title: Oxygen sensing is impaired in ATM-defective cells.
abstract: The transcription factor hypoxia-inducible factor 1α (HIF-1α) is a master regulator of cell adaptation to decreasing oxygen levels. High oxygen tension promotes proteosomal degradation of HIF-1α via a pathway that requires hydroxylation of prolines 402 and 564. Low oxygen tension, hypoxia, inactivates the hydroxylases responsible for these modifications through a mechanism that is not fully understood but appears to require mitochondrial respiration and production of reactive oxygen species, ROS. Cells from individuals affected by ataxia telangiectasia syndrome have an impaired mitochondrial activity and a constitutive oxidative stress. Here we show that, in these cells, HIF-1α is efficiently degraded even in condition of low oxygen tension. Mechanistically this depends from a blunted increase in intracellular concentration of ROS in response to hypoxia which in turn is due to an increased cellular capacity of buffering ROS. We suggest that regulation of HIF-1α stability may depend on fold change of ROS relative to the basal level more than on their absolute value. Since elevated oxidative stress is a hallmark of many human disorders our finding may be relevant to different pathologies.
authors: Istituto di Biologia Cellulare e Neurobiologia CNR and IRCCS Fondazione Santa Lucia, Rome, Italy.
authors: Maria Patrizia
authors: MP
authors: Mongiardi
authors: Venturina
authors: V
authors: Stagni
authors: Manuela
authors: M
authors: Natoli
authors: Danilo
authors: D
authors: Giaccari
authors: Igea
authors: I
authors: D'Agnano
authors: Maria Laura
authors: ML
authors: Falchetti
authors: Daniela
authors: D
authors: Barilà
authors: Andrea
authors: A
authors: Levi
mesh_terms: D001260:Ataxia Telangiectasia / Q000503:physiopathology*; D015687:Cell Hypoxia / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D015151:Immunoblotting; D008156:Luciferases; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D008156:Luciferases; D010100:Oxygen