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

Cavadas, Miguel A.S., Mesnieres, Marion, Crifo, Bianca, Manresa, Mario C., Selfridge, Andrew C., Scholz, Carsten C., Cummins, Eoin P., Cheong, Alex and Taylor, Cormac T. (2015). REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia. Scientific Reports, 5 ,

Abstract

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.

Publication DOI: https://doi.org/10.1038/srep17851
Divisions: Life & Health Sciences > Pharmacy
Life & Health Sciences
Additional Information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ Supplementary Information: http://www.nature.com/article-assets/npg/srep/2015/151209/srep17851/extref/srep17851-s1.pdf
Uncontrolled Keywords: General
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2015-12-09
Authors: Cavadas, Miguel A.S.
Mesnieres, Marion
Crifo, Bianca
Manresa, Mario C.
Selfridge, Andrew C.
Scholz, Carsten C.
Cummins, Eoin P.
Cheong, Alex ( 0000-0003-2482-9078)
Taylor, Cormac T.

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