REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia


The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1α- (but not HIF-2α-) dependent manner. Finally, REST promotes the resolution of HIF-1α protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1α in prolonged hypoxia, thus contributing to the resolution of the HIF-1α response.

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Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
College of Health & Life Sciences
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Uncontrolled Keywords: General
Publication ISSN: 2045-2322
Last Modified: 29 Apr 2024 07:13
Date Deposited: 11 Jan 2016 12:40
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2015-12-09
Accepted Date: 2015-11-03
Authors: Cavadas, Miguel A.S.
Mesnieres, Marion
Crifo, Bianca
Manresa, Mario C.
Selfridge, Andrew C.
Scholz, Carsten C.
Cummins, Eoin P.
Cheong, Alex (ORCID Profile 0000-0003-2482-9078)
Taylor, Cormac T.



Version: Published Version

License: Creative Commons Attribution

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