Background

Apoptosis is a regulated physiological process leading to cell death. Caspases, a family of cysteine acid proteases, are central regulators of apoptosis. Initiator caspases are closely coupled to proapoptotic signals. Once activated, these caspases cleave and activate downstream effector caspases, which in turn cleave cytoskeletal and nuclear proteins like PARP, α-fodrin, DFF, and lamin A and induce apoptosis. Cytochrome c released from mitochondria is coupled to the activation of caspase-9, a key initiator caspase. Proapoptotic stimuli include FasL, TNF-α, DNA damage and ER stress. Fas and TNFR activate caspase-8 and -10, DNA damage leads to the activation of caspase-9 and ER stress leads to the calcium-mediated activation of caspase-12. The inhibitor of apoptosis protein family includes XIAP and survivin and functions by binding and inhibiting several caspases. Smac/Diablo, a mitochondrial protein, is released into the cytosol upon mitochondrial stress and competes with caspases for binding of IAPs. The interaction of Smac/Diablo with IAPs relieves the inhibitory effects of IAPs on caspases.

References

[1] Baker, S.J. and Reddy, E.P. (1998) Oncogene 17, 3261-3270.
[2] Budihardjo, I. et al. (1999) Annu. Rev. Cell Dev. Biol. 15, 269-290.
[3] Nakagawa, T. et al. (2000) Nature 403, 98-103.
[4] Deveraux, Q. L. et al. (1998) EMBO J. 17, 2215-2223.
[5] Li, F. et al. (1998) Nature 396, 580-584.
[6] Du, C. et al. (2000) Cell 102, 33-42.