Cited by 191Cancer, Hypoxia, and MetabolismRNA and protein synthesis mechanismsIron Metabolism and Disorders

Small-molecule inhibitors of HIF-2a translation link its 5'UTR iron-responsive element to oxygen sensing

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Zimmer, Michael, Ebert, Benjamin L., Neil, Christopher, Brenner, Keith, Papaioannou, Ioannis, Melas, Antonia, Tolliday, Nicola, Lamb, Justin +3 more·2008·Molecular Cell

Abstract

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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Crossref · 10.1016/j.molcel.2008.12.004

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  • HIF-2α, but not HIF-1α, is regulated by iron through an iron-responsive element in the 5' UTR of its transcript.

    “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].”

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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)
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
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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