Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.7/533
Título: REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia
Autor: Cavadas, Miguel A. S.
Mesnieres, Marion
Crifo, Bianca
Manresa, Mario C.
Selfridge, Andrew C.
Scholz, Carsten C.
Cummins, Eoin P.
Cheong, Alex
Taylor, Cormac T.
Palavras-chave: Gene regulation
Transcriptional regulatory elements
Data: 9-Dez-2015
Editora: Nature Publishing Group
Citação: Cavadas, M. A. S. et al. REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia. Sci. Rep. 5, 17851; doi: 10.1038/srep17851 (2015).
Resumo: 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.
Peer review: yes
URI: http://hdl.handle.net/10400.7/533
DOI: 10.1038/srep17851
Versão do Editor: http://www.nature.com/articles/srep17851
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