Two routes to apoptosis. In the “intrinsic” cell death pathway, various upstream stimuli, such as activation of p53, induce expression or activation of proapoptotic Bcl-2 family proteins (e.g., Bax, Puma, Noxa) that converge on mitochondria and induce cytochrome c release. In the cytosol, cytochrome c binds Apaf1, which activates caspase-9. In the “extrinsic” pathway, TNF-family receptors trigger caspase-8 activation. Active caspase-8 and caspase-9 cleave and activate caspase-3 and possibly other downstream effector caspases. Caspase-8 can also cleave and activate Bid, resulting in mitochondrial release of cytochrome c. Once activated, downstream caspases can also damage mitochondria, representing a potential amplification mechanism. The putative point of Survivin intervention at caspase-9 is shown. Cdc2 may be required for apoptosis suppression by Survivin. Expression of Cdc2 can be repressed by p53 in G₂-phase. DD, death domain; DED, death effector domain.