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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

Authors 

D H ShinS H LiS W YangB L LeeMyung Kyu LeeJ W Park

Publisher 

Wiley-Blackwell

Issue Date 

2009

Citation 

FEBS Journal, vol. 276, no. 13, pp. 3470-3480

Keywords 

factor inhibiting hypoxia-inducible factor (FIH)hypoxia-inducible factor-1 (HIF-1)IκBαnuclear factor-kappaB (NF-κB)protein interaction

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.

ISSN 

1742-464X

Link 

http://dx.doi.org/10.1111/j.1742-4658.2009.07069.x

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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