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Endoplasmic reticulum localized Bcl-2 prevents apoptosis when redistribution of cytochrome c is a late event

Oncogene volume 20, pages 1939–1952 (2001)Cite this article

Abstract

The disruption of mitochondrial function is a key component of apoptosis in most cell types. Localization of Bcl-2 to the outer mitochondrial and endoplasmic reticulum membranes is consistent with a role in the inhibition of many forms of apoptosis. In Rat-1 cells, a Bcl-2 mutant targeted exclusively to the endoplasmic reticulum (Bcl-cb5) was effective at inhibiting apoptosis induced by serum starvation/myc, or ceramide but not apoptosis induced by etoposide. The former conditions cause a decrease in mitochondrial transmembrane potential (Δψm) as an early event that precedes the release of cytochrome c from mitochondria. By contrast, when cells are exposed to etoposide, a situation in which cytochrome c release and membrane localization of the pro-apoptotic protein Bax precede loss of Δψm, wild type Bcl-2 but not Bcl-cb5 prevents apoptosis. Therefore, Bcl-2 functions in spatially distinct pathways of apoptosis distinguished by the order of cytochrome c release and loss of Δψm.

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Acknowledgements

The authors thank Drs Radhey Gupta and Richard Youle for generously supplying us with antibodies. This work was supported by a Medical Research Council of Canada grant (DW Andrews and B Leber), with additional funds from the Chedoke-McMaster Hospital/DesRoches Bone Marrow Transplant Foundation and a special grant from the Ligue Nationale contre le Cancer (G Kroemer). DWA is the recipient of a Senior Scientist Award from the Medical Research Council of Canada.

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Authors and Affiliations

  1. Department of Biochemistry, McMaster University, Hamilton, L8N 3Z5, Canada

    Matthew G Annis, Weijia Zhu, Brian Leber & David W Andrews

  2. Department of Medicine and Laboratory Medicine, McMaster University, Hamilton, L8N 3Z5, Canada

    Brian Leber

  3. Centre National de la Recherche Scientifique UMR1599, Institut Gustave Roussy, F94805, Villejuif, France

    Naoufal Zamzami & Guido Kroemer

  4. Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, Canada

    Linda Z Penn

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Annis, M., Zamzami, N., Zhu, W. et al. Endoplasmic reticulum localized Bcl-2 prevents apoptosis when redistribution of cytochrome c is a late event. Oncogene 20, 1939–1952 (2001). https://doi.org/10.1038/sj.onc.1204288

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