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Journal of Virology, December 2002, p. 12503-12512, Vol. 76, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.24.12503-12512.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Epstein-Barr Virus Immediate-Early Protein BZLF1 Regulates p53 Function through Multiple Mechanisms

Amy Mauser,1 Shin'ichi Saito,2 Ettore Appella,2 Carl W. Anderson,3 William T. Seaman,1 and Shannon Kenney1,4,5*

Lineberger Comprehensive Cancer Center,1 Department of Medicine,4 Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599,5 Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,2 Biology Department, Brookhaven National Laboratory, Upton, New York 119733

Received 13 March 2002/ Accepted 11 September 2002

The Epstein-Barr virus (EBV) immediate-early protein BZLF1 is a transcriptional activator that mediates the switch between the latent and the lytic forms of EBV infection. It was previously reported that BZLF1 inhibits p53 transcriptional function in reporter gene assays. Here we further examined the effects of BZLF1 on p53 function by using a BZLF1-expressing adenovirus vector (AdBZLF1). Infection of cells with the AdBZLF1 vector increased the level of cellular p53 but prevented the induction of p53-dependent cellular target genes, such as p21 and MDM2. BZLF1-expressing cells had increased p53-specific DNA binding activity in electrophoretic mobility shift assays, increased p53 phosphorylation at multiple residues (including serines 6, 9, 15, 33, 46, 315, and 392), and increased acetylation at lysine 320 and lysine 382. Thus, the inhibitory effects of BZLF1 on p53 transcriptional function cannot be explained by its effects on p53 phosphorylation, acetylation, or DNA binding activity. BZLF1 substantially reduced the level of cellular TATA binding protein (TBP) in both normal human fibroblasts and A549 cells, and the inhibitory effects of BZLF1 on p53 transcriptional function could be partially rescued by the overexpression of TBP. Thus, BZLF1 has numerous effects on p53 posttranslational modification but may inhibit p53 transcriptional function in part through an indirect mechanism involving the suppression of TBP expression.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295. Phone: (919) 966-1248. Fax: (919) 966-8212. E-mail: shann{at}med.unc.edu.

Journal of Virology, December 2002, p. 12503-12512, Vol. 76, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.24.12503-12512.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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