Biochemical pathways of caspase activation during apoptosis

Caspase activation plays a central role in the execution of apoptosis. The key components of the biochemical pathways of caspase activation have been recently elucidated. In this review, we focus on the two most well-studied pathways of caspase activation: the cell surface death receptor pathway and the mitochondria-initiated pathway. In the cell surface death receptor pat hway, activation of caspase-8 following its recruitment to the death-induci ng signaling complex (DISC) is the critical event that transmits the death signal. This event is regulated at several different levels by various vira l and mammalian proteins. Activated caspase-8 can activate downstream caspa ses by direct cleavage or indirectly by cleaving Bid and inducing cytochrom e c release from the mitochondria. In the mitochondrial-initiated pathway, caspase activation is triggered by the formation of a multimeric Apaf-1/cytochrome c complex that is fully fun ctional in recruiting and activating procaspase-9. Activated caspase-9 will then cleave and activate downstream caspases such as caspase-3, -6, and -7 . This pathway is regulated at several steps, including the release of cyto chrome c from the mitochondria, the binding and hydrolysis of dATP/ATP by A paf-1, and the inhibition of caspase activation by the proteins that belong to the inhibitors of apoptosis (IAP).