A Bax/Bak-independent Mechanism of Cytochrome c Release

Bax and Bak are multidomain pro-apoptotic members of the Bcl-2 family of proteins that regulate mitochondria-mediated apoptosis by direct modulation of mitochondrial membrane permeability. Since double-knock-out mouse embryonic fibroblasts with deficiency of Bax and Bak are resistant to multiple apo...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-06, Vol.282 (22), p.16623-16630
Main Authors: Mizuta, Takeshi, Shimizu, Shigeomi, Matsuoka, Yousuke, Nakagawa, Takashi, Tsujimoto, Yoshihide
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Apoptosis - physiology
Arachidonic Acid - pharmacology
bcl-2 Homologous Antagonist-Killer Protein - deficiency
bcl-2 Homologous Antagonist-Killer Protein - metabolism
bcl-2-Associated X Protein - deficiency
bcl-2-Associated X Protein - metabolism
Calcimycin - pharmacology
Caspases - metabolism
Cell Membrane Permeability - drug effects
Cell Membrane Permeability - physiology
Cells, Cultured
Cytochromes c - metabolism
Ionophores - pharmacology
Mice
Mice, Knockout
Mitochondria - enzymology
Serine Proteinase Inhibitors - pharmacology
Signal Transduction - drug effects
Signal Transduction - physiology
Sulfones - pharmacology
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Summary:Bax and Bak are multidomain pro-apoptotic members of the Bcl-2 family of proteins that regulate mitochondria-mediated apoptosis by direct modulation of mitochondrial membrane permeability. Since double-knock-out mouse embryonic fibroblasts with deficiency of Bax and Bak are resistant to multiple apoptotic stimuli, Bax and Bak are considered to be an essential gateway for various apoptotic signals. Here we showed that the combination of calcium ionophore A23187 and arachidonic acid induced cytochrome c release and caspase-dependent death of double-knock-out mouse embryonic fibroblasts, indicating that other mechanisms of cytochrome c release exist. Furthermore, A23187/arachidonic acid (ArA)-induced caspase-dependent death was significantly suppressed by the treatment of several serine protease inhibitors including 4-(2-aminoethyl)benzenesulfonylfluoride and l-1-chloro-3-(4-tosylamido)-4-phenyl-2-butanone but not the overexpression of anti-apoptotic Bcl-2 family of proteins or the inhibition of mitochondrial membrane permeability transition. These results indicate that there are at least two mechanisms of cytochrome c release leading to caspase activation, a Bax/Bak-dependent mechanism and a Bax/Bak-independent, but serine protease(s)-dependent, mechanism.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M611060200