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MDM2’s dual mRNA binding domains co-ordinate its oncogenic and tumour suppressor activities

Cell growth requires a high level of protein synthesis and oncogenic pathways stimulate cell proliferation and ribosome biogenesis. Less is known about how cells respond to dysfunctional mRNA translation and how this feeds back into growth regulatory pathways. The Epstein-Barr virus (EBV)-encoded EB...

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Autores principales: Gnanasundram, Sivakumar Vadivel, Malbert-Colas, Laurence, Chen, Sa, Fusée, Leila, Daskalogianni, Chrysoula, Muller, Petr, Salomao, Norman, Fåhraeus, Robin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337897/
https://www.ncbi.nlm.nih.gov/pubmed/32453417
http://dx.doi.org/10.1093/nar/gkaa431
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author Gnanasundram, Sivakumar Vadivel
Malbert-Colas, Laurence
Chen, Sa
Fusée, Leila
Daskalogianni, Chrysoula
Muller, Petr
Salomao, Norman
Fåhraeus, Robin
author_facet Gnanasundram, Sivakumar Vadivel
Malbert-Colas, Laurence
Chen, Sa
Fusée, Leila
Daskalogianni, Chrysoula
Muller, Petr
Salomao, Norman
Fåhraeus, Robin
author_sort Gnanasundram, Sivakumar Vadivel
collection PubMed
description Cell growth requires a high level of protein synthesis and oncogenic pathways stimulate cell proliferation and ribosome biogenesis. Less is known about how cells respond to dysfunctional mRNA translation and how this feeds back into growth regulatory pathways. The Epstein-Barr virus (EBV)-encoded EBNA1 causes mRNA translation stress in cis that activates PI3Kδ. This leads to the stabilization of MDM2, induces MDM2’s binding to the E2F1 mRNA and promotes E2F1 translation. The MDM2 serine 166 regulates the interaction with the E2F1 mRNA and deletion of MDM2 C-terminal RING domain results in a constitutive E2F1 mRNA binding. Phosphorylation on serine 395 following DNA damage instead regulates p53 mRNA binding to its RING domain and prevents the E2F1 mRNA interaction. The p14Arf tumour suppressor binds MDM2 and in addition to preventing degradation of the p53 protein it also prevents the E2F1 mRNA interaction. The data illustrate how two MDM2 domains selectively bind specific mRNAs in response to cellular conditions to promote, or suppress, cell growth and how p14Arf coordinates MDM2’s activity towards p53 and E2F1. The data also show how EBV via EBNA1-induced mRNA translation stress targets the E2F1 and the MDM2 - p53 pathway.
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spelling pubmed-73378972020-07-13 MDM2’s dual mRNA binding domains co-ordinate its oncogenic and tumour suppressor activities Gnanasundram, Sivakumar Vadivel Malbert-Colas, Laurence Chen, Sa Fusée, Leila Daskalogianni, Chrysoula Muller, Petr Salomao, Norman Fåhraeus, Robin Nucleic Acids Res Molecular Biology Cell growth requires a high level of protein synthesis and oncogenic pathways stimulate cell proliferation and ribosome biogenesis. Less is known about how cells respond to dysfunctional mRNA translation and how this feeds back into growth regulatory pathways. The Epstein-Barr virus (EBV)-encoded EBNA1 causes mRNA translation stress in cis that activates PI3Kδ. This leads to the stabilization of MDM2, induces MDM2’s binding to the E2F1 mRNA and promotes E2F1 translation. The MDM2 serine 166 regulates the interaction with the E2F1 mRNA and deletion of MDM2 C-terminal RING domain results in a constitutive E2F1 mRNA binding. Phosphorylation on serine 395 following DNA damage instead regulates p53 mRNA binding to its RING domain and prevents the E2F1 mRNA interaction. The p14Arf tumour suppressor binds MDM2 and in addition to preventing degradation of the p53 protein it also prevents the E2F1 mRNA interaction. The data illustrate how two MDM2 domains selectively bind specific mRNAs in response to cellular conditions to promote, or suppress, cell growth and how p14Arf coordinates MDM2’s activity towards p53 and E2F1. The data also show how EBV via EBNA1-induced mRNA translation stress targets the E2F1 and the MDM2 - p53 pathway. Oxford University Press 2020-07-09 2020-05-26 /pmc/articles/PMC7337897/ /pubmed/32453417 http://dx.doi.org/10.1093/nar/gkaa431 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Molecular Biology
Gnanasundram, Sivakumar Vadivel
Malbert-Colas, Laurence
Chen, Sa
Fusée, Leila
Daskalogianni, Chrysoula
Muller, Petr
Salomao, Norman
Fåhraeus, Robin
MDM2’s dual mRNA binding domains co-ordinate its oncogenic and tumour suppressor activities
title MDM2’s dual mRNA binding domains co-ordinate its oncogenic and tumour suppressor activities
title_full MDM2’s dual mRNA binding domains co-ordinate its oncogenic and tumour suppressor activities
title_fullStr MDM2’s dual mRNA binding domains co-ordinate its oncogenic and tumour suppressor activities
title_full_unstemmed MDM2’s dual mRNA binding domains co-ordinate its oncogenic and tumour suppressor activities
title_short MDM2’s dual mRNA binding domains co-ordinate its oncogenic and tumour suppressor activities
title_sort mdm2’s dual mrna binding domains co-ordinate its oncogenic and tumour suppressor activities
topic Molecular Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337897/
https://www.ncbi.nlm.nih.gov/pubmed/32453417
http://dx.doi.org/10.1093/nar/gkaa431
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