Up-regulation of Apoptosis Inhibitory Protein IAP-2 by Hypoxia

Abstract

Hypoxia is a key determinant of tissue pathology during tumor development and organ ischemia. However, little is known regarding hypoxic regulation of genes that are directly involved in cell death or death resistance. Here we report the striking induction by severe hypoxia of the anti-apoptotic protein IAP-2. Hypoxic cells with IAP-2 up-regulation became resistant to apoptosis. IAP-2 was induced by hypoxia per se rather than by the secondary effects of hypoxia, including ATP depletion and cell injury. The inductive response did not relate to alterations of cellular redox status or arrest of mitochondrial respiration. On the other hand, IAP-2 induction was attenuated by actinomycin D, suggesting a role for gene transcription. In vitro nuclear run-on assays demonstrated specific increases in IAP-2 transcriptional activity after hypoxia exposure. HIF-1, the primary transcription factor that 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 degrees of hypoxia; severe hypoxia or anoxia was required for IAP-2 induction. Moreover, 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 suggests the participation of novel hypoxia-responsive transcription mechanisms.

Hypoxia increases normal prostate epithelial cell resistance to receptor‐mediated apoptosis via AKT activation

“…Up regulation of cIAP2 was identified supporting previous studies in rat kidney proximal tubule cells, 26 which had used a chemical inducer of hypoxia, OXYRASE. There was no change in cIAP1 and interestingly there was a decreased expression of XIAP and Survivin, which could contribute to the eventual induction of apoptosis in these cells.…”

Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability

“…Products of these genes control the metabolic switch to glycolysis, increase oxygen delivery to tissues by stimulation of angiogenesis and erythropoiesis, and enhance cellular survival. The expression of most of the genes regulating the adaptive response to hypoxia is HIF-1-dependent (Dong et al, 2001;Semenza, 1999). However, after prolonged and severe hypoxia, for example in such acute pathologies as stroke and myocardial infarction, the above adaptive responses may not be sufficient, and as a result cell death processes are initiated.…”

“…Hypoxia is capable of changing this balance through the activation and repression of pro-and antiapoptotic genes via both HIF-1-dependent and independent mechanisms. Among anti-apoptotic genes, IGF2 (Feldser et al, 1999) and IAP2 (Dong et al, 2001) are induced by hypoxia through HIF1-dependent (7) of tetracycline and either under normal (control) or low serum (7serum) conditions. For details, see text and Materials and methods.…”

Investigation of cavernosal smooth muscle dysfunction in low flow priapism using an in vitro model

“…This suggests that other factors such as hypoxia-inducible factor 23,24 or anti-apoptotic protein 25 might be involved in the initiation of ischaemic cell death before ATP depletion occurs. Investigation of these pathways in priapism is currently in progress in our laboratory.…”