Programmed cell death plays a prominent role in embryonic development as well as the maintenance of homeostasis within many adult tissues. One mammalian death pathway gene has been identified, Bcl-2, that functions as a repressor of programmed cell death. Bcl-2 was isolated at the chromosomal breakpoint of t(14;18) bearing follicular B cell lymphomas. Transgenic mice bearing a Bcl-2-Ig minigene demonstrated B cell hyperplasia, prolonged B cell memory and established that extended cell survival is oncogenic. Bcl-2 is widely expressed in the embryo and restricted in adult tissues indicating roles in numerous cell lineages. We examined Bcl-2 protein interactions to search for further known or novel molecules that function in a mammalian death pathway. Co- immunoprecipitation revealed, Bax, a novel protein that showed extensive homology with Bcl-2 in two conserved domains. Bax homodimerizes and forms heterodimers with Bcl-2 in vivo. Overexpressed Bax counters Bcl-2 and accelerates programmed cell death. To fully understand the developmental roles of mammalian cell death genes, genetic manipulations must be conducted within whole organisms to assess lineage development, organogenesis, and homeostasis. This proposal takes an aggressive genetic approach to cell death by creating lineage specific gain of function transgenic mice and gene ablated loss of function mice. An emerging family of Bcl-2 related/interacting proteins will be assessed including Bcl-2, Bax, Bcl-x, Brp and new potential isolates. Overexpression and elimination will provide the most complete assessment of each as an effector or repressor of cell death. Both effector and repressor molecules of apopotosis could contribute to neoplasia by either gain or loss of function mutation, respectively. The murine models within this proposal provide a test of this hypothesis.
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