EPSTEIN — BARR VIRUS LMP1 TRIGGERS THE EXPRESSION OF INHIBITOR OF APOPTOSIS PROTEIN SURVIVIN VIA NFkB AND AP-1 SIGNALING PATHWAYS IN NASOPHARYNGEAL CARCINOMA
To elucidate the anti-apoptotic mechanism of Epstein — Barr virus-encoded LMP1, we investigated whether LMP1 regulated the expression of survivin through NFkB and AP-1 signaling pathways using a tetracycline-regulated LMP1-expressing nasopharyngeal carcinoma (NPC) cell line (Tet-on-LMP1-HNE2), NPC cell line expressing dominant negative ІкВ mutant (DIkB-HNE2), and NPC cell lines expressing various LMP1 mutants — LMP1 del CTARl (carboxyterminal activating region)-HNE2, LMP1 del CTAR2-HNE2, LMP1 del CTAR1 and CTRA2-HNE2. We have shown that the expression of survivin, NFkB activity and AP-1 activity increased after inducible expression of LMP1 with Doxycycline in a dose-dependent manner. LMP1 mutant HNE2 cell lines had different expression levels of survivin. The survivin expression in the cell line expressing wild-type LMP1 was higher than in LMP1 mutant cell lines. After introduction of the dominant-negative mutant of ІкВ (DIkB) or the dominant-negative mutant of AP-1 (c-Jun) (TAM67) into Tet-on-LMPl-HNE2 cells, expression of survivin RNA and protein reduced slightly. After introduction of the dominant-negative mutant of AP-1 (c-Jun) in DIkB-HNE2 cells, survivin expression was significantly inhibited. The results indicated that in NPC cells, LMP1 might trigger the expression of survivin at the RNA and the protein levels via NFkB and AP-1 signalling pathway.
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