This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Deming, P. B.
Right arrow Articles by Kornbluth, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Deming, P. B.
Right arrow Articles by Kornbluth, S.

 Previous Article  |  Next Article 

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.



This article has been cited by other articles:

  • Lavallard, V. J., Pradelli, L. A., Paul, A., Beneteau, M., Jacquel, A., Auberger, P., Ricci, J.-E. (2009). Modulation of Caspase-Independent Cell Death Leads to Resensitization of Imatinib Mesylate-Resistant Cells. Cancer Res. 69: 3013-3020 [Abstract] [Full Text]  
  • Kurokawa, M., Zhao, C., Reya, T., Kornbluth, S. (2008). Inhibition of Apoptosome Formation by Suppression of Hsp90{beta} Phosphorylation in Tyrosine Kinase-Induced Leukemias. Mol. Cell. Biol. 28: 5494-5506 [Abstract] [Full Text]  
  • Schafer, Z. T., Parrish, A. B., Wright, K. M., Margolis, S. S., Marks, J. R., Deshmukh, M., Kornbluth, S. (2006). Enhanced Sensitivity to Cytochrome c-Induced Apoptosis Mediated by PHAPI in Breast Cancer Cells. Cancer Res. 66: 2210-2218 [Abstract] [Full Text]  
  • Martin, M. C., Allan, L. A., Lickrish, M., Sampson, C., Morrice, N., Clarke, P. R. (2005). Protein Kinase A Regulates Caspase-9 Activation by Apaf-1 Downstream of Cytochrome c. J. Biol. Chem. 280: 15449-15455 [Abstract] [Full Text]  
  • Kharas, M. G., Fruman, D. A. (2005). ABL Oncogenes and Phosphoinositide 3-Kinase: Mechanism of Activation and Downstream Effectors. Cancer Res. 65: 2047-2053 [Abstract] [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»