Journal
PLOS PATHOGENS
Volume 9, Issue 3, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1003186
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Funding
- La Ligue Contre le Cancer (Comite's du Rhone, Drome and Savoie)
- Association pour la Recherche sur le Cancer
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Many studies have proved that oncogenic viruses develop redundant mechanisms to alter the functions of the tumor suppressor p53. Here we show that Epstein-Barr virus (EBV), via the oncoprotein LMP-1, induces the expression of Delta Np73 alpha, a strong antagonist of p53. This phenomenon is mediated by the LMP-1 dependent activation of c-Jun NH2-terminal kinase 1 (JNK-1) which in turn favours the recruitment of p73 to Delta Np73 alpha promoter. A specific chemical inhibitor of JNK-1 or silencing JNK-1 expression strongly down-regulated Delta Np73 alpha mRNA levels in LMP-1-containing cells. Accordingly, LMP-1 mutants deficient to activate JNK-1 did not induce Delta Np73 alpha accumulation. The recruitment of p73 to the Delta Np73 alpha promoter correlated with the displacement of the histone-lysine N-methyltransferase EZH2 which is part of the transcriptional repressive polycomb 2 complex. Inhibition of Delta Np73 alpha expression in lymphoblastoid cells (LCLs) led to the stimulation of apoptosis and up-regulation of a large number of cellular genes as determined by whole transcriptome shotgun sequencing (RNA-seq). In particular, the expression of genes encoding products known to play anti-proliferative/proapoptotic functions, as well as genes known to be deregulated in different B cells malignancy, was altered by Delta Np73 alpha down-regulation. Together, these findings reveal a novel EBV mechanism that appears to play an important role in the transformation of primary B cells.
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