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  • Original Paper
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Hsp27 functions as a negative regulator of cytochrome c-dependent activation of procaspase-3

Oncogene volume 19, pages 1975–1981 (2000)Cite this article

Abstract

The release of mitochondrial cytochrome c by genotoxic stress induces the formation of a cytosolic complex with Apaf-1 (mammalian CED4 homolog) and thereby the activation of procaspase-3 (cas-3) and procaspase-9 (cas-9). Here we demonstrate that heat-shock protein 27 (Hsp27) inhibits cytochrome c (cyt c)-dependent activation of cas-3. Hsp27 had no effect on cyt c release, Apaf-1 and cas-9 activation. By contrast, our results show that Hsp27 associates with cas-3, but not Apaf-1 or cas-9, and inhibits activation of cas-3 by cas-9-mediated proteolysis. Furthermore, the present results demonstrate that immunodepletion of Hsp27 depletes cas-3. Importantly, treatment of cells with DNA damaging agents dissociates the Hsp27/cas-3 complex and relieves inhibition of cas-3 activation. These findings define a novel function for Hsp27 and provide the first evidence that a heat shock protein represses cas-3 activation.

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Acknowledgements

We thank Dr Lawrence Prochaska for providing antibody to cyt c; Drs Michael Bonneli, Robert Blackburn and Yong Lee for providing L929/Hsp27 cell lines and Hsp27 cDNA; Dr X Wang for anti-Apaf-1 and anti-cas-9 antibodies and Dr. Robert Talanian for cas-3 and cas-9 cDNAs. We also thank Andrew Place for technical assistance. This investigation was supported by PHS Grant CA75216 (SK) and CA29431 (DK) awarded by the National Cancer Institute, DHHS.

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Authors and Affiliations

  1. Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, MA, USA

    Pramod Pandey, Rebecca Farber, Atsuko Nakazawa, Shailendra Kumar, Ajit Bharti, Donald Kufe & Surender Kharbanda

  2. Novartis Pharmaceuticals Corporation, East Hanover, 07936, New Jersey, NJ, USA

    Carlo Nalin

  3. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, 60637, Illinois, IL, USA

    Ralph Weichselbaum

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  1. Pramod Pandey
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Pandey, P., Farber, R., Nakazawa, A. et al. Hsp27 functions as a negative regulator of cytochrome c-dependent activation of procaspase-3. Oncogene 19, 1975–1981 (2000). https://doi.org/10.1038/sj.onc.1203531

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