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

Steve Braunstein; Ksenia Karpisheva; Carolina Pola; Judith Goldberg; Tsivia Hochman; Herman Yee; Joan Cangiarella; Rezina Arju; Silvia C Formenti; Robert J Schneider

doi:10.1016/j.molcel.2007.10.019

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.

Authors

Steve Braunstein¹, Ksenia Karpisheva, Carolina Pola, Judith Goldberg, Tsivia Hochman, Herman Yee, Joan Cangiarella, Rezina Arju, Silvia C Formenti, Robert J Schneider

Affiliation

¹ Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.

PMID: 17996713
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 Cycle Proteins
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
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