Inhibitor of nuclear factor-kappaB alpha derepresses hypoxia-inducible factor-1 during moderate hypoxia by sequestering factor inhibiting hypoxia-inducible factor from hypoxia-inducible factor 1α
2009
Shin, Dong Hoon | Li, Shan Hua | Yang, Seung-Won | Lee, Byung Lan | Lee, Myung Kyu | Park, Jong-Wan
Hypoxia and inflammation often develop concurrently in numerous diseases, and both hypoxia-inducible factor (HIF)-1α and nuclear factor-kappaB (NF-κB) are key transcription factors of stress response genes. An NF-κB inhibitor, inhibitor of NF-κBα (IκBα), was found to interact with factor inhibiting HIF (FIH) and to be hydroxylated by FIH. However, FIH did not functionally regulate IκBα, and the consequence of the FIH-IκBα interaction thus remains uncertain. In the present study, we tested the possibility that IκBα regulates FIH. FIH-IκBα binding was confirmed by yeast two-hybrid and coimmunoprecipitation analyses. Functionally, IκBα expression further enhanced the transcriptional activity of HIF-1α under hypoxic conditions. Furthermore, IκBα knockdown repressed HIF-1α activity. Mechanistically, IκBα derepressed HIF-1α activity by inhibiting the FIH-mediated Asn803 hydroxylation of HIF-1α. It was also found that IκBα activated HIF-1α by sequestering FIH from HIF-1α. However, the effect of IκBα on HIF-1α activity was only observed in atmospheres containing 1% or more of oxygen. After tumor necrosis factor-α treatment, IκBα downregulation, Asn803 hydroxylation and HIF-1α inactivation all occurred up to 8 h, but subsided later. On the basis of these results, we propose that IκBα plays a positive regulatory role during HIF-1-mediated gene expression. Therefore, IκBα, owing to its interactions with NF-κB and HIF-1α, may play a pivotal role in the crosstalk between the molecular events that underlie inflammatory and hypoxic responses.
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