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Translation from unconventional 5′ start sites drives tumour initiation


Sendoel, Ataman; Dunn, Joshua G; Rodriguez, Edwin H; Naik, Shruti; Gomez, Nicholas C; Hurwitz, Brian; Levorse, John; Dill, Brian D; Schramek, Daniel; Molina, Henrik; Weissman, Jonathan S; Fuchs, Elaine (2017). Translation from unconventional 5′ start sites drives tumour initiation. Nature, 541(7638):494-499.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:11 January 2017
Deposited On:13 Feb 2017 12:53
Last Modified:26 Mar 2017 05:45
Publisher:Nature Publishing Group
ISSN:0028-0836
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/nature21036
Official URL:http://www.nature.com/nature/journal/v541/n7638/full/nature21036.html
Related URLs:http://www.nature.com/nature/journal/v541/n7638/full/nature21036.html
PubMed ID:28077873

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