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Cited by 190Iron Metabolism and DisordersCancer, Hypoxia, and MetabolismErythropoietin and Anemia Treatment

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

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Bianchi, L., Tacchini, L., Cairo, G.·1999·Nucleic Acids Research
DOI 10.1093/nar/27.21.4223PMC PMC148697
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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.

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  • The GAA triplet-repeat expansion in the frataxin gene interferes with frataxin gene transcription because of a self-associated triplex formation at long GAA:TTC repeats (sticky DNA).

    “The GAA triplet-repeat expansion in the frataxin gene was shown to interfere with frataxin gene transcription (223) because of a self-associated triplex formation at long GAA:TTC repeats (sticky DNA) (22, 193, 267, 268).”

    From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [22]

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  1. Casey,J.L., Di Jeso,B., Rao,K., Klausner,R.D. and Harford,J.B. (1988) Proc. Natl Acad. Sci. USA, 85, 1787-1791.
  2. Hentze,M.W. and Kuhn,L.C. (1996) Proc. Natl Acad. Sci. USA, 93, 8175-8182.
  3. Mattia,E., den Blaauwen,J., Ashwell,G. and van Renswoude,J. (1989) Proc. Natl Acad. Sci. USA, 86, 1801-1805.

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Authors
Bianchi, L., Tacchini, L., & Cairo, G.
Affiliations
University of Milan (IT)
Corresponding author
Cairo, G.
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
1999-11-01
Volume
27
Issue
21
Pages
4223-4227
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/27.21.4223
PMC
PMC148697
OpenAlex
W2130304025
Cited by
189
References
33
Citations by year
2026: 3 · 2025: 7 · 2024: 7 · 2023: 12 · 2022: 9 · 2021: 12 · 2020: 8 · 2019: 5 · 2018: 2 · 2017: 3 · 2016: 4 · 2015: 4 · 2014: 4 · 2013: 7 · 2012: 6
FWCI
2.15
Type
journal article
Language
en
Open access
Locations
  • Nucleic Acids Research (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Consiglio Nazionale delle Ricerche
  • Ministero dell'Università e della Ricerca
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Keywords
HIF-1, transferrin receptor, iron chelation, deferoxamine, iron deficiency, hypoxia response element, transcriptional regulation, HIF-1α, hepatoma cells, iron absorption, gene expression
MeSH terms
Iron Deficiencies, Animals, Base Sequence, Cobalt, Deferoxamine, DNA, DNA-Binding Proteins, Carcinoma, Hepatocellular, Humans, Iron, Iron Chelating Agents, Mutation, Nuclear Proteins, Promoter Regions, Genetic, Receptors, Transferrin, Transcription Factors, Transcription, Genetic, Transfection, Tumor Cells, Cultured, Transcriptional Activation, Cell Hypoxia, Response Elements, Mice, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit

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