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Contribution of C/EBP Proteins to Epstein-Barr Virus Lytic Gene Expression and Replication in Epithelial Cells

Jian Huang,^1,2 Gangling Liao,¹ Honglin Chen,^1, Frederick Y. Wu,¹ Lindsey Hutt-Fletcher,³ Gary S. Hayward,¹ and S. Diane Hayward^1,2*

Viral Oncology Program, Sidney Kimmel Cancer Center,¹ Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21231,² Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130³

Received 22 July 2005/ Accepted 1 November 2005

The contribution of C/EBP proteins to Epstein-Barr virus (EBV) lytic gene expression and replication in epithelial cells was examined. Nasopharyngeal carcinoma cell lines constitutively expressed C/EBPß and had limited C/EBP expression, while the AGS gastric cancer cell line expressed significant levels of both C/EBP and C/EBPß. Induction of the lytic cycle in EBV-positive AGS/BX1 cells with phorbol ester and sodium butyrate treatment led to a transient stimulation of C/EBPß expression and a prolonged increase in C/EBP expression. In AGS/BX1 cells, endogenous C/EBP and C/EBPß proteins were detected associated with the ZTA and oriLyt promoters but not the RTA promoter. Electrophoretic mobility shift assays confirmed binding of C/EBP proteins to multiple sites in the ZTA and oriLyt promoters. The response of these promoters in reporter assays to transfected C/EBP and C/EBPß proteins was consistent with the promoter binding assays and emphasized the relative importance of C/EBPs for activation of the ZTA promoter. Mutation of the oriLyt promoter proximal C/EBP site had little effect on ZTA activation of the promoter in a reporter assay. However, this mutation impaired oriLyt DNA replication, suggesting a separate replication-specific contribution for C/EBP proteins. Finally, the overall importance of C/EBP proteins for lytic gene expression was demonstrated using CHOP10 to antagonize C/EBP DNA binding activity. Introduction of CHOP10 significantly impaired induction of the ZTA, RTA, and BMRF1 proteins in chemically treated AGS/BX1 cells. Thus, C/EBPß and C/EBP expression are associated with lytic induction in AGS cells, and expression of C/EBP proteins in epithelial cells may contribute to the tendency of these cells to exhibit constitutive low-level ZTA promoter activity.

Present address: Department of Microbiology, The University of Hong Kong, Hong Kong.

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