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

M. Olsson, H. Vakifahmetoglu, P. M. Abruzzo, K. Högstrand, A. Grandien, B. Zhivotovsky

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1949-1959
Number of pages11
Issue number18
Publication statusPublished - May 2009


  • Apoptosis
  • Caspase-2
  • Caspase-8
  • DISC
  • DNA damage

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics


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