Journal
JOURNAL OF VIROLOGY
Volume 90, Issue 8, Pages 3873-3889Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.03227-15
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Funding
- Japan Agency for Medical Research and Development (AMED) [15ek0109098]
- Senshin Medical Research Foundation
- Kanae Foundation for Promotion of Medical Science
- General Assembly of the Japanese Association of Medical Sciences
- Institute for Genetic Medicine, Hokkaido University
- Ministry of Education, Culture, Sports, Science, and Technology (MEXT) [23390118, 23114512, 15K08494, 14J01982, 25293109]
- Takeda Science Foundation
- Ministry of Health, Labour and Welfare (MHLW)
- Uehara Memorial Foundation
- Grants-in-Aid for Scientific Research [25293109, 15K08494, 23390118, 14J01982] Funding Source: KAKEN
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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-J kappa, NF-kappa B, 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. IMPORTANCE 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.
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