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Small-molecule inhibitors of HIF-2a translation link its 5'UTR iron-responsive element to oxygen sensing
Open accessAbstract
Cells transiently adapt to hypoxia by globally decreasing protein translation. However, specific proteins needed to respond to hypoxia evade this translational repression. The mechanisms of this phenomenon remain unclear. We screened for and identified small molecules that selectively decrease HIF-2a translation in an mTOR-independent manner, by enhancing the binding of Iron-Regulatory Protein 1 (IRP1) to a recently reported iron-responsive element (IRE) within the 5'-untranslated region (UTR) of the HIF-2a message. Knocking down the expression of IRP1 by shRNA abolished the effect of the compounds. Hypoxia derepresses HIF-2a translation by disrupting the IRP1-HIF-2a IRE interaction. Thus, this chemical genetic analysis describes a molecular mechanism by which translation of the HIF-2a message is maintained during conditions of cellular hypoxia through inhibition of IRP-1-dependent repression. It also provides the chemical tools for studying this phenomenon.
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“Consistent with the central role of HIF-2α in the regulation of iron homeostasis, HIF-2α (but not HIF-1α) is also regulated by iron due to the presence of an RNA stem-loop element known as an iron-responsive element (IRE), in the 5’ untranslated region (UTR) of the HIF-2α transcript [22].”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [22]
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Self-citationThe tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
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Self-citationHIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
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Self-citationRegulation of cellular iron metabolism
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Metadata
- Authors
- Zimmer, M., Ebert, B. L., Neil, C., Brenner, K., Papaioannou, I., Melas, A., Tolliday, N., Lamb, J., Pantopoulos, K., Golub, T., & Iliopoulos, O.
- Affiliations
- Massachusetts General Hospital (US)
- Broad Institute (US)
- Harvard University (US)
- Lady Davis Institute for Medical Research (CA)
- Corresponding author
- Iliopoulos, Othon
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2008-12
- Volume
- 32
- Issue
- 6
- Pages
- 838-848
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3978139
- OpenAlex
- W2034427729
- Cited by
- 191
- References
- 65
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 12 · 2020: 13 · 2019: 9 · 2018: 7 · 2017: 6 · 2016: 14 · 2015: 10 · 2014: 16 · 2013: 13 · 2012: 19
- FWCI
- 5.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1725 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Cancer Institute
- Dana-Farber/Harvard Cancer Center
- National Institutes of Health (5R01CA104574)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- iron-responsive element, iron regulatory protein 1, 5' untranslated region, hypoxia, protein synthesis inhibition, oxygen sensing, small molecule inhibitors, chemical genetics, mRNA translation
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Dose-Response Relationship, Drug, Gene Expression Regulation, Humans, Iron, Iron Chelating Agents, Oxygen, Protein Binding, Protein Kinases, Receptors, Transferrin, RNA, Messenger, Protein Biosynthesis, Cell Hypoxia, Culture Media, Conditioned, 5' Untranslated Regions, Response Elements, Gene Expression Profiling, RNA Stability, Iron-Regulatory Proteins, Endothelial Cells, Cell Proliferation, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Small Molecule Libraries, Protein Stability, TOR Serine-Threonine Kinases
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