XIAP, a member of the Inhibitor-of-Apoptosis Protein (IAP) family, is one of the most potent inhibitors of apoptosis.Increases in protein levels of XIAP in cancer ceils have been associated with resistance to apoptosis induced by cellular stress.Herein we demonstrate that the upregulation of XIAP protein levels is regulated by MDM2 in irradiated cancer cells having overexpression of MDM2.MDM2 was found to physically interact with the internal ribosome entry segment (IRES) of the XIAP 5-untranslated region (5-UTR) in vitro and in vivo, and to positively regulate XIAP IRES activity.In addition, this XIAP IRES-dependent translation was significantly increased in MDM2-transfected cells where MDM2 accumulated in the cytoplasm.Cellular stress and DNA damage triggered by irradiation induced the dephosphorylation of MDM2, resulting in a redistribution of MDM2 from the nucleus to the cytoplasm, which also led to an increase in IRES-dependent XIAP translation.Upregulation of XIAP in MDM2-overexpressing cancer cells in response to irradiation resulted in resistance of these cells to radiation-induced apoptosis.These results identify a novel p53-independent role for MDM2 in regulating the IRES-dependent translation of XIAP during cellular stress, and suggest a critical role for MDM2-mediated XIAP expression in effecting the cellular response to DNA damage.