title: Translation from unconventional 5' start sites drives tumour initiation.
abstract: We are just beginning to understand how translational control affects tumour initiation and malignancy. Here we use an epidermis-specific, in vivo ribosome profiling strategy to investigate the translational landscape during the transition from normal homeostasis to malignancy. Using a mouse model of inducible SOX2, which is broadly expressed in oncogenic RAS-associated cancers, we show that despite widespread reductions in translation and protein synthesis, certain oncogenic mRNAs are spared. During tumour initiation, the translational apparatus is redirected towards unconventional upstream initiation sites, enhancing the translational efficiency of oncogenic mRNAs. An in vivo RNA interference screen of translational regulators revealed that depletion of conventional eIF2 complexes has adverse effects on normal but not oncogenic growth. Conversely, the alternative initiation factor eIF2A is essential for cancer progression, during which it mediates initiation at these upstream sites, differentially skewing translation and protein expression. Our findings unveil a role for the translation of 5' untranslated regions in cancer, and expose new targets for therapeutic intervention.
authors.affiliation: Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Ataman
authors.initials: A
authors.lastname: Sendoel
authors.affiliation: Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA.
authors.forename: Joshua G
authors.initials: JG
authors.lastname: Dunn
authors.affiliation: Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA.
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Rodriguez
authors.affiliation: Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Shruti
authors.initials: S
authors.lastname: Naik
authors.affiliation: Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Gomez
authors.affiliation: Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Hurwitz
authors.affiliation: Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.
authors.forename: John
authors.initials: J
authors.lastname: Levorse
authors.affiliation: Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Dill
authors.affiliation: Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schramek
authors.affiliation: Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Henrik
authors.initials: H
authors.lastname: Molina
authors.affiliation: Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Weissman
authors.affiliation: Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Fuchs
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004817:Epidermis / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D006801:Humans; D015603:Keratinocytes; D008297:Male; D051379:Mice; D009857:Oncogenes / Q000235:genetics; D016366:Open Reading Frames / Q000235:genetics*; D010442:Peptide Chain Initiation, Translational / Q000235:genetics*; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*
chemical_list: D020121:5' Untranslated Regions; D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse