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

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.

• Authors: Steve Braunstein, Ksenia Karpisheva, Carolina Pola, Judith Goldberg, Tsivia Hochman, Herman Yee, Joan Cangiarella, Rezina Arju, Silvia C Formenti, Robert J Schneider
• Journal: Molecular cell (Mol Cell) Vol. 28 Issue 3 Pg. 501-12 (Nov 09 2007) ISSN: 1097-2765 [Print] United States
• PMID: 17996713 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

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

Topics

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