DISC-mediated activation of caspase-2 in DNA damage-induced apoptosis.
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.
Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
M
M
Olsson
H
H
Vakifahmetoglu
P M
PM
Abruzzo
K
K
Högstrand
A
A
Grandien
B
B
Zhivotovsky
D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000737:chemistry / Q000378:metabolism*; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D004249:DNA Damage; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology; D016158:Genes, p53; D045325:HCT116 Cells; D006801:Humans; D007700:Kinetics; D034741:RNA, Small Interfering / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053418:Death Domain Receptor Signaling Adaptor Proteins; D034741:RNA, Small Interfering; D019014:fas Receptor; D053143:Caspase 2; D053181:Caspase 8; D005472:Fluorouracil