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Molecular and Cellular Biology, December 2004, p. 10289-10299, Vol. 24, No. 23
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.23.10289-10299.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Bcr-Abl-Mediated Protection from Apoptosis Downstream of Mitochondrial Cytochrome c Release

Paula B. Deming,1,{dagger} Zachary T. Schafer,1,{dagger} Jessica S. Tashker,1 Malia B. Potts,2 Mohanish Deshmukh,2 and Sally Kornbluth1*

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham,1 Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina2

Received 28 June 2004/ Returned for modification 11 August 2004/ Accepted 9 September 2004

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.

* Corresponding author. Mailing address: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813, Durham, NC 27710. Phone: (919) 613-8624. Fax: (919) 681-1005. E-mail: kornb001{at}mc.duke.edu.

{dagger} P.B.D. and Z.T.S. contributed equally to this work.

Molecular and Cellular Biology, December 2004, p. 10289-10299, Vol. 24, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.23.10289-10299.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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