Extrinsic (receptor-mediated) and intrinsic (stress or oxidant-mediated) pathways that initiate apoptosis. Receptors such as CD95 and DR4 initiate apoptosis by interacting with death domain proteins such as FADD or TRADD, leading to the cleavage and activation of procaspase-8 with subsequent activation of downstream caspases and the initiation of the nuclear and cytoplasmic events that comprise apoptosis. In the intrinsic pathway, stress or oxidant-mediated injury leads to activation of proapoptotic BH3 proteins such as BAX or BAK; these then induce disruption of mitochondrial polarity leading to the release of cytochrome c, which binds APAF-1 in the “apoptosome,” leading to cleavage and activation of caspase-9. This then leads to downstream caspase activation. Cross-talk from the extrinsic pathway via the truncation of Bid (to t-Bid) can also elicit disruptions of mitochondrial polarity so that both pathways may be activated. Mitochondrial integrity is regulated by a series of related antiapoptotic (Bcl-2, Bcl-xL) and proapoptotic (Bad, Bax, Bak) proteins. The downstream caspase cascade can be inhibited by inhibitors of apoptosis such as XIAP, cIAP-1, and cIAP-2.
