Ras superfamily GTPases, oncogenes, signal transduction, and target-based anti-cancer drug discovery
Research Synopsis:
The broad goal of our research is to delineate the molecular basis for cancer. One major emphasis of our studies is
the study of Ras oncoproteins, which are key regulators of signal transduction pathways that control normal cell growth
and differentiation. Mutated Ras proteins are found in 30% of human cancers and promote cancer cell growth, invasion,
and metastasis. We are evaluating how aberrant Ras proteins alter the regulation of cell cycle progression, programmed
cell death, and gene expression to promote oncogen sxdsxdesis. One facet of these studies involves a dissection of the complex
signaling mechanisms that are deregulated by Ras in cancer cells, including the Raf-MEK-ERK mitogen-activated protein
kinase cascade. A long-term goal of these studies is to use this information for the development of anti-Ras drugs as
novel approaches for cancer treatment (e.g., farnesyltransferase and kinase inhibitors). Another major aspect of our
studies involves the study of Ras-related proteins. The human Ras proteins are but a small branch of a larger superfamily
of Ras-related GTPases. While Ras proteins are mediators of positive growth regulation, Ras-related proteins control a
range of diverse cellular processes that include actin cytoskeletal organization ( Rho proteins) and negative growth
regulation (DBC2, Rerg, NOEY2). A major goal of our studies has been to determine whether the aberrant activities of
Ras-related proteins also contribute to malignant transformation. In particular, we have focused on the study of Rho
family small GTPases, regulators of actin cytoskeletal organization and gene expression, and mediators of tumor cell
invasion and metastasis. We utilize human cell culture and mouse models, as well as genetic studies in C. elegans to
study mechanisms of signal transduction. Our studies focus on the role of aberrant signaling in the development and
growth of cancers of the breast, ovary, pancreas, colon, lung and skin. (Figure of Ras Superfamily) [to see details better view as .pdf]
Recent Publications:
Capell, B.C., Erdos, M.R., Madigan, J.P., Fiordalisi, J.J., Varga, R., Conneely, K.N., Gordon, L.B., Der, C.M., Cox, A.D., and Collins, F.S. (2005) Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Guilford progeria syndrome. Proc Natl Acad Sci USA 102(36): 12879-84. Abstract
Mitin, N., Rossman, K.L., and Der, C.J. (2005) Signaling interplay in Ras Superfamily function. Curr Biol 15(14): R563-74. Abstract
Lim, K.H., Baines, A.T., Fiordalisi, J.J., Shipitsin, M., Feig, L.A., Cox, A.D., Der, C.J., and Counter, C.M. (2005) Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell 7(6): 533-45. Abstract
Shutes, A., Berzat, A., Cox, A.D. and Der, C.J. (2004) Atypical regulation of the Wrch-1 Rho family small GTPase. Curr Biol 14(22): 2052-6. Abstract
Repasky, G., Chenette, E.J., and Der, C.J. (2004) Renewing the conspiracy theory debate: does Raf function alone to cause Ras transformation? Trends Cell Biol 14(11): 639-7. Abstract
