Regulation of the X-linked Inhibitor of Apoptosis Protein (XIAP) expression through alternative non-coding regions

Abstract

The X-linked Inhibitor of Apoptosis Protein (XIAP) counters diverse apoptotic pathways through inhibition of caspases. The levels of XIAP protein can be increased translationally in response to pathophysiological stress, elevating the apoptotic threshold of cells. Here, I have characterized two XIAP mRNA isoforms, which differ only in their 5' untranslated regions. When global translation is attenuated during pathophysiological stress, the translation of one XIAP mRNA isoform is dramatically increased through the action of an Internal Ribosome Entry Site (IRES). In contrast, the second XIAP mRNA isoform supports cap-dependent translation of Xiap, but does not contain a functional IRES element. The physiological relevance and contribution of the XIAP mRNA variants to XIAP protein levels have been examined using RNA Interference, in conjunction with a cellular stress model. The distinct translational activities of these two transcripts under cellular stress suggest a model for a dual mode of XIAP regulation, which may be a common mechanism.