title: Epstein - Barr virus transforming protein LMP-1 alters B cells gene expression by promoting accumulation of the oncoprotein ΔNp73α.
abstract: 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.
authors.affiliation: International Agency for Research on Cancer, World Health Organization, Lyon, France.
authors.forename: Rosita
authors.initials: R
authors.lastname: Accardi
authors.forename: Ikbal
authors.initials: I
authors.lastname: Fathallah
authors.forename: Henri
authors.initials: H
authors.lastname: Gruffat
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mariggiò
authors.forename: Florence
authors.initials: F
authors.lastname: Le Calvez-Kelm
authors.forename: Catherine
authors.initials: C
authors.lastname: Voegele
authors.forename: Birke
authors.initials: B
authors.lastname: Bartosch
authors.forename: Hector
authors.initials: H
authors.lastname: Hernandez-Vargas
authors.forename: James
authors.initials: J
authors.lastname: McKay
authors.forename: Bakary S
authors.initials: BS
authors.lastname: Sylla
authors.forename: Evelyne
authors.initials: E
authors.lastname: Manet
authors.forename: Massimo
authors.initials: M
authors.lastname: Tommasino
mesh_terms: D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism* / Q000821:virology; D002472:Cell Transformation, Viral / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D009687:Nuclear Proteins; D012333:RNA, Messenger; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014763:Viral Matrix Proteins