Requirement of Apaf-1 for mitochondrial events and the cleavage or activation of all procaspases during genotoxic stress-induced apoptosis

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 th...

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Bibliographic Details
Published in:Biochemical journal 2007-07, Vol.405 (1), p.115-122
Main Authors: Franklin, Emily E, Robertson, John D
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - metabolism
Apoptosis - physiology
Apoptotic Protease-Activating Factor 1 - genetics
Apoptotic Protease-Activating Factor 1 - metabolism
Caspase 2 - genetics
Caspase 2 - metabolism
Caspase 9 - metabolism
Cells, Cultured
DNA Damage
Enzyme Activation
Etoposide - metabolism
Fibroblasts - cytology
Fibroblasts - physiology
Humans
Jurkat Cells
Membrane Potentials - physiology
Mice
Mice, Knockout
Mitochondria - metabolism
Mitoxantrone - metabolism
RNA Interference
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Summary: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.
ISSN:0264-6021
1470-8728
DOI:10.1042/BJ20061576