Anti-apoptotic oncogenes prevent caspase-dependent and independent commitment for cell death (original) (raw)

Cell Death & Differentiation volume 5, pages 298–306 (1998)Cite this article

Abstract

Apoptosis is a morphologically defined type of cell death associated with the activation of certain proteases belonging to the ICE/CED-3 family, known as caspases. Resistance to apoptosis has been implicated as one of the mechanisms that participates in oncogenesis. We found that the broad-spectrum peptide inhibitor of the caspases, zVAD-fmk, interferes in a dose-dependent way with all the morphological and biochemical changes associated with apoptosis induced by anti-CD95 mAb, staurosporine, VP-16 and Act-D. However, with the exception of anti-CD95-triggered apoptosis, the insulted cells lost their clonogenic potential, even when pre-treated with a high dose of zVAD-fmk. Under these circumstances, the dying cells displayed no signs of apoptosis, including activation of caspases, externalization of phosphatidylserine, nuclear condensation, or DNA fragmentation. Instead, this cell death was characterized by cytoplasmic and nuclear vacuolization followed by the loss of plasma membrane integrity. Thus, preventing the onset of apoptosis by blocking caspase activity did not rescue cells from dying in response to drugs such as staurosporine, VP-16 and Act-D. In comparison, ectopic expression of anti-apoptotic oncogenes such as bcl-2 and bcr-abl not only inhibited apoptosis but also preserved the clonogenic potential of the cells. Therefore, oncogenesis is promoted not by simply interfering with caspase-mediated apoptosis, but by preventing an upstream event which we define as the commitment point for cell death.

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  1. Gustavo P Amarante-Mendes
    Present address: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
  2. Seamus J Martin
    Present address: Department of Biology, Molecular Cell Biology Laboratory, Maynooth College, Maynooth, County Kildare, Ireland
  3. Gustavo P Amarante-Mendes and Deborah M Finucane: GP Amarante-Mendes and DM Finucane have contributed equally to this work

Authors and Affiliations

  1. Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, 92121, California, USA
    Gustavo P Amarante-Mendes, Deborah M Finucane, Seamus J Martin & Douglas R Green
  2. Biochemistry Department, Tumor Biology Laboratory, University College Cork, Ireland
    Thomas G Cotter
  3. The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California, USA
    Guy S Salvesen

Authors

  1. Gustavo P Amarante-Mendes
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  2. Deborah M Finucane
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  3. Seamus J Martin
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  4. Thomas G Cotter
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  5. Guy S Salvesen
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  6. Douglas R Green
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Edited by R.A. Knight

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Amarante-Mendes, G., Finucane, D., Martin, S. et al. Anti-apoptotic oncogenes prevent caspase-dependent and independent commitment for cell death.Cell Death Differ 5, 298–306 (1998). https://doi.org/10.1038/sj.cdd.4400354

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