BCL2, the proto-oncogene that is deregulated in the most common translocation of follicular lymphomas, enhances oncogenesis by preventing programmed cell death. The BCL2 family of proteins are central to the regulation of apoptosis and include a number of interacting molecules. Both BCL2 and its close homolog BCL-XL have cell cycle activities separable from their anti-apoptotic function. The pro-apoptotic protein BAD heterodimerizes with BCL2 and BCL-XL, and promotes cell death. We have found that while BAD counters BCL2 and BCL-XL's anti-apoptotic activity, it does not affect their cell cycle functions. When control cells growth arrest, cells expressing BAD continue to cycle in the absence of serum and undergo accelerated apoptosis. These data suggest the hypothesis that BAD functions both in cell cycle and cell death. This grant proposes to determine the molecular mechanism of the cell cycle and cell death functions of BAD and BAD/BCL-XL heterodimers. First, the precise effect of BAD and BAD/BCL-XL in the cell cycle response to growth arrest signals will be determined. The structure-function relationship of the cell cycle and cell death activities will be defined to determine whether these function co-segregate. To further investigate the mechanism of BAD function, downstream protein targets of BAD and BAD/BCL-XL will be identified and cloned. These data will provide mechanistic insight into the normal function of the BCL2 family of cell death regulators and how their dysfunction contribute to oncogenesis.
