthesis (S phase). Cells require persistent growth factor stimulation throughout most of the G1 interval of the cell cycle, but once they commit to enter S phase, cells can complete division in the absence of mitogens. Ligand-activated tyrosine kinase receptors relay proliferative signals via multiple pathways that alter patterns of gene transcription and ultimately lead to the decision to enter S phase. Expression of the c-myc and the D-type G1 cyclin genes is essential for growth factor-induced cell proliferation, and both sets of genes are rate limiting for S phase entry. Myc and D-cyclins are often overexpressed in certain types of tumors in which deregulated cell growth becomes independent of extracellular regulatory signals. We have demonstrated that myc and D cyclins act synergistically and functionally cooperate to enforce G1 progression. D-type cyclins act as regulatory subunits of cyclin dependent kinases (cdks), with cdk4 and cdk6 representing their principle partners. The activities of cyclin D-cdk complexes are positively regulated by cdk phosphorylation and are inhibited by so-called Ink4 proteins (inhibitors of cdk4), now recognized to be encoded by at least four distinct INK4 genes. Enforced expression of Ink4 proteins during G1 inhibits cyclin D-cdk4 activity and thereby prevents cells from entering S phase. Conversely, deletions of INK4 genes can lead to tumorigenesis. For example, on family member, p16ink4a or MTS1, cloned as a suppressor gene in familial melanomas, is now recognized to undergo frequent deletions in many forms of human cancer. Our laboratory is currently investigating the role of different INK4 family members in childhood cancers.

CURRENT RESEARCH SUPPORT:
RO1-CA56819-0-1-04 NCI "FMS Transformation/CSF-1 Receptor Signal Transduction" June 12, 1992 - March 31, 1997; P.I., M.F. Roussel, 75% effort. Direct costs 01 year: $150,573.

PUBLICATIONS: (representative publications out of 90)
Roussel, M., Saule, S., Lagrou, C., Rommens, C., Beug, H., Graf, T., and Stehelin, D. (1979) DLVs: Three new types of viral oncogenes of cell origin specific for hematopoietic cell transformation. Nature, 281, 452-455.
Roussel, M.F., Sherr, C.J., Barker, P.E., and Ruddle, F.H. (1983) Molecular cloning of the c-fms locus and its assignment to human chromosome 5. J. Virol., 48, 770-773.
Roussel, M.F., Rettenmier, C.W., Look, A.T., and Sherr, C.J. (1984) Cell surface expression of v-fms-coded glycoproteins is required for transformation. Mol. Cell. Biol., 4, 1999-2009.
Sherr, C.J., Rettenmeier, C.W., Sacca, R., Roussel, M.F., Look, A.T., and Stanley, E.R. (1985) The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1. Cell, 41, 665-676.
Roussel, M.F., Dull, T.J., Rettenmier, C.W., Ralph, P., Ullrich, A., and Sherr, C.J. (1987) Transforming potential of the c-fms proto-oncogene (CSF-1 receptor). Nature, 325, 549-552.
Rettenmier, C.W. and Roussel, M.F. (1988) Differential processing of colony-stimulating factor-1 precursors encoded by two human cDNAs. Mol. Cell. Biol,. 8, 5026-5034.
Roberts, W.M., Look, A.T., Roussel, M.F., and Sherr, C.J. (1988) Tandem linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes. Cell, 55, 655-661.
Roussel, M.F., Downing, J.R., Ashmun, R.A., Rettenmier, C.W., and Sherr, C.J. (1988) Colony- stimulating factor 1-mediated regulation of a chimeric c-fms/v-fms receptor containing the v-fms-coded tyrosine kinase domain. Proc. Natl. Acad. Sci. USA, 85, 5903-5907.
Roussel, M.F., Downing, J.R., Rettenmier, C.W., and Sherr, C.J. (1988) A point mutation in the extracellular domain of the human CSF-1 receptor (c-fms proto-oncogene product) activates its transforming potential. Cell, 55, 979-988.
Roussel, M.F. and Sherr, C.J. (1989) Mouse NIH/3T3 cells expressing human CSF-1 receptors overgrow in serum-free medium containing human CSF-1 as their only growth factor.
Proc. Natl. Acad. Sci. USA, 86, 7924-7927.
Roussel, M.F., Transy, C., Kato, J-Y., Reinherz, E., and Sherr, C.J. (1990) Antibody-induced mitogenicity mediated by a chimeric CD2-c-fms receptor. Mol. Cell. Biol., 10, 2407-2412.
Roussel, M.F., Downing, J.R., and Sherr, C.J. (1990) Transforming activities of human CSF-1 receptors with different point mutations at codon 301 in their extracellular domains.
Oncogene, 5, 25-30.
Roussel, M.F., Shurtleff, S.A., Downing, J.R., and Sherr, C.J. (1990) A point mutation at tyrosine 809 in the human colony-stimulating factor 1 receptor impairs mitogenesis without abrogating tyrosine kinase activity, association with phosphatidylinositol 3-kinase, or induction of fos and junB genes. Proc. Natl. Acad. Sci. USA, 87, 6738-6742.
Matsushime, H., Roussel, M.F., Ashmun, R.A., and Sherr, C.J. (1991) Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell,, 65, 701-713.
Roussel, M.F., Cleveland, J.L., Shurtleff, S.A., and Sherr, C.J. (1991) MYC rescue of a mutant CSF-1 receptor impaired in mitogenic signaling. Nature, 353, 361-363.
Courtneidge, S.A., Dhand, R., Pilat, D., Twamley, G.M., Waterfield, M.D., and Roussel, M.F. (1993) Activation of SRC family kinases by colony stimulating factor-1, and their association with its receptor. EMBO J., 12, 943-950.
Quelle, D.E., Ashmun, R.A., Shurtleff, S.A., Kato, J-Y., Bar-Sagi, D., Roussel, M.F., and Sherr, C.J. (1993) Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes &Devel., 7, 1559-1571.
Roussel, M.F., Davis, J.N., Cleveland, J.L., Ghysdael, J., and Hiebert, S.W. (1994) Dual control of myc expression through a single DNA binding site targeted by ets family proteins and E2F-1. Oncogene,9, 405-415.
Hirai, H., Roussel, M.F., Kato, J-Y., Ashmun, R.A., and Sherr, C.J. (1995) Novel INK4 proteins, p19 and p18: Specific inhibitors of cyclin D-dependent kinases, cdk4 and cdk6.
Mol. Cell Biol., 10, 1229-1234.
Roussel, M.F., Theodoras, A.M., Pagano, M., and Sherr, C.J. (1995) Rescue of defective mitogenic signaling by D-type cyclins. PNAS, 92, 6837-6841.
Afar, D.E.H., McLaughlin, J., Sherr, C.J., Witte, O.N., and Roussel, M.F. Signaling by ABL oncogenes through cyclin D1. PNAS, in press.