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Hsp27 negatively regulates cell death by interacting with cytochrome c

Nature Cell Biology volume 2, pages 645–652 (2000)Cite this article

Abstract

Mammalian cells respond to stress by accumulating or activating a set of highly conserved proteins known as heat-shock proteins (HSPs). Several of these proteins interfere negatively with apoptosis. We show that the small HSP known as Hsp27 inhibits cytochrome-c-mediated activation of caspases in the cytosol. Hsp27 does not interfere with granzyme-B-induced activation of caspases, nor with apoptosis-inducing factor-mediated, caspase-independent, nuclear changes. Hsp27 binds to cytochrome c released from the mitochondria to the cytosol and prevents cytochrome-c-mediated interaction of Apaf-1 with procaspase-9. Thus, Hsp27 interferes specifically with the mitochondrial pathway of caspase-dependent cell death.

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Figure 1: Hsp27-mediated inhibition of apoptosis.
Figure 2: Hsp27 inhibits cytochrome c-mediated caspase activation in a cell-free system.
Figure 3: Activation of caspases by granzyme B in cell-free extracts.
Figure 4: Interaction of Hsp27 with the mitochondria.
Figure 5: Influence of Hsp27 on the AIF pathway.
Figure 6: Interaction of Hsp27 with cytochrome c in whole-cell and cell-free extracts.
Figure 7: Influence of Hsp27 on the formation of the apoptosome and determination of the region of Hsp27 necessary for cytochome c binding.

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Acknowledgements

The authors wish to thank Elisabeth Bates, Olivier Sordet and Cédric Rébé for technical help, and Alena Pance and Kathryn Nason-Burchenal for helpful advices. This work was supported by grants from INSERM, Conseil Régional de Bourgogne, ARC (6515 and 5204), Comités de Côte d'Or, Saône et Loire, Nièvre de la Ligue Nationale Contre le Cancer et ARERS (E.S.), as well as special grants from the Ligue Nationale contre le Cancer (G.K. and E.S.).

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Authors and Affiliations

  1. INSERM U-517, Faculty of Medicine and Pharmacy, 7 Boulevard Jeanne d'Arc, Dijon, 21033, France

    Jean-Marie Bruey, Philippe Bonniaud, Sandeep Gurbuxani, Eric Solary & Carmen Garrido

  2. Stress Laboratory, CNRS UMR-5534, 69622 , Villeurbanne, France

    Cécile Ducasse, Chantal Diaz-Latoud & André-Patrick Arrigo

  3. CNRS UMR 1599, Institute Gustave Roussy, Villejuif, 94805, France

    Luigi Ravagnan, Santos A. Susin & Guido Kroemer

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Correspondence to Carmen Garrido.

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Bruey, JM., Ducasse, C., Bonniaud, P. et al. Hsp27 negatively regulates cell death by interacting with cytochrome c. Nat Cell Biol 2, 645–652 (2000). https://doi.org/10.1038/35023595

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