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Journal of Virology, November 2006, p. 11200-11208, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.00897-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus EBNA-3C Is Targeted to and Regulates Expression from the Bidirectional LMP-1/2B Promoter

Carmilia Jiménez-Ramírez, Andrew J. Brooks, Linus Plym Forshell, Konstantin Yakimchuk, Bo Zhao, Tacha Zi Fulgham, and Clare E. Sample^*

Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Received 2 May 2006/ Accepted 24 August 2006

Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA-3C) is essential for EBV-mediated immortalization of human B lymphocytes and regulates both the cell cycle and transcription. Transient reporter gene assays have implicated a pivotal role for EBNA-3C in the regulation of transcription of the majority of latency-associated genes expressed during the EBV growth program, including the viral oncoprotein LMP-1. To examine the regulation of latency gene expression by EBNA-3C, we generated an EBV-positive cell line that inducibly expresses EBNA-3C. This cell line allowed us to examine expression from the endogenous latency gene promoters in the context of an actual latent infection and the presence of other EBNA proteins, in particular EBNA-2, which is presumed to coregulate transcription with EBNA-3C. EBNA-3C induced the expression of both LMP-1 and LMP-2B mRNAs from the bidirectional LMP-1/LMP-2B promoter. In contrast, no effect was seen on expression from the common EBNA promoter Cp, which is responsive to EBNA-3C in reporter assays. Activation of LMP expression was not the consequence of increases in EBNA-2, PU.1 or Spi-B transcription factors, all of which are believed to be critical for activation of LMP-1. Chromatin immunoprecipitation assays furthermore indicated that EBNA-3C is present at the bidirectional LMP-1/LMP-2B promoter. These results indicate that EBNA-3C directly activates the expression of LMP-1 and LMP-2B but is unlikely to significantly regulate EBNA expression via Cp under normal growth conditions.

Published ahead of print on 6 September 2006.

Present address: Quality Analytical Laboratories, Department of Biochemistry, Amgen Manufacturing Ltd., Juncos, Puerto Rico.

Present address: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.

Present address: Channing Laboratory, Brigham and Women's Hospital, Boston, Mass.