The Epstein-Barr virus protein BMRF1 activates gastrin transcription.
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.
Holley-Guthrie
Elizabeth A
EA
Lineberger Comprehensive Cancer Center, CB # 7295, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Seaman
William T
WT
Bhende
Prasanna
P
Merchant
Juanita L
JL
Kenney
Shannon C
SC
D000956:Antigens, Viral / Q000502:physiology*; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000378:metabolism; D005755:Gastrins / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D000956:Antigens, Viral; D004268:DNA-Binding Proteins; C083204:Epstein-Barr virus early antigen diffuse component; D005755:Gastrins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; C110951:ZNF148 protein, human