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

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

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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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Research works printed but not linked: 3

  1. Semenza, 1992, Mol. Cell. Biol., 12, 5447
  2. Wenger, 1997, Biol. Chem., 378, 609
  3. Chomczynski, 1987, Anal. Biochem., 162, 156, 10.1016/0003-2697(87)90021-2 · DOI

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Metadata

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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