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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA050239-19
Application #
7015028
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mccarthy, Susan A
Project Start
1989-07-01
Project End
2008-01-31
Budget Start
2006-03-08
Budget End
2008-01-31
Support Year
19
Fiscal Year
2006
Total Cost
$609,928
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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
Barclay, Lauren A; Wales, Thomas E; Garner, Thomas P et al. (2015) Inhibition of Pro-apoptotic BAX by a noncanonical interaction mechanism. Mol Cell 57:873-886
Zhang, Tejia; Walensky, Loren D; Saghatelian, Alan (2015) A nonapoptotic role for BAX and BAK in eicosanoid metabolism. ACS Chem Biol 10:1398-403
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Zhang, Tejia; Barclay, Lauren; Walensky, Loren D et al. (2015) Regulation of mitochondrial ceramide distribution by members of the BCL-2 family. J Lipid Res 56:1501-10
Lee, Susan; Braun, Craig R; Bird, Gregory H et al. (2014) Photoreactive stapled peptides to identify and characterize BCL-2 family interaction sites by mass spectrometry. Methods Enzymol 544:25-48
Walensky, Loren D; Bird, Gregory H (2014) Hydrocarbon-stapled peptides: principles, practice, and progress. J Med Chem 57:6275-88
Bird, Greg H; Gavathiotis, Evripidis; LaBelle, James L et al. (2014) Distinct BimBH3 (BimSAHB) stapled peptides for structural and cellular studies. ACS Chem Biol 9:831-7
Walensky, Loren D (2013) Direct BAKtivation. Nat Struct Mol Biol 20:536-8
Leshchiner, Elizaveta S; Braun, Craig R; Bird, Gregory H et al. (2013) Direct activation of full-length proapoptotic BAK. Proc Natl Acad Sci U S A 110:E986-95

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