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
Services
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 Kurokawa, M.
Right arrow Articles by Kornbluth, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kurokawa, M.
Right arrow Articles by Kornbluth, S.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, September 2008, p. 5494-5506, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00265-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Inhibition of Apoptosome Formation by Suppression of Hsp90β Phosphorylation in Tyrosine Kinase-Induced Leukemias{triangledown}

Manabu Kurokawa, Chen Zhao, Tannishtha Reya, and Sally Kornbluth*

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710

Received 15 February 2008/ Returned for modification 14 April 2008/ Accepted 19 June 2008

Constitutively active tyrosine kinases promote leukemogenesis by increasing cell proliferation and inhibiting apoptosis. However, mechanisms underlying apoptotic inhibition have not been fully elucidated. In many settings, apoptosis occurs by mitochondrial cytochrome c release, which nucleates the Apaf-1/caspase-9 apoptosome. Here we report that the leukemogenic kinases, Bcr-Abl, FLT3/D835Y, and Tel-PDGFRβ, all can inhibit apoptosome function. In cells expressing these kinases, the previously reported apoptosome inhibitor, Hsp90β, bound strongly to Apaf-1, preventing cytochrome c-induced Apaf-1 oligomerization and caspase-9 recruitment. Hsp90β interacted weakly with the apoptosome in untransformed cells. While Hsp90β was phosphorylated at Ser 226/Ser 255 in untransformed cells, phosphorylation was absent in leukemic cells. Expression of mutant Hsp90β (S226A/S255A), which mimics the hypophosphorylated form in leukemic cells, conferred resistance to cytochrome c-induced apoptosome activation in normal cells, reflecting enhanced binding of nonphosphorylatable Hsp90β to Apaf-1. In Bcr-Abl-positive mouse bone marrow cells, nonphosphorylatable Hsp90β expression conferred imatinib (Gleevec) resistance. These data provide an explanation for apoptosome inhibition by activated leukemogenic tyrosine kinases and suggest that alterations in Hsp90β-apoptosome interactions may contribute to chemoresistance in leukemias.

* 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

{triangledown} Published ahead of print on 30 June 2008.

Molecular and Cellular Biology, September 2008, p. 5494-5506, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00265-08
Copyright © 2008, 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]  
  • Matsumiya, T., Imaizumi, T., Yoshida, H., Satoh, K., Topham, M. K., Stafforini, D. M. (2009). The Levels of Retinoic Acid-Inducible Gene I Are Regulated by Heat Shock Protein 90-{alpha}. J. Immunol. 182: 2717-2725 [Abstract] [Full Text]  
  • Ledgerwood, E. C., Morison, I. M. (2009). Targeting the Apoptosome for Cancer Therapy. Clin. Cancer Res. 15: 420-424 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»