The major research interest is to understand the mechanisms by which extra-cellular signals regulate the cell cycle machinery and how a loss of this regulation leads to oncogenesis. We focus 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 interactions by a small peptide inhibits cell proliferation as well as VEGF-induced angiogenic process. Attempts are being made to identify potential drugs that can mimic this peptide. 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. Our lab is 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 mechanism by which prohibitin regulates cell proliferation and apoptosis. A recent avenue of research has been on the role of nicotinic receptor signaling in lung cancer, especially how exposure to nicotine promotes the growth and progression of tumors and renders them resistant to death induced by chemotherapeutic drugs. We believe our studies will identify molecular targets for developing novel chemotherapeutic agents.
Key words: Rb, Raf-1, E2F, Cell cycle, prohibitin, nicotine, lung cancer, ASK1, p38, angiogenesis.