Differential Requirements for eIF4E Dose in Normal Development and Cancer

Morgan L. Truitt, Crystal S. Conn, Zhen Shi, Xiaming Pang, Taku Tokuyasu, Alison M. Coady, Youngho Seo, Maria Barna, Davide Ruggero

Research output: Contribution to journalArticlepeer-review

245 Scopus citations

Abstract

eIF4E, the major cap-binding protein, has long been considered limiting for translating the mammalian genome. However, the eIF4E dose requirement at an organismal level remains unexplored. By generating an Eif4e haploinsufficient mouse, we found that a 50% reduction in eIF4E expression, while compatible with normal development and global protein synthesis, significantly impeded cellular transformation. Genome-wide translational profiling uncovered a translational program induced by oncogenic transformation and revealed a critical role for the dose of eIF4E, specifically in translating a network of mRNAs enriched for a unique 5′ UTR signature. In particular, we demonstrate that the dose of eIF4E is essential for translating mRNAs that regulate reactive oxygen species, fueling transformation and cancer cell survival in vivo. Our findings indicate eIF4E is maintained at levels in excess for normal development that are hijacked by cancer cells to drive a translational program supporting tumorigenesis.

Original languageEnglish (US)
Pages (from-to)59-71
Number of pages13
JournalCell
Volume162
Issue number1
DOIs
StatePublished - Jul 2 2015
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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