PI3Kδ activates E2F1 synthesis in response to mRNA translation stress

• Published in: Nature communications Vol. 8; no. 1; pp. 2103 - 10
• Main Authors: Gnanasundram, Sivakumar Vadivel, Pyndiah, Slovénie, Daskalogianni, Chrysoula, Armfield, Kate, Nylander, Karin, Wilson, Joanna B., Fåhraeus, Robin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-12-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/337; 631/67; 631/80; Animals; B-cell lymphoma; c-Myc protein; Cell activation; Cell death; Cell growth; Cell Line; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Cellular stress response; Class I Phosphatidylinositol 3-Kinases - genetics; Class I Phosphatidylinositol 3-Kinases - metabolism; Coding; E2F1 Transcription Factor - genetics; E2F1 Transcription Factor - metabolism; Epstein-Barr virus; Epstein-Barr Virus Nuclear Antigens - genetics; Epstein-Barr Virus Nuclear Antigens - metabolism; Gene Expression Regulation, Neoplastic; Herpesvirus 4, Human - genetics; Herpesvirus 4, Human - physiology; Host-Pathogen Interactions - genetics; Humanities and Social Sciences; Humans; Lymphocytes B; Mice; mRNA; multidisciplinary; Myc protein; Neoplasms - genetics; Neoplasms - pathology; Neoplasms - virology; Protein Biosynthesis; Protein synthesis; RNA, Messenger - genetics; Science; Science (multidisciplinary); Stresses; Transcription; Translation; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02282-w

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.
The oncogenic activity of EBNA1 protein is unknown; it contains a glycine and alanine repeat sequence (GAr) which regulates its own translation in
cis
. Here the authors show that GAr stimulates PI3Kδ-mediated induction of
E2F1
translation, leading to c-Myc induction and stimulation of proliferation.