XIAP: apoptotic brake and promising therapeutic target

The X-linked Inhibitor of Apoptosis, XIAP, is a key member of the newly discovered family of intrinsic inhibitors of apoptosis (IAP) proteins. IAPs block cell death both in vitro and in vivo by virtue of inhibition of distinct caspases. Although other proteins have been identified which inhibit upstream caspases, only the IAPs have been demonstrated to be endogenous repressors of the terminal caspase cascade. In turn, the caspase inhibiting activity of XIAP is negatively regulated by at least two XIAP-interacting proteins, XAF1 and Smac/DIABLO. In addition to the inhibition of caspases, recent discoveries from several laboratories suggest that XIAP is also involved in a number of other biologically significant cellular activities including modulation of receptor-mediated signal transduction and protein ubiquitination. XIAP is also translated by a rare cap-independent mechanism mediated by a specific sequence called IRES (for Internal Ribosome Entry Site) which is found in the XIAP 5(') UTR. XIAP protein is thus synthesized under various conditions of cellular stress such as serum starvation and low dose gamma-irradiation induced apoptosis, conditions that lead to the inhibition of cellular protein synthesis. The multiple biological activities of XIAP, its unique translational and post-translational control and the centrality of the caspase cascade make the control of XIAP expression an exceptionally promising molecular target for modulating apoptosis. Therapeutic benefits can 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 apoptosis induction is the desired outcome.