The DOI matches its Crossref record; 43 of the 44 references it cites were found in a registry or an index.
Oxygen-regulated Transferrin Expression Is Mediated by Hypoxia-inducible Factor-1
Open accessAbstract
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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“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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“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]
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“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]
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Citations
Cites
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Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1
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- Wenger, 1997, Biol. Chem., 378, 609
- Chomczynski, 1987, Anal. Biochem., 162, 156, 10.1016/0003-2697(87)90021-2 · DOI
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Sorted by citations
Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients
Locatelli, F., Fishbane, S. N., Block, G. A., & Macdougall, I. C. (2017) · American Journal of Nephrology · doi:10.1159/000455166 · Cited by 4,836
Regulation of Mammalian O 2 Homeostasis by Hypoxia-Inducible Factor 1
Semenza, G. L. (1999) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.15.1.551 · Cited by 1,914
HIF-1: mediator of physiological and pathophysiological responses to hypoxia
Semenza, G. L. (2000) · Journal of Applied Physiology · doi:10.1152/jappl.2000.88.4.1474 · Cited by 1,822
Hypoxia-Inducible Factor-1 (HIF-1)
Ke, Q., & Costa, M. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.027029 · Cited by 1,690
Wenger, R. H. (2002) · The FASEB Journal · doi:10.1096/fj.01-0944rev · Cited by 1,135
Self-citation
Metadata
- Authors
- Rolfs, A., Kvietikova, I., Gassmann, M., & Wenger, R. H.
- Affiliations
- University of Zurich (CH)
- Corresponding author
- Wenger, Roland H.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1997-08
- Volume
- 272
- Issue
- 32
- Pages
- 20055-20062
- ISSN
- 0021-9258 (ISSN-L)
- 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
- hybrid
- doi.org
- 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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