Overview of apoptosis and the main anti-apoptotic molecules: Binding of death receptors (Fas, TNF-R, TRAIL-R) to their ligands (Fas-L, TNF, TRAIL) initiates the extrinsic apoptotic pathway. Association of adaptor molecules (FADD - Fas-associated death domain protein, TRADD–TNF receptor associated death domain protein) induces the formation of DISC (death inducing signaling complex), which activates caspase 8 and subsequently caspase 3. FLIP is the main anti-apoptotic molecule of this pathway, as it prevents caspase 8 activation. Release of cytochrome c from the mitochondria in response to cellular stress initiates the intrinsic apoptotic pathway. Cytochrome c associates with Apaf-1 and procaspase 9 to form the apoptosome, a multimeric protein complex that induces cleavage of inactive caspase 9 to its active form. Both pathways converge with activation of caspase 3, the main effector caspase. The two pathways are also connected by the ability of active caspase 8 to activate Bid (BH3-interacting domain death agonist) – tBid (truncated Bid) is a proapoptotic molecule that can induce release of cytochrome c from the mitochondria and thus initiate the intrinsic pathway. The two main antiapoptotic families are Bcl2 and IAPs. Anti-apoptotic Bcl2 members maintain mitochondrial integrity, while IAP can inactivate caspases. IAP activity is antagonized by Smac (also known as Diablo), a proapoptotic molecule released from the mitochondria [, , ].
