A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer

Mol Cell. 2007 Nov 9;28(3):501-12. doi: 10.1016/j.molcel.2007.10.019.

Abstract

Translational regulation is critical in cancer development and progression. Translation sustains tumor growth and development of a tumor vasculature, a process known as angiogenesis, which is activated by hypoxia. Here we first demonstrate that a majority of large advanced breast cancers overexpress translation regulatory protein 4E-BP1 and initiation factor eIF4G. Using model animal and cell studies, we then show that overexpressed 4E-BP1 and eIF4G orchestrate a hypoxia-activated switch from cap-dependent to cap-independent mRNA translation that promotes increased tumor angiogenesis and growth at the level of selective mRNA translation. Elevated levels of 4E-BP1 trigger hypoxia inhibition of cap-dependent mRNA translation at high-oxygen levels and, with eIF4G, increase selective translation of mRNAs containing internal ribosome entry sites (IRESs) that include key proangiogenic, hypoxia, and survival mRNAs. The switch from cap-dependent to cap-independent mRNA translation facilitates tumor angiogenesis and hypoxia responses in animal models.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adult
  • Animals
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Cell Hypoxia
  • Cell Line, Tumor
  • Eukaryotic Initiation Factor-4G / genetics
  • Eukaryotic Initiation Factor-4G / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein Biosynthesis / physiology*
  • RNA Caps / metabolism
  • RNA, Messenger / metabolism
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • EIF4EBP1 protein, human
  • EIF4G1 protein, human
  • Eukaryotic Initiation Factor-4G
  • Phosphoproteins
  • RNA Caps
  • RNA, Messenger
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A