Sequential activation of caspases is critical for the execution of apoptosis. Recent evidence suggests caspase 2 is a significant upstream caspase capable of initiating mitochondrial events, such as the release of cytochrome c. In particular, in vitro studies using recombinant proteins have shown that cleaved caspase 2 can induce mitochondrial outer membrane permeabilization directly or by cleaving the BH3-only protein BID (BH3 interacting domain death agonist). However, whether interchain cleavage or activation of procaspase 2 occurs prior to Apaf-1-mediated procaspase 9 activation under more natural conditions remains unresolved. In the present study, we show that Apaf-1-deficient Jurkat T-lymphocytes and mouse embryonic fibroblasts were highly resistant to DNA-damage-induced apoptosis and failed to cleave or activate any apoptotic procaspase, including caspase 2. Significantly, drug-induced cytochrome c release and loss of mitochondrial membrane potential were inhibited in cells lacking Apaf-1. By comparison, procaspase proteolysis and apoptosis were only delayed slightly in Apaf-1-deficient Jurkat cells upon treatment with anti-Fas antibody. Our data support a model in which Apaf-1 is necessary for the cleavage or activation of all procaspases and the promotion of mitochondrial apoptotic events induced by genotoxic drugs.
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Research Article|
June 13 2007
Requirement of Apaf-1 for mitochondrial events and the cleavage or activation of all procaspases during genotoxic stress-induced apoptosis
Emily E. Franklin
;
Emily E. Franklin
1
Department of Pharmacology, Toxicology & Therapeutics and the Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A.
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John D. Robertson
John D. Robertson
1
1
Department of Pharmacology, Toxicology & Therapeutics and the Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A.1
To whom correspondence should be addressed (email jrobertson3@kumc.edu).
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Biochem J (2007) 405 (1): 115-122.
Article history
Received:
October 18 2006
Revision Received:
March 05 2007
Accepted:
March 09 2007
Accepted Manuscript online:
March 09 2007
Citation
Emily E. Franklin, John D. Robertson; Requirement of Apaf-1 for mitochondrial events and the cleavage or activation of all procaspases during genotoxic stress-induced apoptosis. Biochem J 1 July 2007; 405 (1): 115–122. doi: https://doi.org/10.1042/BJ20061576
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