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Bax membrane insertion during Fas(CD95)-induced apoptosis precedes cytochrome c release and is inhibited by Bcl-2

Oncogene volume 18, pages 5991–5999 (1999)Cite this article

Abstract

Ligation of the Fas cell surface receptor leads to activation of caspases and subsequent apoptosis. Members of the Bcl-2 family of proteins control the cellular commitment to apoptosis, although their role in Fas-induced apoptosis is ill-defined. In this report we demonstrate that the pro-apoptotic protein, Bax, translocates from the cytosol specifically to the mitochondria following Fas ligation in MCF10A1 breast epithelial cells. Bax translocation was dependent on caspase activation, and preceded the release of cytochrome c and loss of mitochondrial respiratory activity. Bax translocation occurred in concert with activation of downstream caspases as determined by cleavage of a synthetic substrate, proteolysis of poly(ADP-ribose) polymerase, and processing of procaspase-3 and -7. Overexpression of the anti-apoptotic protein, Bcl-2, prevented Bax insertion, cytochrome c release, complete processing of caspase-3 and -7, and full activation of DEVD-specific cleavage activity. These data establish a role for Bax mitochondrial insertion during Fas-mediated apoptosis, and support a model in which Bax insertion amplifies the Fas apoptotic cascade through cytochrome c release and complete processing of caspases-3 and -7. In addition, our findings indicate that prevention of Bax insertion into the mitochondria represents a novel mechanism by which Bcl-2 inhibits Fas-induced apoptosis.

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Acknowledgements

The authors thank Dr Maria Kavallaris for technical assistance with the immunofluorescence and confocal microscopy. This work was supported by the Children's Cancer Institute Australia for Medical Research which is affiliated with the University of New South Wales and Sydney Children's Hospital. KM Murphy is supported in part by a grant from the DEPSCoR initiative in Kentucky to Uldis N Streips.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Louisville, Louisville, 40292, Kentucky, KY, USA

    Kathleen M Murphy & Uldis N Streips

  2. Children's Cancer Institute Australia for Medical Research, Sydney Children's Hospital, High Street, Randwick, 2031, NSW, Australia

    Richard B Lock

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  2. Uldis N Streips
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Murphy, K., Streips, U. & Lock, R. Bax membrane insertion during Fas(CD95)-induced apoptosis precedes cytochrome c release and is inhibited by Bcl-2. Oncogene 18, 5991–5999 (1999). https://doi.org/10.1038/sj.onc.1203001

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