title: Induction of Epstein-Barr Virus Oncoprotein LMP1 by Transcription Factors AP-2 and Early B Cell Factor.
abstract: Latent membrane protein 1 (LMP1) is a major oncogene essential for primary B cell transformation by Epstein-Barr virus (EBV). Previous studies suggested that some transcription factors, such as PU.1, RBP-Jκ, NF-κB, and STAT, are involved in this expression, but the underlying mechanism is unclear. Here, we identified binding sites for PAX5, AP-2, and EBF in the proximal LMP1 promoter (ED-L1p). We first confirmed the significance of PU.1 and POU domain transcription factor binding for activation of the promoter in latency III. We then focused on the transcription factors AP-2 and early B cell factor (EBF). Interestingly, among the three AP-2-binding sites in the LMP1 promoter, two motifs were also bound by EBF. Overexpression, knockdown, and mutagenesis in the context of the viral genome indicated that AP-2 plays an important role in LMP1 expression in latency II in epithelial cells. In latency III B cells, on the other hand, the B cell-specific transcription factor EBF binds to the ED-L1p and activates LMP1 transcription from the promoter.
  
  
  OBJECTIVE
  Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is crucial for B cell transformation and oncogenesis of other EBV-related malignancies, such as nasopharyngeal carcinoma and T/NK lymphoma. Its expression is largely dependent on the cell type or condition, and some transcription factors have been implicated in its regulation. However, these previous reports evaluated the significance of specific factors mostly by reporter assay. In this study, we prepared point-mutated EBV at the binding sites of such transcription factors and confirmed the importance of AP-2, EBF, PU.1, and POU domain factors. Our results will provide insight into the transcriptional regulation of the major oncogene LMP1.
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan tmurata@med.nagoya-u.ac.jp.|Division of Virology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Murata
authors.affiliation: Division of Virology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Noda
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.|Division of Virology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Narita
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Ashio
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Fumi
authors.initials: F
authors.lastname: Goshima
authors.affiliation: Division of Virology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan.|Division of Microbiology and Oncology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan.
authors.forename: Teru
authors.initials: T
authors.lastname: Kanda
authors.affiliation: Research Center for Infection-associated Cancer, Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo, Japan.|Department of Microbiology, Shimane University Faculty of Medicine, Izumo City, Shimane, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Yoshiyama
authors.affiliation: Division of Virology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tsurumi
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
mesh_terms: D001665:Binding Sites; D002472:Cell Transformation, Viral; D015967:Gene Expression Regulation, Viral; D057809:HEK293 Cells; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009857:Oncogenes; D050809:POU Domain Factors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D050656:Transcription Factor AP-2 / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000235:genetics*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D050809:POU Domain Factors; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D050656:Transcription Factor AP-2; D014763:Viral Matrix Proteins; D000099232:Proto-Oncogene Protein Spi-1; C081976:EBF1 protein, human; C037662:EBV-associated membrane antigen, Epstein-Barr virus
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