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.

Department of Medical Biosciences Umeå University Building 6M SE 901 85 Umeå Sweden

Inserm UMRS1162 Equipe Labellisée la Ligue Contre le Cancer Institut de Génétique Moléculaire Université Paris 7 Hôpital St Louis 75010 Paris France

RECAMO Masaryk Memorial Cancer Institute Zluty kopec 7 65653 Brno Czech Republic

School of Life Sciences College of Medical Veterinary and Life Sciences University of Glasgow Glasgow G12 8QQ UK

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