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Negative regulation of the Apaf-1 apoptosome by Hsp70

Nature Cell Biology volume 2, pages 476483 (2000) | Download Citation

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Abstract

Release of cytochrome c from mitochondria by apoptotic signals induces ATP/dATP-dependent formation of the oligomeric Apaf-1–caspase-9 apoptosome. Here we show that the documented anti-apoptotic effect of the principal heat-shock protein, Hsp70, is mediated through its direct association with the caspase-recruitment domain (CARD) of Apaf-1 and through inhibition of apoptosome formation. The interaction between Hsp70 and Apaf-1 prevents oligomerization of Apaf-1 and association of Apaf-1 with procaspase-9. On the basis of these results, we propose that resistance to apoptosis exhibited by stressed cells and some tumours, which constitutively express high levels of Hsp70, may be due in part to modulation of Apaf-1 function by Hsp70.

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Acknowledgements

We thank the members of Robbins’ laboratory, especially M. Serrano, B. Baldwin, T. Kenniston and J. Mai, for technical support. We also thank Y. Lazebnik and S. H. Kaufmann for Apaf-1 and caspase-9 antibodies, respectively, and R. Morimoto for hsp70 cDNA. This work was supported by NIH grants AG14357 and AG13487 (to E.S.A.) and CA55227 (to P.D.R.).

Correspondence and requests for materials should be addressed to E.S.A.

Author information

Author notes

    • Ayman Saleh
    •  & Srinivasa M. Srinivasula

    These authors contributed equally to this work

    • Paul D. Robbins
    •  & Emad S. Alnemri

    These authors contributed equally to this work

Affiliations

  1. Center for Apoptosis Research and Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA E_Alnemri@lac.jci.tju.edu

    • Ayman Saleh
    • , Srinivasa M. Srinivasula
    •  & Emad S. Alnemri
  2. Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA

    • Ayman Saleh
    • , Levent Balkir
    •  & Paul D. Robbins

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DOI

https://doi.org/10.1038/35019510

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