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Inhibition of apoptosome formation by suppression of Hsp90beta phosphorylation in tyrosine kinase-induced leukemias.

Publication ,  Journal Article
Kurokawa, M; Zhao, C; Reya, T; Kornbluth, S
Published in: Molecular and cellular biology
September 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-PDGFRbeta, all can inhibit apoptosome function. In cells expressing these kinases, the previously reported apoptosome inhibitor, Hsp90beta, bound strongly to Apaf-1, preventing cytochrome c-induced Apaf-1 oligomerization and caspase-9 recruitment. Hsp90beta interacted weakly with the apoptosome in untransformed cells. While Hsp90beta was phosphorylated at Ser 226/Ser 255 in untransformed cells, phosphorylation was absent in leukemic cells. Expression of mutant Hsp90beta (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 Hsp90beta to Apaf-1. In Bcr-Abl-positive mouse bone marrow cells, nonphosphorylatable Hsp90beta expression conferred imatinib (Gleevec) resistance. These data provide an explanation for apoptosome inhibition by activated leukemogenic tyrosine kinases and suggest that alterations in Hsp90beta-apoptosome interactions may contribute to chemoresistance in leukemias.

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Published In

Molecular and cellular biology

DOI

EISSN

1098-5549

ISSN

0270-7306

Publication Date

September 2008

Volume

28

Issue

17

Start / End Page

5494 / 5506

Related Subject Headings

  • Pyrimidines
  • Protein-Tyrosine Kinases
  • Protein Binding
  • Piperazines
  • Phosphoserine
  • Phosphorylation
  • Mutant Proteins
  • Mice
  • Leukemia
  • Imatinib Mesylate
 

Citation

APA
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MLA
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Kurokawa, M., Zhao, C., Reya, T., & Kornbluth, S. (2008). Inhibition of apoptosome formation by suppression of Hsp90beta phosphorylation in tyrosine kinase-induced leukemias. Molecular and Cellular Biology, 28(17), 5494–5506. https://doi.org/10.1128/mcb.00265-08
Kurokawa, Manabu, Chen Zhao, Tannishtha Reya, and Sally Kornbluth. “Inhibition of apoptosome formation by suppression of Hsp90beta phosphorylation in tyrosine kinase-induced leukemias.Molecular and Cellular Biology 28, no. 17 (September 2008): 5494–5506. https://doi.org/10.1128/mcb.00265-08.
Kurokawa M, Zhao C, Reya T, Kornbluth S. Inhibition of apoptosome formation by suppression of Hsp90beta phosphorylation in tyrosine kinase-induced leukemias. Molecular and cellular biology. 2008 Sep;28(17):5494–506.
Kurokawa, Manabu, et al. “Inhibition of apoptosome formation by suppression of Hsp90beta phosphorylation in tyrosine kinase-induced leukemias.Molecular and Cellular Biology, vol. 28, no. 17, Sept. 2008, pp. 5494–506. Epmc, doi:10.1128/mcb.00265-08.
Kurokawa M, Zhao C, Reya T, Kornbluth S. Inhibition of apoptosome formation by suppression of Hsp90beta phosphorylation in tyrosine kinase-induced leukemias. Molecular and cellular biology. 2008 Sep;28(17):5494–5506.

Published In

Molecular and cellular biology

DOI

EISSN

1098-5549

ISSN

0270-7306

Publication Date

September 2008

Volume

28

Issue

17

Start / End Page

5494 / 5506

Related Subject Headings

  • Pyrimidines
  • Protein-Tyrosine Kinases
  • Protein Binding
  • Piperazines
  • Phosphoserine
  • Phosphorylation
  • Mutant Proteins
  • Mice
  • Leukemia
  • Imatinib Mesylate