title: Cezanne regulates E2F1-dependent HIF2α expression.
abstract: Mechanisms regulating protein degradation ensure the correct and timely expression of transcription factors such as hypoxia inducible factor (HIF). Under normal O2 tension, HIFα subunits are targeted for proteasomal degradation, mainly through vHL-dependent ubiquitylation. Deubiquitylases are responsible for reversing this process. Although the mechanism and regulation of HIFα by ubiquitin-dependent proteasomal degradation has been the object of many studies, little is known about the role of deubiquitylases. Here, we show that expression of HIF2α (encoded by EPAS1) is regulated by the deubiquitylase Cezanne (also known as OTUD7B) in an E2F1-dependent manner. Knockdown of Cezanne downregulates HIF2α mRNA, protein and activity independently of hypoxia and proteasomal degradation. Mechanistically, expression of the HIF2α gene is controlled directly by E2F1, and Cezanne regulates the stability of E2F1. Exogenous E2F1 can rescue HIF2α transcript and protein expression when Cezanne is depleted. Taken together, these data reveal a novel mechanism for the regulation of the expression of HIF2α, demonstrating that the HIF2α promoter is regulated by E2F1 directly and that Cezanne regulates HIF2α expression through control of E2F1 levels. Our results thus suggest that HIF2α is controlled transcriptionally in a cell-cycle-dependent manner and in response to oncogenic signalling.
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Sonia
authors.initials: S
authors.lastname: Moniz
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bandarra
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: John
authors.initials: J
authors.lastname: Biddlestone
authors.affiliation: Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors.forename: Kirsteen J
authors.initials: KJ
authors.lastname: Campbell
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: David
authors.initials: D
authors.lastname: Komander
authors.affiliation: Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Strasse 15, Frankfurt am Main 60438, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Bremm
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK s.rocha@dundee.ac.uk.
authors.forename: Sonia
authors.initials: S
authors.lastname: Rocha
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D015687:Cell Hypoxia / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D059748:Proteolysis; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050687:E2F1 Transcription Factor; D010450:Endopeptidases; D000099162:Endothelial PAS Domain-Containing Protein 1; C493753:E2F1 protein, human; C476458:OTUD7B protein, human
keywords: Cell cycle; Cezanne; ChIP; E2F1; HIF2α; Hypoxia