The DOI matches its Crossref record; 50 of the 51 references it cites were found in a registry or an index.
Iron-regulatory proteins limit hypoxia-inducible factor-2α expression in iron deficiency
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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In the citing paper
“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 [98]
In the citing paper
“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 [98]
In the citing paper
“Indeed the HIF2α mRNA bears an IRE in its 5’UTR (Sanchez et al., 2007)”
From Iron Regulatory Proteins Mediate Host Resistance to Salmonella Infection (2015) · cites this paper as Sanchez et al., 2007
Citations
Cites
Wang, G. L., Jiang, B. H., Rue, E. A., & Semenza, G. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5510 · Cited by 6,212
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180
Oxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068
Semenza, G. L., Jiang, B.-H., Leung, S. W., Passantino, R., Concordet, J.-P., Maire, P., & Giallongo, A. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.51.32529 · Cited by 1,752
Hentze, M. W., Muckenthaler, M. U., & Andrews, N. C. (2004) · Cell · doi:10.1016/s0092-8674(04)00343-5 · Cited by 1,736
Self-citationHIF‐1α is required for solid tumor formation and embryonic vascularization
Ryan, H. E., Lo, J., & Johnson, R. S. (1998) · The EMBO Journal · doi:10.1093/emboj/17.11.3005 · Cited by 1,579
Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch
Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J., & Whitelaw, M. L. (2002) · Science · doi:10.1126/science.1068592 · Cited by 1,558
Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation
Hu, C.-J., Wang, L.-Y., Chodosh, L. A., Keith, B., & Simon, M. C. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.24.9361-9374.2003 · Cited by 1,386
Tian, H., McKnight, S. L., & Russell, D. W. (1997) · Genes & Development · doi:10.1101/gad.11.1.72 · Cited by 1,351
Ema, M., Taya, S., Yokotani, N., Sogawa, K., Matsuda, Y., & Fujii-Kuriyama, Y. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.9.4273 · Cited by 1,016
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1 of the 51 references couldn’t be matched to a known paper.
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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
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
Kaelin, W. G., & Ratcliffe, P. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.009 · Cited by 3,251
Hypoxia-inducible factors and the response to hypoxic stress
Majmundar, A. J., Wong, W. J., & Simon, M. C. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.022 · Cited by 2,380
Two to tango: Regulation of Mammalian iron metabolism
Hentze, M. W., Muckenthaler, M. U., Galy, B., & Camaschella, C. (2010) · Cell · doi:10.1016/j.cell.2010.06.028 · Cited by 2,120
Self-citationHIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Keith, B., Johnson, R. S., & Simon, M. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3183 · Cited by 1,693
Metadata
- 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
- Venue
- Nature Structural & Molecular Biology
- Published
- 2007-04-08
- Volume
- 14
- Issue
- 5
- Pages
- 420-426
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- 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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