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Dis Model Mech. 2015 Feb;8(2):169-81. doi: 10.1242/dmm.017285. Epub 2014 Dec 15.

HIF-1α restricts NF-κB-dependent gene expression to control innate immunity signals.

Author information

1
Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow Street, DD1 5EH, UK.
2
Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, DD1 5EH, UK.
3
Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow Street, DD1 5EH, UK. s.rocha@dundee.ac.uk.

Abstract

Hypoxia and inflammation are intimately linked. It is known that nuclear factor κB (NF-κB) regulates the hypoxia-inducible factor (HIF) system, but little is known about how HIF regulates NF-κB. Here, we show that HIF-1α represses NF-κB-dependent gene expression. HIF-1α depletion results in increased NF-κB transcriptional activity both in mammalian cells and in the model organism Drosophila melanogaster. HIF-1α depletion enhances the NF-κB response, and this required not only the TAK-IKK complex, but also CDK6. Loss of HIF-1α results in an increased angiogenic response in mammalian cancer cells and increased mortality in Drosophila following infection. These results indicate that HIF-1α is required to restrain the NF-κB response, and thus prevents excessive and damaging pro-inflammatory responses.

KEYWORDS:

Drosophila; HIF-1; Hypoxia; IKK; Inflammation; NF-κB

PMID:
25510503
PMCID:
PMC4314782
DOI:
10.1242/dmm.017285
[Indexed for MEDLINE]
Free PMC Article

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