Bcl-2 and Bax are known regulators of cell death or apoptosis. Bcl-2 has been well studied because of its association with B Cell Lymphoma. While Bax is structurally similar to Bcl-2, it has been shown to be pro-apoptotic. Previous studies and our preliminary data have found that both Bcl-2 and Bax can either promote or inhibit tumor development. We hypothesize that these paradoxical findings for both Bcl-2 and Bax are explained by the ability of these genes to regulate cell growth as well as cell death. The studies proposed in this grant are aimed at understanding how both Bax and Bcl-2 regulate cell growth or proliferation and how this intersects with tumor development. Central to our proposal are mutant forms of Bcl-2, which retain antiapoptotic function but have lost their anti-proliferative activity. We have recently generated new transgenic mice expressing mutant Bcl-2. The oncogenic and proliferative activity of mutant Bcl-2 will be determined. Other studies will focus on the role of glutathione metabolism and REDOX regulation in BcI-2 and cell cycle control. Other studies will examine the mechanism by which Bcl-2 regulated p27 expression and function. Comparison of these cells and/or mice will allow us to dissect the signaling pathway by which Bcl-2 inhibits cell proliferation.
The Specific Aims for this work are as follows: 1) Determine the oncogenic potential of mutant forms of Bcl-2 that have lost their anti-proliferative activity and determine if Bax and Bcl-2 cooperate in oncogenesis: 2) Examine how Bcl-2 regulates changes in glutathione levels and examine the importance of these changes on Bcl-2 regulation of cell proliferation 3) Determine the molecular basis for Bcl-2 regulation of p27 levels and function Blocking the anti-apoptotic activity of Bcl-2 without blocking its anti-proliferative function would have great potential in the treatment of cancer. Similarly, blocking the proliferative function of Bax without blocking its pro-apoptotic activity may be therapeutic. With these therapeutic goals in mind, we have proposed a series of studies that will provide mechanistic insight into these pathways. At the same time our animals models will provide a """"""""proof of principle"""""""" regarding the selective regulation of these two pathways and its effect on tumor development. We believe a better understanding of the molecular basis by which Bcl-2 family members regulate proliferation and contribute to oncogenesis is very important. Our molecular studies will provide insight into the cross talk that occurs between cell death and cell proliferative pathways.
