University of South Florida

Cancer Biology Ph.D. Program at the

Srikumar Chellappan , Ph.D. Professor in the Department of Oncologic Sciences Member-in-Residence of the Moffitt Cancer Center, Drug Discovery Program E-mail: Srikumar.Chellappan@moffitt.org Phone: (813)745-6892

Training
B.S., University of Kerala, 1979
Ph.D., Indian Institute of Science, 1987
Postdoctoral Fellow, Duke University, 1987-1991

Research Interests
Our laboratory is interested in understanding the mechanisms by which extra-cellular signals regulate the cell cycle machinery and how a loss of this regulation leads to oncogenesis. We have been focusing on how the retinoblastoma protein and its downstream target E2F transcription factor mediate proliferation, differentiation and apoptosis in response to specific signaling cascades. In this context, we have observed that the signaling molecule Raf-1 can physically interact with the Rb protein in response to proliferative signals and inactivate it independent of cyclins and cyclin dependent kinases. Disruption of the Rb - Raf-1 interaction by a small peptide inhibits cell proliferation as well as VEGF-induced angiogenic process. Attempts are being made to identify potential agents that can mimic this peptide. Changes in gene expression profiles during angiogenesis and the contribution of Rb and E2F to the process is being evaluated. Our studies have also shown that JNK1 and p38 kinases can modulate Rb and E2F activity in opposite fashions. The potential role of these events in apoptosis is being evaluated.

We are also studying the role of prohibitin, a potential tumor suppressor protein that interacts with Rb and represses E2F transcriptional activity. Mutations of the prohibitin gene have been reported in breast cancer and we find that prohibitin can inhibit certain apoptotic pathways. Efforts are being made to understand the specific mechanisms by which prohibitin regulates cell proliferation and apoptosis. We believe our studies will identify molecular targets for developing novel chemotherapeutic agents.

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Selected Publications
1. Wang, S., Ghosh, R. and Chellappan, S.P. (1998). RAF-1 protein physically interacts with Rb and regulates its function: A link between mitogenic signaling and cell cycle regulation. Mol. Cell. Biol., 18, 7487-7498

2. Wang, S., Nath, N., Minden, A. and Chellappan, S.P. (1999). Regulation of Rb and E2F by signaling cascades: Divergent effects of JNK1 and p38 kinases. EMBO J. 1999 18 (6): p. 1559-1570.

3. Wang, S., Nath, N., Adlam, M., and Chellappan, S.P. (1999). Prohibitin, a potential tumor suppressor, interacts with Rb and regulates E2F function. Oncogene, 18: 3501-3510

4. Wang, S., Nath, N., Fusaro, G. and Chellappan, S. P. (1999) Rb and prohibitin target distinct regions of E2F1 for repression and respond to different upstream signals. Mol. Cell. Biol. 19 (11), 7447-7460.