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.Epstein-Barr virus (EBV) is a human herpesvirus that infects most individuals and causes the clinical syndrome infectious mononucleosis. The EBV genome is commonly found in certain malignancies, including African Burkitt lymphoma, Bcell lymphomas in immunocompromised patients, and nasopharyngeal carcinoma (22,40). The EBV genome is also found in a subset (approximately 10%) of gastric carcinomas (50). The exact role of EBV infection in the development of gastric cancer, if any, remains unclear.Like all herpesviruses, EBV can infect cells in either the latent or the lytic form. While EBV infection in B cells usually results in one of the latent forms of infection, infection of oral epithelial cells (as exemplified by the lateral tongue lesion oral hairy leukoplakia) (39) is normally completely lytic (53). Nevertheless, in the epithelial tumor nasopharyngeal carcinoma, most cells contain the type II form of latent viral infection, and only a small percentage of tumor cells are lytically infected (33). In EBV-positive gastric carcinoma cells, the majority of tumor cells are also found to contain a latent form of viral infection (50). However, the lytic form of EBV infection is also found in a small number of EBV-positive gastric carcinoma cells (18). Whether normal gastric epithelial cells are infected by EBV in healthy individuals remains unknown.During the ...