Abstract
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.
Highlights
Oncogenic viruses like Simian virus 40 (SV40), human papilloma virus (HPV) and adenovirus target the pRb-E2F and the p53 pathways and stimulate cell proliferation [1]
We have previously shown that when the gly-ala repeat (GAr) of the EBNA1 is fused to the 5 coding sequence of mRNAs it causes translation stress in cis and this stimulates cell proliferation by promoting E2F1 synthesis in a PI3K␦dependent fashion [8]
We examined MDM2’s activity towards E2F1 during GAr-induced mRNA translation stress in p53 null H1299 cells and we observed an increase in E2F1 levels following expression of the GAr, that was further enhanced by the expression of MDM2 (similar data was observed with the human MDM2 (HDM2), without significant changes in the E2F1 mRNA levels (Figure 1A, B and Supplementary Figure S1A)
Summary
Oncogenic viruses like Simian virus 40 (SV40), human papilloma virus (HPV) and adenovirus target the pRb-E2F and the p53 pathways and stimulate cell proliferation [1]. We have previously shown that EBNA1 suppresses its own translation in cis to minimize the production of antigenic peptides for the major histocompatibility complex (MHC) class I pathway This causes mRNA translation stress which leads to an increase in cell proliferation and ribosomal biogenesis by stimulating E2F1 synthesis and c-myc expression in a PI3K␦-dependent fashion [4,5,6,7,8,9]. EBNA1 mediates its oncogenic activity by suppressing its own synthesis, which explains why two transgenic animal models show an inverse phenotype between EBNA1 protein expression and tumour phenotype [10,11] Both loss and gain of PI3K␦ function has been linked to immune deficiency syndromes and to affect T and B cell populations but it is detected in non-immune cells. The data illustrate how MDM2, depending on cellular conditions and via different RNA binding domains, binds the p53 or E2F1 mRNAs and thereby acts as an oncogene or tumour suppressor and how p14Arf manages MDM2’s activity towards p53 and E2F1
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