Abstract
Abstract Many aspects of cell signaling are regulated by protein:protein interactions including growth factor receptor signal transduction pathways, transcriptional regulatory complexes and programmed cell death. The Bcl-2 family proteins regulate programmed cell death via a series of protein:protein interactions that occur in the cytoplasm and in membranes. These interactions are regulated by the amount of the proteins, their locations and by post-translational modifications. The multi-domain pro-apoptotic Bcl-2 family members Bax and Bak directly regulate mitochondrial outer membrane permeabilization (MOMP), an event widely accepted as committing most cells to apoptosis. MOMP results from an ordered series of steps beginning with activation of one or more Bcl-2 homology 3 proteins (BH3-proteins). Once activated, BH3-proteins bind to mitochondria, directly recruit and activate Bax and the constitutively membrane bound Bak. In some cases ‘activation’ involves releasing a previously activated Bax or Bak from inhibition by an anti-apoptotic protein of the Bcl-2 family. Oligomerization of integral membrane Bax and/or Bak culminates in membrane permeabilization. The embedded together model describes these interactions as a series of dynamic equilibria that change when the proteins interact with membranes. Because of their role regulating apoptosis in cancer cells and in response to chemotherapy, Bcl-2 family proteins are attractive targets for the development of small molecule inhibitors. The rational development of small molecules requires understanding in detail the molecular interactions that regulate activity. However, studying protein:protein interactions for membrane bound proteins is fraught with difficulties. I will describe some of the challenges of studying this family of proteins and the successes and surprises that resulted from our analyzing and perturbing their interactions for a variety of Bcl-2 family proteins in live cells. I will highlight recent data that suggests new avenues to targeting Bcl-2 family protein:protein interactions therapeutically. Citation Format: David W. Andrews. Bcl-2 family proteins as a paradigm for protein:protein interactions as chemotherapy targets. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY37-04. doi:10.1158/1538-7445.AM2014-SY37-04
Published Version
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