Caspase activation: Stepping on the gas or releasing the brakes?

SY30-3 Apoptosis is initiated by activation of caspase-8 (death receptor pathways), or caspase-9 (some developmental, stress and genomic damage pathways). The initiators converge on the direct activation of executioner caspases-3 and 7 by limited proteolysis. Thus, a minimal two step activation cascade is at the heart of apoptosis. Despite the differing triggering events of initiator and executioner caspase activation, we hypothesize a conserved zymogen activation mechanism. This pathway is regulated by endogenous caspase inhibitors: members of the IAP family of zinc finger proteins. These proteins operate as direct fast binding active site directed inhibitors of caspases 3, 7 and 9. We hypothesize that the IAPs regulate cell death by providing a catastrophic threshold that must be exceeded for apoptosis to occur. This talk will consider the extent to which zymogen activation (stepping on the gas) and derepression of IAPs (releasing the breaks) contribute to execution of the apoptotic program.