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Cited by 384Cancer, Hypoxia, and MetabolismIron Metabolism and DisordersErythropoietin and Anemia Treatment

Identification of a hypoxia response element in the transferrin receptor gene

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Lok, Chun Nam, Ponka, Prem·1999·Journal of Biological Chemistry
DOI 10.1074/jbc.274.34.24147
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Abstract

Expression of the transferrin receptor, which mediates iron uptake from transferrin, is negatively regulated post-transcriptionally by intracellular iron through iron-responsive elements in the 3'-untranslated region of the transferrin receptor mRNA. Transcriptional mechanisms are also involved in receptor expression, but these are poorly understood. In this study we have characterized the transferrin receptor promoter region and identified a functional hypoxia response element that contains a binding site for hypoxia-inducible factor-1 (HIF-1). Exposure of K562 and HeLa cells to hypoxia for 16 h resulted in a 2- to 3-fold increase in transferrin receptor mRNA expression. A motif with multipartite organization similar to the hypoxia response element of a number of hypoxia-inducible genes such as erythropoietin was identified within a 100-base pair sequence upstream of the transcriptional start site. Mutation of a site similar to the consensus HIF-binding site (HBS) in this motif attenuated the hypoxic response by 80%. Transient co-expression of the two HIF-1 subunits (HIF-1alpha and HIF-1beta) enhanced the wild type transferrin receptor promoter activity, but that which contained a mutated HBS yielded no such response. Electrophoretic mobility shift assays revealed that HIF-1 was stimulated and bound to the transferrin receptor HBS upon hypoxic challenge. Our results indicate that the transferrin receptor is a target gene for HIF-1.

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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 [193]

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Authors
Lok, C. N., & Ponka, P.
Affiliations
Jewish General Hospital (CA)
Corresponding author
Ponka, Prem
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1999-08
Volume
274
Issue
34
Pages
24147-24152
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.274.34.24147
OpenAlex
W1967855521
Cited by
380
References
35
Citations by year
2026: 6 · 2025: 11 · 2024: 15 · 2023: 12 · 2022: 17 · 2021: 6 · 2020: 13 · 2019: 11 · 2018: 12 · 2017: 11 · 2016: 8 · 2015: 15 · 2014: 12 · 2013: 19 · 2012: 12
FWCI
5.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Keywords
transferrin receptor, hypoxia response element, HIF-1, transcriptional regulation, iron absorption, promoter analysis, HIF-1α, ARNT, hypoxia, K562 cells, HeLa cells
MeSH terms
Base Sequence, DNA-Binding Proteins, Gene Expression Regulation, HeLa Cells, Humans, Iron, Iron-Sulfur Proteins, Molecular Sequence Data, Nuclear Proteins, Promoter Regions, Genetic, Receptors, Transferrin, Transcription Factors, Cell Hypoxia, RNA-Binding Proteins, K562 Cells, Response Elements, Iron-Regulatory Proteins, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit

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