Srikumar Chellappan, PhD

The major focus of our laboratory is to understand the molecular events underlying cell cycle regulation and how a loss of this regulation leads to oncogenesis. The retinoblastoma tumor suppressor gene, Rb, is a major cell cycle regulatory protein; earlier studies had revealed that Rb exerts its effects by controlling the activity of a cellular transcription factor, E2F. Components of the cell cycle machinery respond to extra-cellular signals by inducing proliferation, differentiation or apoptosis, but it is not yet clear how signals received at cell surface receptors contact the cell cycle machinery. We are interested in studying the role of Rb and E2F in such events, with special emphasis on elucidating the pathways that link them to cell surface signaling.

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. Similarly, other signaling molecules like JNK1 and p38 kinase can modulate E2F activity in different fashions in response to specific signal transduction pathways. We are also studying the role of prohibitin, a potential tumor suppressor protein, in regulating E2F function as well as IgM receptor mediated signaling. We find that prohibitin can bind to the Rb protein and repress E2F transcriptional activity; prohibitin does not appear to target the transcriptional activation domain of E2F, but a conserved region of unknown function. Our lab recently cloned a novel factor, DP2, which can interact with and up-regulate the function of E2F, and we are elucidating its function. We believe that our studies will throw light on molecular events that regulate cell proliferation.

Selected Publications:

• Chellappan, S.P., Hiebert, S.W., Mudryj, M.M., Horowitz, J.M., and Nevins, J.R. The E2F transcription factor is a cellular target for the Rb protein. Cell. 65: 1053-1061 (1991).

• Zhang, Y.Z., and Chellappan, S.P. Cloning and characterization of DP-2, a novel dimerization partner of E2F. Oncogene 10: 2085-2093 (1995).

• Zhang, Y., and Chellappan, S.P. Transcriptional activation and expression of DP transcription factors during cell cycle and TPA-induced differentiation. Mol. Cell. Differ. 4: 297-316 (1996).

• Zhang, Y., Venkatraj, V., Fisher, S., Wharburton, D., and Chellappan, S.P. Genomic cloning and chromosomal assignment of the E2F Dimerization Partner TFDP gene family. Genomics. 39: 95-98 (1997).

• Chellappan, S.P., Giordano, A., and Fisher, P.B. The role of cyclin dependent kinases and their inhibitors in cellular differentiation and development. Current Topics in Microbiology and Immunology 227: 57-103 (1998).

• Wang, S., Ghosh, R., and Chellappan, S.P. 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 (1998).

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

• Nath, N., Bian, H., Reed, E., and Chellappan, S.P. HLA class I-mediated induction of cell proliferation involves cyclin E-mediated inactivation of Rb function and induction of E2F activity. J. Immunol., 162: 5351-5368 (1999).
Wang, S., Nath, N., Adlam, M., and Chellappan, S.P. Prohibitin, a potential tumor suppressor, interacts with Rb and regulates E2F function. Oncogene 18: (23) (in press, 1999).