期刊
ONCOGENE
卷 28, 期 18, 页码 1949-1959出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2009.36
关键词
apoptosis; caspase-2; caspase-8; DISC; DNA damage
资金
- Swedish Science Foundation
- Swedish and Stockholm Cancer Societies
- Swedish Childhood Cancer Foundation
- Swedish Society of Medical Research
- EC-FP-6
- EC-FP-7
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. Oncogene (2009) 28, 1949-1959; doi:10.1038/onc.2009.36; published online 6 April 2009
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