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Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2

Oncogene volume 19, pages 2286–2295 (2000)Cite this article

Abstract

Apoptosis involves mitochondrial steps such as the release of the apoptogenic factor cytochrome c which are effectively blocked by Bcl-2. Although Bcl-2 may have a direct action on the mitochondrial membrane, it also resides and functions on the endoplasmic reticulum (ER), and there is increasing evidence for a role of the ER in apoptosis regulation as well. Here we uncover a hitherto unrecognized, apoptotic crosstalk between the ER and mitochondria that is controlled by Bcl-2. After triggering massive ER dilation due to an inhibition of secretion, the drug brefeldin A (BFA) induces the release of cytochrome c from mitochondria in a caspase-8- and Bid-independent manner. This is followed by caspase-3 activation and DNA/nuclear fragmentation. Surprisingly, cytochrome c release by BFA is not only blocked by wild-type Bcl-2 but also by a Bcl-2 variant that is exclusively targeted to the ER (Bcl-2/cb5). Similar findings were obtained with tunicamycin, an agent interfering with N-linked glycosylations in the secretory system. Thus, apoptotic agents perturbing ER functions induce a novel crosstalk between the ER and mitochondria that can be interrupted by ER-based Bcl-2.

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Acknowledgements

We are grateful to Donald Nicholson for anti-caspase-3, Walter Hunziker for anti-Lamp-1 and Peter Krammer for anti-CD95 antibodies. We thank Stephen Sligar and Nica Borgese for providing us with the rat cytochrome b5 cDNA, Danièle Uldry and Marco Celio for performing the electron microscopy, Marco Baggiolini for advice and support and Thomas Kaufmann and Yasodha Natkunam for critically reading the manuscript. This work was supported by grants from the Swiss National Science Foundation (31-46930.96 and 31-34600.92), the Swiss Cancer League (KFS-231-12-95) and the Foundation for Ageing Research, Geneva (AETAS).

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  1. Laurent Monney

    Present address: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, 02115, MA, USA

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  1. Institute of Biochemistry, University of Fribourg, Rue du Musée 5, Fribourg, CH-1700, Switzerland

    Jürg Häcki, Lotti Egger, Laurent Monney, Sébastien Conus, Thierry Rossé, Isabelle Fellay & Christoph Borner

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Häcki, J., Egger, L., Monney, L. et al. Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2. Oncogene 19, 2286–2295 (2000). https://doi.org/10.1038/sj.onc.1203592

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