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.
| 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 |
| Hetz, Claudio; Bernasconi, Paula; Fisher, Jill et al. (2006) Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science 312:572-6 |
| Walensky, Loren D; Pitter, Kenneth; Morash, Joel et al. (2006) A stapled BID BH3 helix directly binds and activates BAX. Mol Cell 24:199-210 |
| Opferman, Joseph T; Iwasaki, Hiromi; Ong, Christy C et al. (2005) Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 307:1101-4 |
| Zinkel, Sandra S; Hurov, Kristen E; Ong, Christy et al. (2005) A role for proapoptotic BID in the DNA-damage response. Cell 122:579-91 |
| Schinzel, Anna C; Takeuchi, Osamu; Huang, Zhihong et al. (2005) Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci U S A 102:12005-10 |
| Oakes, Scott A; Scorrano, Luca; Opferman, Joseph T et al. (2005) Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum. Proc Natl Acad Sci U S A 102:105-10 |
| Bassik, Michael C; Scorrano, Luca; Oakes, Scott A et al. (2004) Phosphorylation of BCL-2 regulates ER Ca2+ homeostasis and apoptosis. EMBO J 23:1207-16 |
| Walensky, Loren D; Kung, Andrew L; Escher, Iris et al. (2004) Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305:1466-70 |
| Cheng, Emily H Y; Sheiko, Tatiana V; Fisher, Jill K et al. (2003) VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science 301:513-7 |
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