title: Redox control of iron regulatory protein 2 stability.
abstract: Iron regulatory protein 2 (IRP2) is a critical switch for cellular and systemic iron homeostasis. In iron-deficient or hypoxic cells, IRP2 binds to mRNAs containing iron responsive elements (IREs) and regulates their expression. Iron promotes proteasomal degradation of IRP2 via the F-box protein FBXL5. Here, we explored the effects of oxygen and cellular redox status on IRP2 stability. We show that iron-dependent decay of tetracycline-inducible IRP2 proceeds efficiently under mild hypoxic conditions (3% oxygen) but is compromised in severe hypoxia (0.1% oxygen). A treatment of cells with exogenous H(2)O(2) protects IRP2 against iron and increases its IRE-binding activity. IRP2 is also stabilized during menadione-induced oxidative stress. These data demonstrate that the degradation of IRP2 in iron-replete cells is not only oxygen-dependent but also sensitive to redox perturbations.
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Anja
authors.initials: A
authors.lastname: Hausmann
authors.forename: Julie
authors.initials: J
authors.lastname: Lee
authors.forename: Kostas
authors.initials: K
authors.lastname: Pantopoulos
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004795:Enzyme Stability; D005290:Ferric Compounds / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D035942:Iron Regulatory Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020218:Response Elements; D017262:Siderophores / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D005290:Ferric Compounds; D016877:Oxidants; D000644:Quaternary Ammonium Compounds; D011993:Recombinant Fusion Proteins; D017262:Siderophores; D006861:Hydrogen Peroxide; D007501:Iron; D035942:Iron Regulatory Protein 2; D010100:Oxygen; C013531:ferric ammonium citrate