title: PRDX2 and PRDX4 are negative regulators of hypoxia-inducible factors under conditions of prolonged hypoxia.
abstract: Hypoxia-inducible factors (HIFs) control the transcription of genes that are crucial for the pathogenesis of cancer and other human diseases. The transcriptional activity of HIFs is rapidly increased upon exposure to hypoxia, but expression of some HIF target genes decreases during prolonged hypoxia. However, the underlying mechanism for feedback inhibition is not completely understood. Here, we report that peroxiredoxin 2 (PRDX2) and PRDX4 interact with HIF-1α and HIF-2α in vitro and in hypoxic HeLa cells. Prolonged hypoxia increases the nuclear translocation of PRDX2 and PRDX4. As a result, PRDX2 and PRDX4 impair HIF-1 and HIF-2 binding to the hypoxia response elements of a subset of HIF target genes, thereby inhibiting gene transcription in cells exposed to prolonged hypoxia. PRDX2 and PRDX4 have no effect on the recruitment of p300 and RNA polymerase II to HIF target genes and the enzymatic activity of PRDX2 and PRDX4 is not required for inhibition of HIF-1 and HIF-2. We also demonstrate that PRDX2 is a direct HIF target gene and that PRDX2 expression is induced by prolonged hypoxia. These findings uncover a novel feedback mechanism for inhibition of HIF transcriptional activity under conditions of prolonged hypoxia.
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.|Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Weibo
authors.initials: W
authors.lastname: Luo
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Chen
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Duah
authors.initials: D
authors.lastname: Alkam
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.|Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Yingfei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004622:Embryo, Mammalian / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008156:Luciferases; D054464:Peroxiredoxins; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C086065:PRDX2 protein, human; C515980:PRDX4 protein, human
keywords: HIFs; PRDX2; PRDX4; transcriptional corepressor
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