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Cited by 379Iron Metabolism and DisordersCancer, Hypoxia, and MetabolismErythropoietin and Anemia Treatment

Transferrin Receptor Induction by Hypoxia

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Tacchini, Lorenza, Bianchi, Laura, Bernelli-Zazzera, Aldo, Cairo, Gaetano·1999·Journal of Biological Chemistry
DOI 10.1074/jbc.274.34.24142
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Abstract

The tight relationship between oxygen and iron prompted us to investigate whether the expression of transferrin receptor (TfR), which mediates cellular iron uptake, is regulated by hypoxia. In Hep3B human hepatoma cells incubated in 1% O(2) or treated with CoCl(2), which mimics hypoxia, we detected a 3-fold increase of TfR mRNA despite a decrease of iron regulatory proteins activity. Increased expression resulted from a 4-fold stimulation of the nuclear transcription rate of the TfR gene by both hypoxia and CoCl(2). A role for hypoxia-inducible factor (HIF-1), which activates transcription by binding to hypoxia-responsive elements in the activation of TfR, stems from the following observations. (a) Hypoxia and CoCl(2)-dependent expression of luciferase reporter gene in transiently transfected Hep3B cells was mediated by a fragment of the human TfR promoter containing a putative hypoxia-responsive element sequence, (b) mutation of this sequence prevented hypoxic stimulation of luciferase activity, (c) binding to this sequence of HIF-1alpha, identified by competition experiments and supershift assays, was induced in Hep3B cells by hypoxia and CoCl(2). In erythroid K562 cells, the same treatments did not affect iron regulatory proteins activity, thus resulting in a stimulation of TfR gene expression higher than in hepatoma cells.

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  • Other bona fide HIF-regulated genes involved in iron metabolism include transferrin, TFR1, ceruloplasmin, and heme-oxygenase-1.

    “Other bona fide HIF-regulated genes involved in iron metabolism include transferrin, which transports serum iron in its ferric form (Fe3+), its high affinity receptor TFR1, 183–185 ceruloplasmin, which oxidizes Fe2+ to Fe3+ and is important for iron transport, 186 and heme-oxygenase-1, which is critical for the recycling of iron from phagocytosed erythrocytes.”

    From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [185]

  • Other bona fide HIF-regulated genes involved in iron metabolism include transferrin, TFR1, ceruloplasmin, and heme-oxygenase-1.

    “Other bona fide HIF-regulated genes involved in iron metabolism include transferrin, which transports serum iron in its ferric form (Fe3+), its high affinity receptor TFR1, 183–185 ceruloplasmin, which oxidizes Fe2+ to Fe3+ and is important for iron transport, 186 and heme-oxygenase-1, which is critical for the recycling of iron from phagocytosed erythrocytes.”

    From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [184]

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  1. Rouault, T. A., and Klausner, R. D. (1996) in Stress-inducible Cellular Responses (Feige, U., Morimoto, R. I. Yahara I., and Polla B., eds) pp. 183-197, Birkhauser Verlag, Basel, Switzerland
  2. Hentze, M. W., and Kuhn, L. C. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 8175-8182
  3. Keyse, S. M., and Tyrrel, R. M. (1989) Proc. Natl. Acad. Sci. U. S. A. 86, 99 -103
  4. Leibold, E. A., and Munro, H. N. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 2171-2175

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Authors
Tacchini, L., Bianchi, L., Bernelli-Zazzera, A., & Cairo, G.
Affiliations
University of Milan (IT)
Corresponding author
Cairo, Gaetano
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1999-08
Volume
274
Issue
34
Pages
24142-24146
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.274.34.24142
OpenAlex
W2007919022
Cited by
379
References
38
Citations by year
2026: 10 · 2025: 15 · 2024: 15 · 2023: 17 · 2022: 14 · 2021: 13 · 2020: 17 · 2019: 14 · 2018: 6 · 2017: 16 · 2016: 12 · 2015: 15 · 2014: 7 · 2013: 15 · 2012: 13
FWCI
6.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • INFM-OAR (INFN Catania) (submittedVersion, cc-by)
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
transferrin receptor, hypoxia, HIF-1, HIF-1α, iron regulatory proteins, iron absorption, hypoxia response element, gene transcription, cobalt chloride
MeSH terms
DNA, DNA-Binding Proteins, Gene Expression Regulation, Humans, Iron-Sulfur Proteins, Nuclear Proteins, Promoter Regions, Genetic, Receptors, Transferrin, RNA, Messenger, Transcription Factors, Tumor Cells, Cultured, Transcriptional Activation, Cell Hypoxia, RNA-Binding Proteins, Iron-Regulatory Proteins, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit

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