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Mol Cell DOI:10.1016/j.molcel.2008.12.004

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

Publication TypeJournal Article
Year of Publication2008
AuthorsZimmer, M, Ebert, BL, Neil, C, Brenner, K, Papaioannou, I, Melas, A, Tolliday, N, Lamb, J, Pantopoulos, K, Golub, T, Iliopoulos, O
JournalMol Cell
Date Published2008 Dec 26
Keywords5' Untranslated Regions, Basic Helix-Loop-Helix Transcription Factors, Cell Hypoxia, Cell Proliferation, Culture Media, Conditioned, Dose-Response Relationship, Drug, Endothelial Cells, Gene Expression Profiling, Gene Expression Regulation, Humans, Iron, Iron Chelating Agents, Iron-Regulatory Proteins, Oxygen, Protein Binding, Protein Biosynthesis, Protein Kinases, Protein Stability, Receptors, Transferrin, Response Elements, RNA Stability, RNA, Messenger, Small Molecule Libraries, TOR Serine-Threonine Kinases

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.


Alternate JournalMol. Cell
PubMed ID19111663
PubMed Central IDPMC3978139
Grant List5R01CA104574 / CA / NCI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
R01 CA104574 / CA / NCI NIH HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
N01-CO-12400 / CO / NCI NIH HHS / United States