title: HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation.
abstract: Treatment with iron chelators mimics hypoxic induction of the hypoxia inducible factor (HIF-1) which activates transcription by binding to hypoxia responsive elements (HRE). We investigated whether HIF-1 is involved in transcriptional activation of the transferrin receptor (TfR), a membrane protein which mediates cellular iron uptake, in response to iron deprivation. The transcription rate of the TfR gene in isolated nuclei was up-regulated by treatment of Hep3B human hepatoma cells with the iron chelator desferrioxamine (DFO). The role of HIF-1 in the activation of TfR was indicated by the following observations: (i) DFO-dependent activation of a luciferase reporter gene in transfected Hep3B cells was mediated by a fragment of the human TfR promoter containing a putative HRE sequence; (ii) mutation of this sequence prevented stimulation of luciferase activity; (iii) binding to this sequence of HIF-1alpha, identified by competition experiments and supershift assays, was induced by DFO. Furthermore, in mouse hepatoma cells unable to assemble functional HIF-1, inducibility of TfR transcription by DFO was lost and TfR mRNA up-regulation was reduced. These results, which show the role of HIF-1 in the control of TfR gene expression in conditions of iron depletion, give insights into the mechanisms of transcriptional regulation which concur with the well-characterized post-transcriptional control of TfR expression to expand the extent of response to iron deficiency.
authors.affiliation: Istituto di Patologia Generale and Istituto Scienze Mediche, IRCCS Ospedale Maggiore, Università di Milano, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Bianchi
authors.forename: L
authors.initials: L
authors.lastname: Tacchini
authors.forename: G
authors.initials: G
authors.lastname: Cairo
mesh_terms: D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects; D003035:Cobalt / Q000494:pharmacology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D000090463:Iron Deficiencies; D051379:Mice; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011990:Receptors, Transferrin / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; D009687:Nuclear Proteins; D011990:Receptors, Transferrin; D014157:Transcription Factors; D003035:Cobalt; D004247:DNA; D007501:Iron; C018021:cobaltous chloride; D003676:Deferoxamine