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

Mol Cell
Authors
Keywords
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.

Year of Publication
2008
Journal
Mol Cell
Volume
32
Issue
6
Pages
838-48
Date Published
2008 Dec 26
ISSN
1097-4164
DOI
10.1016/j.molcel.2008.12.004
PubMed ID
19111663
PubMed Central ID
PMC3978139
Links
Grant list
5R01CA104574 / 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