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However, the degree and duration of HIF-1\u03b1 expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1\u03b1 mRNA is suppressed in prolonged hypoxia, suggesting that the control of <jats:italic>HIF1A<\/jats:italic> gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1\u03b1 protein response and the suppression of HIF-1\u03b1 mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1\u03b1 promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1\u03b1 mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1\u03b1- (but not HIF-2\u03b1-) dependent manner. Finally, REST promotes the resolution of HIF-1\u03b1 protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1\u03b1 in prolonged hypoxia, thus contributing to the resolution of the HIF-1\u03b1 response.<\/jats:p>","DOI":"10.1038\/srep17851","type":"journal-article","created":{"date-parts":[[2015,12,9]],"date-time":"2015-12-09T10:28:00Z","timestamp":1449656880000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia"],"prefix":"10.1038","volume":"5","author":[{"given":"Miguel A. 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