Up-regulation of apoptosis inhibitory protein IAP-2 by hypoxia - HIF-1-independent mechanisms

Hypoxia is a key determinant of tissue pathology during tumor development a nd organ ischemia. However, little is known regarding hypoxic regulation of genes that are directly involved in cell death or death resistance. Here w e report the striking induction by severe hypoxia of the anti-apoptotic pro tein IAP-2. Hypoxic cells with IAP-2 up-regulation became resistant to apop tosis. IAP-2 was induced by hypoxia per se rather than by the secondary eff ects of hypoxia, including ATP depletion and cell injury. The inductive res ponse did not relate to alterations of cellular redox status or arrest of m itochondrial respiration. On the other hand, IAP-2 induction was attenuated by actinomycin D, suggesting a role for gene transcription. In vitro nucle ar run-on assays demonstrated specific increases in IAP-2 transcriptional a ctivity after hypoxia exposure. HIF-1, the primary transcription factor tha t is responsible for multiple gene activation under hypoxia, does not have a role in IAP-2 expression. HIF-1 and IAP-2 were induced by different degre es of hypoxia; severe hypoxia or anoxia was required for IAP-2 induction. M oreover, cobalt chloride and desferrioxamine activated HIF-1 but not IAP-2. Finally, IAP-2 was induced by severe hypoxia in mouse embryonic stem cells that were deficient of HIF-1. Thus, this study not only provides the first demonstration of hypoxic regulation of an anti-apoptotic gene but also sug gests the participation of novel hypoxia-responsive transcription mechanism s.