title: Differential Requirements for eIF4E Dose in Normal Development and Cancer.
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.
authors.affiliation: 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.
authors.forename: Morgan L
authors.initials: ML
authors.lastname: Truitt
authors.affiliation: 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.
authors.forename: Crystal S
authors.initials: CS
authors.lastname: Conn
authors.affiliation: Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Xiaming
authors.initials: X
authors.lastname: Pang
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Taku
authors.initials: T
authors.lastname: Tokuyasu
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Coady
authors.affiliation: 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.
authors.forename: Youngho
authors.initials: Y
authors.lastname: Seo
authors.affiliation: Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA. Electronic address: mbarna@stanford.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Barna
authors.affiliation: 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.
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D063646:Carcinogenesis; D002471:Cell Transformation, Neoplastic; D004622:Embryo, Mammalian / Q000378:metabolism*; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics* / Q000378:metabolism*; D018628:Gene Dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014176:Protein Biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D039561:Eukaryotic Initiation Factor-4E; D017382:Reactive Oxygen Species; C000601282:eIF4E protein, mouse