Programmed cell death plays an indispensible role in the development and maintenance of homeostasis within multicellular organisms. Moreover, aberrations in the apoptoticpathway are causally involved in the genesis of cancer and also confer resistance to cancer therapy. Protein interaction cloning, including yeast two-hybnd based screening, was utilized to extend the apoptosis pathway beyond the initial anti-apoptotic member BCL-2.and pro-apoptotic member SAX. This funding period identified the """"""""BH3 domain-only"""""""" pro-apoptotic molecules BID and BAD. Their mechanisms of regulation served to further integrate the apoptotic pathway as they interconnect with proximal death and survival signals, undergoing post-translational modifications which determine their active versus inactive conformation. Their phosphorylation, proteolytic cleavage or myristoylation dictates their subcellular location and protein partners. Recent evidence supports a pro-apoptotic cascade in which """"""""BH3 domain-only"""""""" molecules (BID) induce the homo-oligomerization of """"""""multi-domain"""""""" pro-apoptotic members (BAX/BAK) resulting in the release of cytochrome c and mitochondrial dysfunction. Cells doubly deficient for BAX/BAK are resistant to all intrinsic death signals tested whether they emanate from the plasma membrane, nucleus or endoplasmic reticulum. Thus, """"""""multi-domain"""""""" BAX and BAK are the obligate gateway to mitochondrial dysfunction and cell death following diverse stimuli including cancer therapeutics. The current proposal will dissect this pro-apoptotic cascade by identifying the precise downstream molecules that mediate the mitochondrial demise and detailing their mechanism of action.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Pathology B Study Section (PTHB)
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Mccarthy, Susan A
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Dana-Farber Cancer Institute
United States
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Edwards, Amanda L; Wachter, Franziska; Lammert, Margaret et al. (2015) Cellular Uptake and Ultrastructural Localization Underlie the Pro-apoptotic Activity of a Hydrocarbon-stapled BIM BH3 Peptide. ACS Chem Biol 10:2149-57
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