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Blood, 1 March 2006, Vol. 107, No. 5, pp. 2070-2078.
Prepublished online as a Blood First Edition Paper on November 29, 2005; DOI 10.1182/blood-2005-05-2053.
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Submitted May 23, 2005
Accepted October 20, 2005
EBV Latency III immortalization program sensitizes B-cells to induction of CD95 mediated apoptosis via LMP1: role of NF- B, STAT1 and p53
Christophe Le Clorennec, Ibtissam Youlyouz-Marfak, Eric Adriaenssens, Jean Coll, Georg W Bornkamm, and Jean Feuillard*
UMR CNRS 6101, Universite de Limoges, Faculte de Medecine, Centre National de la Recherche Scientifique, Limoges, France; Laboratoire Hematologie, CHU Dupuytren, Limoges, France
CNRS UMR 8527, Institut de Biologie de Lille, Lille, France; Universite de Lille I, INSERM 8527, Villeneuve d Ascq, France
CNRS UMR 8527, Institut de Biologie de Lille, Lille, France
Institute of Clinical Molecular Biology and Tumor Genetics, GSF-National Research Center for Environment Health, Munich, Germany
* Corresponding author; email: jean.feuillard{at}chu-limoges.fr.
EBV induces CD95 expression and C95 gene is regulated by NF- B, STAT1 and/or p53. To understand the contribution of these factors in the regulation of CD95 by EBV in lymphoblastoid cells (LCL), we have cloned dominant active I-B , active (STAT1) and inactive (STAT1 ) forms of STAT1, p53, a dominant negative mutant of LMP1 and wild type LMP1 into a novel double inducible episomal vector, pRT-1. These plasmids were stably transfected either into wild type LCLs or in EREB2-5 cells, an LCL with an estrogen-regulatable EBNA2 protein. Inhibition of LMP1 signalling decreased expression of CD95, whereas over-expression of LMP1 markedly increased it. Induction of latency III program in EREB 2-5 cells correlated with activation of NF-B, STAT1 and p53. CD95 expression was regulated by these 3 transcriptional systems. STAT1 and p53 activation were secondary to NF-B activation. CD95 surface expression sensitised EBV-infected B-cells to induction of CD95-mediated apoptosis. In vitro inhibition of CD95-CD95 ligand interaction was found to reverse T-cell killing of EBV infected B-cells. Therefore, LMP1 activation of NF-B sensitises infected B-cells to CD95-mediated apoptosis and renders EBV-latency III immortalised B-cells susceptible to elimination by the immune system, allowing the establishment a host/virus equilibrium.
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