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Journal of Virology, November 2004, p. 11798-11806, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.11798-11806.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Inhibition of Epstein-Barr Virus (EBV) Reactivation by Short Interfering RNAs Targeting p38 Mitogen-Activated Protein Kinase or c-myc in EBV-Positive Epithelial Cells

Xiangrong Gao,1 Haoran Wang,2 and Takeshi Sairenji1*

Division of Biosignaling, Department of Biomedical Sciences, School of Life Science, Faculty of Medicine, Tottori University, Yonago, Japan,1 Department of Psychology and Neuroscience Program, University of Toronto, Toronto, Canada2

Received 7 March 2004/ Accepted 15 June 2004

Latent Epstein-Barr virus (EBV) is reactivated by 12-O-tetradecanoylphorbol-13-acetate (TPA) in EBV-infected cells. In this study, we found that TPA up-regulated phosphorylation of p38, a mitogen-activated protein kinase, and activated c-myc mRNA in EBV-positive epithelial GT38 cells. The EBV immediate-early gene BZLF1 mRNA and its product ZEBRA protein were induced following TPA treatment. Protein kinase C inhibitors, 1-(5-isoquinolinesulphonyl)-2, 5-dimethylpiperazine (H7) and staurosporine, inhibited the induction of p38 phosphorylation and the activation of c-Myc by TPA. The p38 inhibitor SB203580 blocked both p38 phosphorylation and ZEBRA expression by TPA. Pretreatment of GT38 cells with the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine inhibited p38 phosphorylation and c-Myc activation by TPA, suggesting that NO may inhibit EBV reactivation via both p38 and c-Myc. By using short interfering RNA (siRNA) targeting either p38 or c-myc, we found that p38 or c-myc siRNA specifically inhibited expression of the respective gene and also suppressed the induction of ZEBRA and EBV early antigen. The interferon (IFN)-responsive gene expression tests ruled out the possibility that the antiviral effect of siRNA is dependent on IFN. Our present study demonstrates for the first time that either p38 or c-myc siRNA can efficiently inhibit TPA-induced EBV reactivation in GT38 cells, indicating that p38- and/or c-myc-associated signaling pathways may play critical roles in the disruption of EBV latency by TPA.

* Corresponding author. Mailing address: Division of Biosignaling, Department of Biomedical Sciences, School of Life Science, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan. Phone: 81 859 34 8041. Fax: 81 859 34 8042. E-mail: sairen{at}grape.med.tottori-u.ac.jp.

Journal of Virology, November 2004, p. 11798-11806, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.11798-11806.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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