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Journal of Virology, January 2005, p. 745-755, Vol. 79, No. 2
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.2.745-755.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Epstein-Barr Virus Protein BMRF1 Activates Gastrin Transcription

Elizabeth A. Holley-Guthrie,1 William T. Seaman,1 Prasanna Bhende,1 Juanita L. Merchant,2 and Shannon C. Kenney1,3,4*

Lineberger Comprehensive Cancer Center,1 Department of Medicine,3 Department of Immunology and Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,4 Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan2

Received 22 June 2004/ Accepted 23 August 2004

The Epstein-Barr virus (EBV) BMRF1 gene encodes an early lytic protein that functions not only as the viral DNA polymerase processivity factor but also as a transcriptional activator. BMRF1 has been previously shown to activate transcription of an EBV early promoter, BHLF1, though a GC-rich motif which binds to SP1 and ZBP-89, although the exact mechanism for this effect is not known (D. J. Law, S. A. Tarle, and J. L. Merchant, Mamm. Genome 9:165-167, 1998). Here we demonstrate that BMRF1 activates transcription of the cellular gastrin gene in telomerase-immortalized keratinocytes. Furthermore, BMRF1 activated a reporter gene construct driven by the gastrin promoter in a variety of cell types, and this effect was mediated by two SP1/ZBP-89 binding sites in the gastrin promoter. ZBP-89 has been previously shown to negatively regulate the gastrin promoter. However, ZBP-89 can function as either a negative or positive regulator of transcription, depending upon the promoter and perhaps other, as-yet-unidentified factors. BMRF1 increased the binding of ZBP-89 to the gastrin promoter, and a ZBP-89-GAL4 fusion protein was converted into a positive transcriptional regulator by cotransfection with BMRF1. BMRF1 also enhanced the transcriptional activity of an SP1-GAL4 fusion protein. These results suggest that BMRF1 activates target promoters through its effect on both the SP1 and ZBP-89 transcription factors. Furthermore, as the EBV genome is present in up to 10% of gastric cancers, and the different forms of gastrin are growth factors for gastrointestinal epithelium, our results suggest a mechanism by which lytic EBV infection could promote the growth of gastric cells.

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

Journal of Virology, January 2005, p. 745-755, Vol. 79, No. 2
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.2.745-755.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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