XIAP: Apoptotic brake and promising therapeutic target

The X-linked Inhibitor of Apoptosis, XIAP, is a key member of the newly dis covered family of intrinsic inhibitors of apoptosis (IAP) proteins. IAPs bl ock cell death both in vitro and in vivo by virtue of inhibition of distinc t caspases. Although other proteins have been identified which inhibit upst ream caspases, only the IAPs have been demonstrated to be endogenous repres sors of the terminal caspase cascade. In turn, the caspase inhibiting activ ity of XIAP is negatively regulated by at least two XIAP-interacting protei ns, XAF1 and Smac/DIABLO. In addition to the inhibition of caspases, recent discoveries from several laboratories suggest that XIAP is also involved i n a number of other biologically significant cellular activities including modulation of receptor-mediated signal transduction and protein ubiquitinat ion. XIAP is also translated by a rare cap-independent mechanism mediated b y a specific sequence called IRES (for Internal Ribosome Entry Site) which is found in the XIAP 5(') UTR. XIAP protein is thus synthesized under vario us conditions of cellular stress such as serum starvation and low dose gamm a -irradiation induced apoptosis, conditions that lead to the inhibition of cellular protein synthesis. The multiple biological activities of XIAP, it s unique translational and post-translational control and the centrality of the caspase cascade make the control of XIAP expression an exceptionally p romising molecular target for modulating apoptosis. Therapeutic benefits ca n be derived from both the suppression of inappropriate cell death such as in neurodegenerative disorders and ischemic injury or in the activation of latent cell death pathways such as in autoimmune disease and cancer where a poptosis induction is the desired outcome.