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DISC-mediated activation of caspase-2 in DNA damage-induced apoptosis

Abstract

The tumor suppressor p53 protein supports growth arrest and is able to induce apoptosis, a signaling cascade regulated by sequential activation of caspases. Mechanisms that lead from p53 to activation of individual initiator caspases are still unclear. The present model for caspase-2 activation includes PIDDosome complex formation. However, in certain experimental models, elimination of complex constituents PIDD or RAIDD did not significantly influence caspase-2 activation, suggesting the existence of an alternative activation platform for caspase-2. Here we have investigated the link between p53 and caspase-2 in further detail and report that the latter is able to utilize the CD95 DISC as an activation platform. The recruitment of caspase-8 to this complex is required for activation of caspase-2. In the experimental system used, the DISC is formed through a distinct, p53-dependent upregulation of CD95. Moreover, we show that caspase-2 and -8 cleave Bid, and that both act simultaneously upstream of mitochondrial cytochrome c release. Finally, a direct interaction between the two caspases and the ability of caspase-8 to cleave caspase-2 are demonstrated. Thus, the observed functional link between caspase-8 and -2 within the DISC represents an alternative mechanism to the PIDDosome for caspase-2 activation in response to DNA damage.

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Abbreviations

5-FU:

5-fluorouracil

DISC:

death-inducing signaling complex

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Acknowledgements

We thank Professor PH Krammer and Dr IN Lavrik (German Cancer Research Center, Heidelberg, Germany) for Abs and Dr GP Nolan (Stanford University, Stanford, CA, USA) for the Phoenix-Ampho packaging cell line. We also thank Professor Sten Orrenius for critical review of the paper and permanent support. This study was supported by grants from the Swedish Science Foundation, the Swedish and Stockholm Cancer Societies, the Swedish Childhood Cancer Foundation and the EC-FP-6 (Oncodeath and Chemores) and EC-FP-7 (APO-SYS). MO is a fellow of the Swedish Society of Medical Research.

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Olsson, M., Vakifahmetoglu, H., Abruzzo, P. et al. DISC-mediated activation of caspase-2 in DNA damage-induced apoptosis. Oncogene 28, 1949–1959 (2009). https://doi.org/10.1038/onc.2009.36

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  • DOI: https://doi.org/10.1038/onc.2009.36

Keywords

  • apoptosis
  • caspase-2
  • caspase-8
  • DISC
  • DNA damage

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