This proposal is based on the theory that the Bcl-2 proto-oncogene has both an anti-apoptotic activity, as well as the proliferation restraining activity. The investigator proposes to test the hypothesis that gain of function mutants of Bcl-2 can lead to enhanced oncogenesis and resistance to chemotherapeutic drugs. Transformation-enhancing mutants of Bcl-2 will be identified by somatic mutations in human tumors, as well as isolated from a random in vitro generated mutant library. The mutants will be transduced into primary bone marrow cells from transgenic mice which over-express the c-Myc oncogene using retroviral vectors. Mutants will be identified by in vitro colony forming assays on soft agar and in vivo by tumor formation in transplanted normal non-transgenic mice. Mutants of Bcl-2 which confer enhanced resistance to apoptosis induced by anti-cancer drugs will also be isolated from naturally drug-resistant human tumor cells. The anti-apoptosis activity, the effect on cell cycle regulation and the ability to form complexes with known cellular proteins and other various mutants will be studied. The long term objective of these specific aims is to design effective anti-Bcl-2 strategies. The final specific aim will investigate the role of the pro-apoptotic gene BIK in inducing apoptosis in tumor cells such as human prostate carcinoma cells which over-express Bcl-2. These studies hope to provide tools and strategies to interfere with Bcl-2 activity in neoplastic diseases.
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