Abstract
Epstein–Barr Virus (EBV) BamHI-A rightward frame 1 (BARF1) protein is considered a viral oncogene in epithelial cells and has immune-modulating properties. During viral lytic replication BARF1 is expressed as an early gene, regulated by the immediate early EBV protein R. However, in viral latency BARF1 is exclusively expressed in epithelial tumors such as nasopharyngeal (NPC) and gastric carcinoma (GC) but not in lymphomas, indicating that activation of the BARF1 promoter is cell type specific. Undifferentiated NPC is characterized by high expression of ΔNp63 isoforms of the epithelial differentiation marker p63, a member of the p53 family of transcription factors. Transcription factor binding site analysis indicated potential p53 family binding sites within the BARF1 promoter region. This study investigated ability of various p53 family members to transactivate the BARF1 promoter. Using BARF1 promoter luciferase reporter constructs we demonstrate that only p63 isoform ΔNp63α is capable of transactivating the BARF1 promoter, but not the TAp63 isoforms, p53 or p73. Direct promoter binding of ΔNp63α was confirmed by Chromatin Immune Precipitation (ChIP) analysis. Deletion mutants of the BARF1 promoter revealed multiple ΔNp63 response elements to be responsible for BARF1 promoter transactivation. However, ΔNp63α alone was not sufficient to induce BARF1 in tumor cells harboring full EBV genomes, indicating that additional cofactors might be required for full BARF1 regulation. In conclusion, in EBV positive NPC and GC, BARF1 expression might be induced by the epithelial differentiation marker ΔNp63α, explaining BARF1 expression in the absence of lytic reactivation.
Highlights
Epstein–Barr virus (EBV) is associated with several human malignancies of B-cell origin, such as Burkitt’s lymphoma, Hodgkin’s disease and lymphoproliferative disorders in immune- compromised individuals, or epithelial origin such as nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC) [1,2]
In addition to well-studied genes as Epstein-Barr nuclear antigen 1 (EBNA1) [3] and the latent membrane proteins 1 and 2 (LMP1 and LMP2) [2], EBV-associated carcinomas are characterized by the selective expression of BamHI-A rightward frame 1 (BARF1) [4,5,6]
The ∆Np63α isoform was capable of inducing the BARF1 promoter. These findings suggest that BARF1 expression in undifferentiated carcinomas is mediated by the epithelial differentiation marker ∆Np63α
Summary
Epstein–Barr virus (EBV) is associated with several human malignancies of B-cell origin, such as Burkitt’s lymphoma, Hodgkin’s disease and lymphoproliferative disorders in immune- compromised individuals, or epithelial origin such as nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC) [1,2]. In addition to well-studied genes as Epstein-Barr nuclear antigen 1 (EBNA1) [3] and the latent membrane proteins 1 and 2 (LMP1 and LMP2) [2], EBV-associated carcinomas are characterized by the selective expression of BamHI-A rightward frame 1 (BARF1) [4,5,6]. There have been no suggestions in regard to why BARF1 is exclusively expressed in EBV positive epithelial malignancies and not in lymphomas, but the cellular background may point towards a role of dissimilar transcription factors. In this study the potential role of p53 family members in the epithelial restricted expression of EBV protein BARF1 was evaluated. The ∆Np63α isoform was capable of inducing the BARF1 promoter These findings suggest that BARF1 expression in undifferentiated carcinomas is mediated by the epithelial differentiation marker ∆Np63α
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