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Differential role of caspase-8 and BID activation during radiation- and CD95-induced apoptosis

Oncogene volume 19, pages 1181–1190 (2000)Cite this article

Abstract

Activation of the CD95 death receptor as well as ionizing radiation induces apoptotic cell death in human lymphoma cells. The activation of caspases is a hallmark of apoptosis induction irrespective of the apoptotic trigger. In contrast to death receptor signaling, the exact mechanisms of radiation-induced caspase activation are not well understood. We provide evidence that both, radiation and CD95 stimulation, induce the rapid activation of caspase-8 and BID followed by apoptosis in Jurkat T-cells. To analyse the relative position of caspase-8 within the apoptotic cascade we studied caspase activation and apoptosis in Jurkat cells overexpressing Bcl-2 or Bcl-xL. Caspase-8 activation, pro-apoptotic BID cleavage and apoptosis in response to radiation were abrogated in these cells, while the responses to CD95 stimulation were only partially attenuated by overexpression of Bcl-2 family members. In parallel, the breakdown of the mitochondrial transmembrane potential (ΔΨm) in response to radiation was inhibited by overexpression of Bcl-2/Bcl-xL Jurkat cells genetically deficient for caspase-8 were found to be completely resistant towards CD95. However, radiation-induced apoptotic responses in caspase-8-negative cells displayed only a modest reduction. We conclude that ionizing radiation activates caspase-8 and BID downstream of mitochondrial damage suggesting that, in contrast to CD95, both events function as executioners rather than initiators of the apoptotic process.

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Acknowledgements

This work was supported by a Fortüne grant (No. 560) to C Belka and Deutsche Krebshilfe (Grant No. 10-1452-GU-I) to C Belka and W Budach. We are thankful to J. Blenis (Boston, MA, USA), J Yuan (Boston, MA, USA), H Walczak (Heidelberg, Germany) and CB Thompson (Chicago, IL, USA) for providing essential reagents and cell lines.

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Author notes

  1. W Budach and K Schulze-Osthoff: W Budach and K Schulze-Osthoff share equal senior authorship

Authors and Affiliations

  1. Department of Radiation Oncology, University of Tuebingen, Hoppe Seyler Str. 3, Tuebingen, D-72076, Germany

    C Belka, J Rudner, P Marini, H Faltin, M Bamberg & W Budach

  2. Department of Internal Medicine I, University of Tuebingen, Hoppe Seyler Str. 3, Tuebingen, D-72076, Germany

    S Wesselborg

  3. Department of Physiology I, University of Tuebingen, Hoppe Seyler Str. 3, Tuebingen, D-72076, Germany

    A Lepple-Wienhues

  4. Division of Immunology and Cell Biology, University of Muenster, Germany

    A Stepczynska & K Schulze-Osthoff

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  1. C Belka
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Belka, C., Rudner, J., Wesselborg, S. et al. Differential role of caspase-8 and BID activation during radiation- and CD95-induced apoptosis. Oncogene 19, 1181–1190 (2000). https://doi.org/10.1038/sj.onc.1203401

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