Translation from unconventional 5′ start sites drives tumour initiation

Ataman Sendoel, Joshua G. Dunn, Edwin H. Rodriguez, Shruti Naik, Nicholas C. Gomez, Brian Hurwitz, John Levorse, Brian D. Dill, Daniel Schramek, Henrik Molina, Jonathan S. Weissman and Elaine Fuchs ()
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Ataman Sendoel: Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University
Joshua G. Dunn: Howard Hughes Medical Institute, University of California
Edwin H. Rodriguez: Howard Hughes Medical Institute, University of California
Shruti Naik: Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University
Nicholas C. Gomez: Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University
Brian Hurwitz: Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University
John Levorse: Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University
Brian D. Dill: Proteomics Resource Center, The Rockefeller University
Daniel Schramek: Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University
Henrik Molina: Proteomics Resource Center, The Rockefeller University
Jonathan S. Weissman: Howard Hughes Medical Institute, University of California
Elaine Fuchs: Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University

Nature, 2017, vol. 541, issue 7638, 494-499

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature21036

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