Figure 1

The Inhibitor of Apoptosis Proteins The human Inhibitor of Apoptosis Protein (IAP) family, originally characterized in baculovirus, currently consists of 6 members: X-Linked Inhibitor of Apoptosis Protein (Xiap), Human Inhibitor of Apoptosis Protein-1 and -2 (Hiap-1, -2), Neuronal Apoptosis Inhibitory Protein (Naip), survivin, and livin. Xiap is a 498-amino acid (~55 kDa) protein and is a potent inhibitor of caspases, including caspase-9, -7, and -3. Xiap contains three Baculoviral Inhibitory Repeat (BIR) domains, which are involved in direct inhibition of target caspases. Furthermore, Xiap contains a C-terminal RING-Zn Finger domain, which contains E3 Ubiquitin Ligase activity. In this regard, Xiap is known to ubiquitinate several target proteins, including caspase-3 and Smac/DIABLO. Xiap is also known to undergo autoubiqutination on Lys322 and Lys328. The role of Xiap's E3 activity in the regulation of apoptosis is unclear. Finally, Xiap is itself cleaved in a caspase-dependent manner during Fas-induced apoptosis. This cleavage occurs at the SESD sequence (amino acids 239–242), located between BIR domains 2 and 3, and results in the production of 2 ~30 kDa fragments of unknown function. Recent data from our laboratory suggests that Xiap is a determinant of cisplatin-mediated chemoresistance, and that the anti-apoptotic effects of Xiap are in part due to upregulation of the PI3K/Akt pathway and to suppression of p53-mediated cell death.