Figure 2

The role of IAPs in the regulation of cell death. Apoptosis induced by TNF or Fas ligand via death receptors (DR) involves adaptor-protein-mediated recruitment and activation of initiator caspases, such as caspase 8 (C8), and the subsequent activation of downstream caspases such as caspase 3 (C3) and 7 (not shown). In cell death induced via stress pathways such as irradiation or drugs, cytochrome c (Cyt c) and DIABLO are released from the mitochondria. Cytochrome c binds to the carboxyl terminus of the adaptor protein Apaf-1, allowing it to unfold, interact with inactive caspase 9 (Pro-C9) and promote its oligomerization and autoprocessing to give active C9; active caspase 9 then can activate downstream caspases. Pro-survival members of the Bcl-2 family inhibit cell death via stress pathways and can prevent release of cytochrome c and DIABLO from mitochondria. The downstream caspases cleave cellular substrates (such as poly (ADP-ribose) polymerase (PARP) and inhibitor of caspase-activated DNase (ICAD)), resulting in many morphological changes and culminating in cell death. IAPs prevent cell death by interacting with and inhibiting active caspases, whereas the IAP antagonist DIABLO can prevent these interactions.