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XB-ART-2743
Mol Cell Biol. December 1, 2004; 24 (23): 10289-99.

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

Deming PB , Schafer ZT , Tashker JS , Potts MB , Deshmukh M , Kornbluth S .


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.

PubMed ID: 15542838
PMC ID: PMC529043
Article link: Mol Cell Biol.
Grant support: R01 CA102702 NCI NIH HHS , R01 CA102702 NCI NIH HHS , R01 CA102702 NCI NIH HHS , R01 CA102702 NCI NIH HHS , R01 CA102702 NCI NIH HHS , R01 CA102702 NCI NIH HHS , R01 NS42197 NINDS NIH HHS

Genes referenced: abl1 apaf1 bcr casp9
Antibodies referenced:
Morpholinos referenced:

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