Epstein - Barr virus transforming protein LMP-1 alters B cells gene expression by promoting accumulation of the oncoprotein ΔNp73α. - Centre de recherche en cancérologie de Lyon (UMR INSERM 1052 ; CNRS 5286 ; Centre Léon Bérard) Accéder directement au contenu
Article Dans Une Revue PLoS Pathogens Année : 2013

Epstein - Barr virus transforming protein LMP-1 alters B cells gene expression by promoting accumulation of the oncoprotein ΔNp73α.

Rosita Accardi
  • Fonction : Auteur
Ikbal Fathallah
  • Fonction : Auteur
Henri Gruffat
Giuseppe Mariggiò
  • Fonction : Auteur
Catherine Voegele
  • Fonction : Auteur
  • PersonId : 771118
  • IdRef : 193031205
Hector Hernandez-Vargas
Bakary S Sylla
  • Fonction : Auteur
Evelyne Manet

Résumé

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 ΔNp73α, 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 ΔNp73α promoter. A specific chemical inhibitor of JNK-1 or silencing JNK-1 expression strongly down-regulated ΔNp73α mRNA levels in LMP-1-containing cells. Accordingly, LMP-1 mutants deficient to activate JNK-1 did not induce ΔNp73α accumulation. The recruitment of p73 to the ΔNp73α promoter correlated with the displacement of the histone-lysine N-methyltransferase EZH2 which is part of the transcriptional repressive polycomb 2 complex. Inhibition of ΔNp73α 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/pro-apoptotic functions, as well as genes known to be deregulated in different B cells malignancy, was altered by ΔNp73α down-regulation. Together, these findings reveal a novel EBV mechanism that appears to play an important role in the transformation of primary B cells.

Dates et versions

hal-00965878 , version 1 (25-03-2014)

Identifiants

Citer

Rosita Accardi, Ikbal Fathallah, Henri Gruffat, Giuseppe Mariggiò, Florence Le Calvez-Kelm, et al.. Epstein - Barr virus transforming protein LMP-1 alters B cells gene expression by promoting accumulation of the oncoprotein ΔNp73α.. PLoS Pathogens, 2013, 9 (3), pp.e1003186. ⟨10.1371/journal.ppat.1003186⟩. ⟨hal-00965878⟩
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