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  • Original Paper
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Bcl-2 targeted to the endoplasmic reticulum can inhibit apoptosis induced by Myc but not etoposide in Rat-1 fibroblasts

Oncogene volume 18, pages 3520–3528 (1999)Cite this article

Abstract

Bcl-2 is a key inhibitor of a broad range of apoptotic pathways, yet neither the mechanism of action nor the role of Bcl-2 subcellular localization are well understood. The subcellular localization of Bcl-2 includes the mitochondrial membrane as well as the contiguous membrane of the endoplasmic reticulum and nuclear envelope. Most studies suggest that the ability of Bcl-2 to confer cell survival is dependent upon its localization to the mitochondria. In this manuscript, we show that Bcl-2 targeted to the endoplasmic reticulum can inhibit Myc-, but not etoposide-induced apoptosis in the Rat-1 fibroblast cell line. By contrast, wild type Bcl-2 can inhibit apoptosis triggered by either death agonist. We further show both Myc and etoposide trigger disruption of mitochondrial membrane potential (MMP) and induce poly-ADP ribose polymerase (PARP) cleavage, but release of calcium was not evident. Bcl-2 abrogates apoptosis at or upstream of MMP depletion showing that Bcl-2 does not have to reside at the mitochondria to prevent apoptosis. These results further elucidate the biochemical events associated with Myc- and etoposide-induced apoptosis and significantly advance our understanding of Bcl-2 function.

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Acknowledgements

We thank Sue Chow and Jim Dimitroulakos for their technical assistance and all members of the Penn lab for critical discussion and review of this manuscript. This research was supported by grants from the National Cancer Institute of Canada (DWH) and the Medical Research Council of Canada (LZP).

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Authors and Affiliations

  1. Department of Medical Biophysics, University of Toronto, Ontario, Canada

    Si Tuen Lee, Klaus P Hoeflich, James R Woodgett, David W Hedley & Linda Z Penn

  2. Divisions of Cellular and Molecular Biology, Ontario Cancer Institute/Princess Margaret Hospital, 610 University Ave., Toronto, M5G 2M9, Ontario, Canada

    Si Tuen Lee, Gihane W Wasfy & Linda Z Penn

  3. Experimental Therapeutics, Ontario Cancer Institute/Princess Margaret Hospital, 610 University Ave., Toronto, M5G 2M9, Ontario, Canada

    Klaus P Hoeflich, James R Woodgett & David W Hedley

  4. Department of Medicine, McMaster University, Hamilton, L8N 3Z5, Ontario, Canada

    Brian Leber

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

    David W Andrews

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Lee, S., Hoeflich, K., Wasfy, G. et al. Bcl-2 targeted to the endoplasmic reticulum can inhibit apoptosis induced by Myc but not etoposide in Rat-1 fibroblasts. Oncogene 18, 3520–3528 (1999). https://doi.org/10.1038/sj.onc.1202716

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