title: Role of reactive oxygen species in the regulation of HIF-1 by prolyl hydroxylase 2 under mild hypoxia.
abstract: The function and survival of eukaryotic cells depends on a constant and sufficient oxygen supply. Cells recognize and respond to hypoxia by accumulation of the transcription factor hypoxia-inducible factor 1 (HIF-1), composed of an oxygen-sensitive HIF-1α and a constitutive HIF-1β subunit. Besides physiology, HIF-1 induction is involved in major pathological processes such as cardiovascular disease, inflammation and cancer, which are associated with the formation of reactive oxygen species (ROS). ROS have been reported to affect HIF-1 activity but the role for ROS in regulating HIF-1 has not been definitely settled. In order to shed light on the redox-regulation of HIF-1 by ROS, we studied the impact of exogenous ROS treatment (H(2)O(2)) on HIF-1α and HIF-1 regulatory protein prolyl hydroxylase 2 (PHD2) in the human osteosarcoma cell line U2OS. At early reaction periods, H(2)O(2) induced HIF-1α but at prolonged observation phases the opposite occurred. Herein, modulation of PHD activity appeared to be the key element, because knockdown and inhibition of the PHD2 prevented reduction of HIF-1α. However, H(2)O(2) treatment constantly suppressed HIF-1 transactivation at all time-points. Our data indicate a dual redox regulation of HIF-1α protein amount with a constant suppression of HIF-1 target gene expression by ROS.
authors.affiliation: Institut für Physiologie, Universität Duisburg-Essen, Germany.
authors.forename: Helene
authors.initials: H
authors.lastname: Niecknig
authors.forename: Suzan
authors.initials: S
authors.lastname: Tug
authors.forename: Buena Delos
authors.initials: BD
authors.lastname: Reyes
authors.forename: Michael
authors.initials: M
authors.lastname: Kirsch
authors.forename: Joachim
authors.initials: J
authors.lastname: Fandrey
authors.forename: Utta
authors.initials: U
authors.lastname: Berchner-Pfannschmidt
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010084:Oxidation-Reduction; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D051793:Hypoxia-Inducible Factor 1; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases