Bcl-2 family and redox control of genomic instability

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DESCRIPTION (provided by applicant): Bcl-2 is an oncogene that controls cell death and is highly expressed in some types of B cell lymphomas. The Bcl-2 family contains both anti-apoptotic (Bcl-2 like) and pro-apoptotic members (Bax like). Despite its anti-apoptotic function, numerous studies and our preliminary data have found that Bcl-2 has paradoxical effects on tumor development. In addition, our preliminary studies demonstrate that that Bax also has unexpected effects on tumor formation (High Bax expression promotes thymic lymphoma development). Genomic instability is a hallmark of oncogenesis. Either chromosomal instability is frequently observed in human malignancies and thought to facilitate tumor formation through increased rates of genetic mutation. In our preliminary data, we find that Bax expression is associated with a high frequency of aneuploid cells and increased aneuploidy in both T cells and thymocytes. Bcl-2 antagonizes Bax induced tumor formation and aneuploidy. Based on this, we hypothesize that the paradoxical effect of Bcl-2 and Bax on oncogenesis and tumor progression is determined by the ability of these proteins to increase or decrease chromosomal instability. Given that Bcl-2 family members are critical regulators of mitochondria, these studies explore the role of mitochondria and/or reactive oxygen species in these effects. Based on this hypothesis we propose the following Specific Aims 1) Determine the rate of chromosome instability in Lck-Bax, Lck-Bcl-2 and control transgenic mice prior to tumor formation. 2) Determine if inhibition of the apoptosome by Caspase 9 dominant negative expression accelerates Bax dependent tumor development. 3) Determine the role of oxidants in Bcl-2 family member induced oncogenesis and chromosome instability. 4) Develop and utilize in vitro models of chromosome instability to determine the effect of Bax and Bcl-2 expression on genomic instability. From the perspective of cancer biology, our preliminary data linking Bax expression to chromosomal instability is both novel and potentially very important in understanding oncogenesis. Linking the Bcl-2 family to chromosomal instability provides novel insight into how the Bcl-2 family controls oncogenesis. Perhaps more importantly, the paradoxical effects of Bcl-2 on cancer and alterations in genomic instability apply to nearly all types of tumors. Understanding the pathways that control genomic instability may result in novel therapeutic strategies for the prevention or treatment of lymphoma and other diverse human malignancies.