Small-molecule Inhibitors of HIF-2a Translation Link Its 5'UTR Iron-Responsive Element to Oxygen Sensing

Mol Cell. 2008 Dec 26;32(6):838-48. doi: 10.1016/j.molcel.2008.12.004.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Hypoxia / drug effects
  • Cell Proliferation / drug effects
  • Culture Media, Conditioned
  • Dose-Response Relationship, Drug
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Humans
  • Iron / metabolism*
  • Iron Chelating Agents / pharmacology
  • Iron-Regulatory Proteins / metabolism
  • Oxygen / pharmacology*
  • Protein Binding / drug effects
  • Protein Biosynthesis / drug effects*
  • Protein Kinases / metabolism
  • Protein Stability / drug effects
  • RNA Stability / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Transferrin / genetics
  • Receptors, Transferrin / metabolism
  • Response Elements / genetics*
  • Small Molecule Libraries / analysis
  • Small Molecule Libraries / pharmacology*
  • TOR Serine-Threonine Kinases

Substances

  • 5' Untranslated Regions
  • Basic Helix-Loop-Helix Transcription Factors
  • Culture Media, Conditioned
  • Iron Chelating Agents
  • Iron-Regulatory Proteins
  • RNA, Messenger
  • Receptors, Transferrin
  • Small Molecule Libraries
  • endothelial PAS domain-containing protein 1
  • Iron
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Oxygen

Associated data

  • GEO/GSE13818