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Cited by 401Cancer, Hypoxia, and MetabolismErythropoietin and Anemia TreatmentIron Metabolism and Disorders

Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1

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Rolfs, Andreas, Kvietikova, Ivica, Gassmann, Max, Wenger, Roland H.·1997·Journal of Biological Chemistry
DOI 10.1074/jbc.272.32.20055
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Abstract

Transferrin (Tf) is a liver-derived iron transport protein whose plasma concentration increases following exposure to hypoxia. Here, we present a cell culture model capable of expressing Tf mRNA in an oxygen-dependent manner. A 4-kilobase pair Tf promoter/enhancer fragment as well as the 300-base pair liver-specific Tf enhancer alone conveyed hypoxia responsiveness to a heterologous reporter gene construct in hepatoma but not HeLa cells. Within this enhancer, a 32-base pair hypoxia-responsive element was identified, which contained two hypoxia-inducible factor-1 (HIF-1) binding sites (HBSs). Mutation analysis showed that both HBSs function as oxygen-regulated enhancers in Tf-expressing as well as in non-Tf-expressing cell lines. Mutation of both HBSs was necessary to completely abolish hypoxic reporter gene activation. Transient co-expression of the two HIF-1 subunits HIF-1alpha and aryl hydrocarbon receptor nuclear translocator (ARNT)/HIF-1beta resulted in enhanced reporter gene expression even under normoxic conditions. Overexpression of a dominant-negative ARNT/HIF-1beta mutant reduced hypoxic activation. DNA binding studies using nuclear extracts from the mouse hepatoma cell line Hepa1 and the ARNT/HIF-1beta-deficient subline Hepa1C4, as well as antibodies raised against HIF-1alpha and ARNT/HIF-1beta confirmed that HIF-1 binds the Tf HBSs. Mutation analysis and competition experiments suggested that the 5' HBS was more efficient in binding HIF-1 than the 3' HBS. Finally, hypoxic induction of endogenous Tf mRNA was abrogated in Hepa1C4 cells, confirming that HIF-1 confers oxygen regulation of Tf gene expression by binding to the two HBSs present in the Tf enhancer.

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  • All HIFs contribute to transcriptional programs maintaining iron metabolism.

    “Consistent with this, all HIFs contribute to transcriptional programs maintaining iron metabolism [[97], [98], [99]]”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [99]

    The paper reports that HIF-1 binds the transferrin enhancer and mediates oxygen-regulated expression of transferrin, an iron-transport protein (opening section; Discussion; page numbers unavailable). This supports a role for HIF-1 in an iron-related transcriptional response, but not the claim that all HIFs contribute to programs maintaining iron metabolism. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Translation of EPAS1 (HIF-2α) mRNA is regulated by an iron-responsive element in its 5′ UTR, coupling HIF-2 activity to iron availability.

    “Translation of EPAS1 (HIF-2α) mRNA is regulated by an iron-responsive element in its 5′ UTR, coupling HIF-2 activity to iron availability [[97], [98], [99]]”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [99]

    The Discussion considers translational up-regulation as a possible mechanism for HIF-1 activation, but does not address EPAS1 (HIF-2α) or an iron-responsive element in its 5′ UTR. Searches for EPAS1, HIF-2α, and iron-responsive translational regulation found no passage supporting the attributed claim. Page numbers were unavailable in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • 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 [183]

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Research works printed but not linked: 5

  1. Goldberg, M. A., Glass, G. A., Cunningham, J. M., and Bunn, H. F. (1987) Proc. Natl. Acad. Sci. U. S. A. 84, 7972-7976
  2. Wang, G. L., Jiang, B.-H., Rue, E. A., and Semenza, G. L. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 5510 -5514
  3. Maxwell, P. H., Pugh, C. W., and Ratcliffe, P. J. (1993) Proc. Natl. Acad. Sci.
  4. Wang, G. L., and Semenza, G. L. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 4304 -4308
  5. Firth. J. D., Ebert, B. L., Pugh, C. W., and Ratcliffe, P. J. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 6496 -6500

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Authors
Rolfs, A., Kvietikova, I., Gassmann, M., & Wenger, R. H.
Affiliations
University of Zurich (CH)
Corresponding author
Wenger, Roland H.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1997-08
Volume
272
Issue
32
Pages
20055-20062
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.272.32.20055
OpenAlex
W1991047577
Cited by
401
References
44
Citations by year
2026: 3 · 2025: 4 · 2024: 15 · 2023: 15 · 2022: 13 · 2021: 14 · 2020: 23 · 2019: 11 · 2018: 13 · 2017: 9 · 2016: 12 · 2015: 8 · 2014: 12 · 2013: 14 · 2012: 14
FWCI
5.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Keywords
transferrin, HIF-1, HIF-1α, hypoxia response element, hepatoma cells, iron transport proteins, transcriptional regulation, dominant-negative mutant
MeSH terms
Animals, Binding Sites, DNA, DNA-Binding Proteins, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Nuclear Proteins, Oxygen, Repetitive Sequences, Nucleic Acid, RNA, Messenger, Transcription Factors, Transferrin, Tumor Cells, Cultured, Helix-Loop-Helix Motifs, Receptors, Aryl Hydrocarbon, Mice, Aryl Hydrocarbon Receptor Nuclear Translocator, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit

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