Inhibitor of nuclear factor-kappaB alpha derepresses hypoxia-inducible factor-1 during moderate hypoxia by sequestering factor inhibiting hypoxia-inducible factor from hypo xia-inducible factor 1α

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Title
Inhibitor of nuclear factor-kappaB alpha derepresses hypoxia-inducible factor-1 during moderate hypoxia by sequestering factor inhibiting hypoxia-inducible factor from hypo xia-inducible factor 1α
Author(s)
D H Shin; S H Li; S W Yang; B L Lee; Myung Kyu Lee; J W Park
Bibliographic Citation
FEBS Journal, vol. 276, no. 13, pp. 3470-3480
Publication Year
2009
Abstract
Hypoxia and inflammation often develop concurrently in numerous diseases, and both hypoxia-inducible factor (HIF)-1α and nuclear factorkappaB (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 IκBαon HIF-1α activity was only observed in atmospheres containing 1% or more of oxygen. After tumor necrosis factor-a 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.
Keyword
factor inhibiting hypoxia-inducible factor (FIH)hypoxia-inducible factor-1 (HIF-1)IκBαnuclear factor-kappaB (NF-κB)protein interaction
ISSN
1742-464X
Publisher
Wiley
DOI
http://dx.doi.org/10.1111/j.1742-4658.2009.07069.x
Type
Article
Appears in Collections:
1. Journal Articles > Journal Articles
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