Control of cell death is vital for normal physiology, and its altered regulation underlies cancer and other diseases. Commitment to apoptosis is governed by interacting proteins of the Bc1-2 family, which includes both prosurvival members like Bc1-2 and pro-apoptotic ones that either resemble Bcl-2 (e.g. Bax or Bak) or bear only the BH3 interaction domain (eg. Bim). This project explores, by both molecular and genetic approaches, how their interactions and association with mitochondria establish commitment to apoptosis and homeostasis.1) To explore Bim physiological function, our discovery that lymphoid homeostasis requires Bim prompts tests of whether Bim governs the attrition during lymphocyte development (negative and positive selection). 2) To investigate association of Bcl-2 -like proteins with organellar membranes. Binding of Bim to Bc1-2 is proposed to induce a conformational change that augments membrane attachment and ablates survival function.3) To explore whether Bcl-2 docks on mitochondrial pores. Our evidence that Bcl-2 complexes with two pore components will be extended, and its relevance to Bc1-2 localization and survival function assessed.4) To investigate how Bcl-2 and BH3 proteins control activation of Bax-like proteins. The requirement for both Bim and Bax or Bak in lymphocyte apoptosis prompts tests of whether ligation of Bcl-2 by Bim generates a signal that indirectly activates Bax/Bak, or whether certain BH3 proteins can directly activate Bax. Justification: As the proposal addresses central issues about the regulation of apoptosis, builds onproductive research, and exploits novel findings, it should significantly advance the molecular dissection of apoptosis.
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