Cited by 294Iron Metabolism and DisordersErythropoietin and Anemia TreatmentRNA and protein synthesis mechanisms

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Iron-regulatory proteins limit hypoxia-inducible factor-2α expression in iron deficiency

Sanchez, Mayka, Galy, Bruno, Muckenthaler, Martina U, Hentze, Matthias W·2007·Nature Structural & Molecular Biology

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Abstract

Hypoxia stimulates erythropoiesis, the major iron-utilization pathway. We report the discovery of a conserved, functional iron-responsive element (IRE) in the 5' untranslated region of the messenger RNA encoding endothelial PAS domain protein-1, EPAS1 (also called hypoxia-inducible factor-2alpha, HIF2alpha). Via this IRE, iron regulatory protein binding controls EPAS1 mRNA translation in response to cellular iron availability. Our results uncover a regulatory link that permits feedback control between iron availability and the expression of a key transcription factor promoting iron utilization. They also show that an IRE that is structurally distinct from, for example, the ferritin mRNA IRE and that has been missed by in silico approaches, can mediate mechanistically similar responses.

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Self-citation
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Authors: Sanchez, M., Galy, B., Muckenthaler, M. U., & Hentze, M. W.
Affiliations: European Molecular Biology Laboratory (DE)
Heidelberg University (DE)
Corresponding author: Muckenthaler, Martina U
Hentze, Matthias W
ORCID: Galy, Bruno
Muckenthaler, Martina U
Hentze, Matthias W
Venue: Nature Structural & Molecular Biology
Publisher: Springer Science and Business Media LLC
Published: 2007-04-08
Volume: 14
Issue: 5
Pages: 420-426
ISSN: 1545-9985 (ISSN-L)
1545-9993
DOI: 10.1038/nsmb1222
OpenAlex: W2008376250
Cited by: 294
References: 51
Citations by year: 2026: 6 · 2025: 19 · 2024: 14 · 2023: 14 · 2022: 19 · 2021: 17 · 2020: 14 · 2019: 12 · 2018: 12 · 2017: 17 · 2016: 7 · 2015: 15 · 2014: 20 · 2013: 21 · 2012: 16
FWCI: 10.48
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Structural & Molecular Biology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords: iron regulatory proteins, HIF-2α, EPAS1, iron-responsive element, iron deficiency, erythropoiesis, iron utilization, mRNA translation regulation, 5' untranslated region, iron availability
MeSH terms: Iron Deficiencies, Endothelial PAS Domain-Containing Protein 1, Gene Expression Regulation, HeLa Cells, Humans, RNA, Messenger, Transcription Factors, Iron Metabolism Disorders, Response Elements, Feedback, Physiological, Iron-Regulatory Proteins, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins

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Iron-regulatory proteins limit hypoxia-inducible factor-2α expression in iron deficiency

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