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Nat Commun. 2017 Dec 13;8(1):2103. doi: 10.1038/s41467-017-02282-w.

PI3Kδ activates E2F1 synthesis in response to mRNA translation stress.

Author information

1
Inserm UMRS1162, Equipe Labellisée la Ligue Contre le Cancer, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 75010, Paris, France.
2
School of Life Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
3
Department of Medical Biosciences, Umeå University, Building 6M, SE-901 85, Umeå, Sweden.
4
Inserm UMRS1162, Equipe Labellisée la Ligue Contre le Cancer, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 75010, Paris, France. robin.fahraeus@inserm.fr.
5
Department of Medical Biosciences, Umeå University, Building 6M, SE-901 85, Umeå, Sweden. robin.fahraeus@inserm.fr.
6
RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653, Brno, Czech Republic. robin.fahraeus@inserm.fr.

Abstract

The c-myc oncogene stimulates ribosomal biogenesis and protein synthesis to promote cellular growth. However, the pathway by which cells sense and restore dysfunctional mRNA translation and how this is linked to cell proliferation and growth is not known. We here show that mRNA translation stress in cis triggered by the gly-ala repeat sequence of Epstein-Barr virus (EBV)-encoded EBNA1, results in PI3Kδ-dependent induction of E2F1 mRNA translation with the consequent activation of c-Myc and cell proliferation. Treatment with a specific PI3Kδ inhibitor Idelalisib (CAL-101) suppresses E2F1 and c-Myc levels and causes cell death in EBNA1-induced B cell lymphomas. Suppression of PI3Kδ prevents E2F1 activation also in non-EBV-infected cells. These data illustrate an mRNA translation stress-response pathway for E2F1 activation that is exploited by EBV to promote cell growth and proliferation, offering new strategies to treat EBV-carrying cancers.

PMID:
29235459
PMCID:
PMC5727396
DOI:
10.1038/s41467-017-02282-w
[Indexed for MEDLINE]
Free PMC Article

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