HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation

Laura Bianchi, Lorenza Tacchini, Gaetano Cairo

Research output: Contribution to journalArticle

122 Citations (Scopus)

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-1α, 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.

Original languageEnglish
Pages (from-to)4223-4227
Number of pages5
JournalNucleic Acids Research
Volume27
Issue number21
DOIs
StatePublished - Nov 1 1999
Externally publishedYes

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Transferrin Receptors
Iron
Deferoxamine
Genes
Chelating Agents
Luciferases
Hepatocellular Carcinoma
Hypoxia-Inducible Factor 1
Reporter Genes
Transcriptional Activation
Membrane Proteins
Up-Regulation
Gene Expression
Messenger RNA
Mutation

ASJC Scopus subject areas

  • Genetics

Cite this

HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation. / Bianchi, Laura; Tacchini, Lorenza; Cairo, Gaetano.

In: Nucleic Acids Research, Vol. 27, No. 21, 01.11.1999, p. 4223-4227.

Research output: Contribution to journalArticle

Bianchi, Laura ; Tacchini, Lorenza ; Cairo, Gaetano. / HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation. In: Nucleic Acids Research. 1999 ; Vol. 27, No. 21. pp. 4223-4227.
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