Gnanasundram, S. V., Pyndiah, S., Daskalogianni, C., Armfield, K., Nylander, K., Wilson, J. B. and Fåhraeus, R. (2017) PI3Kδ activates E2F1 synthesis in response to mRNA translation stress. Nature Communications, 8, 2103. (doi: 10.1038/s41467-017-02282-w) (PMID:29235459) (PMCID:PMC5727396)
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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.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by Equipe Labellisée la Ligue Contre le Cancer, the Inserm, the RECAMO projects GACR P206/12/G151, MEYS-NPS I-L01413, Cancerforskningsfonden Norr and Cancerfonden 160598. S.V.G. was supported by la Ligue Contre le Cancer and S.P. by the ARC and PACRI. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Wilson, Professor Joanna and Armfield, Kate |
| Authors: | Gnanasundram, S. V., Pyndiah, S., Daskalogianni, C., Armfield, K., Nylander, K., Wilson, J. B., and Fåhraeus, R. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Life Sciences College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| Journal Name: | Nature Communications |
| Publisher: | Nature Publishing Group |
| ISSN: | 2041-1723 |
| ISSN (Online): | 2041-1723 |
| Copyright Holders: | Copyright © 2017 The Authors |
| First Published: | First published in Nature Communications 8(1):2103 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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