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

doi:10.1016/j.cell.2015.05.049

Differential Requirements for eIF4E Dose in Normal Development and Cancer

Cell. 2015 Jul 2;162(1):59-71. doi: 10.1016/j.cell.2015.05.049. Epub 2015 Jun 18.

Authors

Morgan L Truitt¹, Crystal S Conn¹, Zhen Shi², Xiaming Pang¹, Taku Tokuyasu³, Alison M Coady³, Youngho Seo⁴, Maria Barna⁵, Davide Ruggero⁶

Affiliations

¹ Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
² Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
³ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94158, USA.
⁵ Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA. Electronic address: mbarna@stanford.edu.
⁶ Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: davide.ruggero@ucsf.edu.

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.

Publication types

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

MeSH terms

5' Untranslated Regions
Animals
Carcinogenesis
Cell Transformation, Neoplastic*
Embryo, Mammalian / metabolism*
Eukaryotic Initiation Factor-4E / genetics*
Eukaryotic Initiation Factor-4E / metabolism*
Gene Dosage*
Mice
Mice, Inbred C57BL
Mice, Knockout
Protein Biosynthesis
Reactive Oxygen Species / metabolism

Differential Requirements for eIF4E Dose in Normal Development and Cancer

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