Apoptotic cell death in lymphocytes can be triggered by activation signals transmitted through cell surface receptors and utilizing signal transduction pathways which are shared with mitogenic programs. The susceptibility of cells to activation-induced cell death is dependent on both the maturation stage and previous activation history of a lymphocyte. The bcl-2 gene product, a mitochondrially targeted protein which inhibits apoptotic death, is another important determinant of cell survival. The detailed understanding of the interaction between these components of an apoptotic pathway in B lymphocytes, signal transduction following sIgM crosslinking, developmental stage, and endogenous inhibitors of cell death is the overall goal of this proposal. Knowledge of important intracellular events leading to self tolerance in B lymphocytes is relevant to human autoimmune diseases and broader problems of premature cell deaths in various cell lineages, many of which appear to involve activation pathways. Bcl-2 function is pivotal in understanding mechanisms of apoptotic death, and we have proposed that bcl-2 functions in a cellular antioxidant pathway. Mice with homozygous deletions of the bcl-2 gene have phenotypes of oxidant injury and accelerated apoptosis. Our previous findings of oxygen free radical-mediated damage as a necessary step i lymphocyte apoptosis will be extended to models of activation-induced death in murine cell lines and immature B lymphocytes. Downregulation of bcl-2 levels and function appear to be important determinants of susceptibility to cell death in many systems. The requirements for bcl-2 mRNA and protein synthesis and degradation in this model and compared to mature B lymphocytes resistant to activation-induced death and the potential interaction of bcl-2 with bax and bcl-x will be determined. Finally, the delayed commitment to cell death will be examined by comparing effects on duration of intracellular signals as a potential decision point for entry into apoptotic versus mitotic programs.
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