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Mol Cell Biol. 2004 Dec;24(23):10289-99.

Bcr-Abl-mediated protection from apoptosis downstream of mitochondrial cytochrome c release.

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  • 1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813, Durham, NC 27710, USA.

Abstract

Bcr-Abl, activated in chronic myelogenous leukemias, is a potent cell death inhibitor. Previous reports have shown that Bcr-Abl prevents apoptosis through inhibition of mitochondrial cytochrome c release. We report here that Bcr-Abl also inhibits caspase activation after the release of cytochrome c. Bcr-Abl inhibited caspase activation by cytochrome c added to cell-free lysates and prevented apoptosis when cytochrome c was microinjected into intact cells. Bcr-Abl acted posttranslationally to prevent the cytochrome c-induced binding of Apaf-1 to procaspase 9. Although Bcr-Abl prevented interaction of endogenous Apaf-1 with the recombinant prodomain of caspase 9, it did not affect the association of endogenous caspase 9 with the isolated Apaf-1 caspase recruitment domain (CARD) or Apaf-1 lacking WD-40 repeats. These data suggest that Apaf-1 recruitment of caspase 9 is faulty in the presence of Bcr-Abl and that cytochrome c/dATP-induced exposure of the Apaf-1 CARD is likely defective. These data provide a novel locus of Bcr-Abl antiapoptotic action and suggest a distinct mechanism of apoptosomal inhibition.

PMID:
15542838
PMCID:
PMC529043
DOI:
10.1128/MCB.24.23.10289-10299.2004
[PubMed - indexed for MEDLINE]
Free PMC Article
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