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NF-κB Signaling Regulates Epstein–Barr Virus BamHI-Q-Driven EBNA1 Expression

Epstein–Barr virus (EBV) nuclear antigen 1 (EBNA1) is one of the few viral proteins expressed by EBV in nasopharyngeal carcinoma (NPC), most likely because of its essential role in maintaining the viral genome in EBV-infected cells. In NPC, EBNA1 expression is driven by the BamHI-Q promoter (Qp), wh...

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Autores principales: Verhoeven, Rob J. A., Tong, Shuang, Zong, Jingfeng, Chen, Yixin, Tsao, Sai-Wah, Pan, Jianji, Chen, Honglin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923374/
https://www.ncbi.nlm.nih.gov/pubmed/29659505
http://dx.doi.org/10.3390/cancers10040119
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author Verhoeven, Rob J. A.
Tong, Shuang
Zong, Jingfeng
Chen, Yixin
Tsao, Sai-Wah
Pan, Jianji
Chen, Honglin
author_facet Verhoeven, Rob J. A.
Tong, Shuang
Zong, Jingfeng
Chen, Yixin
Tsao, Sai-Wah
Pan, Jianji
Chen, Honglin
author_sort Verhoeven, Rob J. A.
collection PubMed
description Epstein–Barr virus (EBV) nuclear antigen 1 (EBNA1) is one of the few viral proteins expressed by EBV in nasopharyngeal carcinoma (NPC), most likely because of its essential role in maintaining the viral genome in EBV-infected cells. In NPC, EBNA1 expression is driven by the BamHI-Q promoter (Qp), which is regulated by both cellular and viral factors. We previously determined that the expression of another group of EBV transcripts, BamHI-A rightward transcripts (BARTs), is associated with constitutively activated nuclear factor-κB (NF-κB) signaling in NPC cells. Here, we show that, like the EBV BART promoter, the EBV Qp also responds to NF-κB signaling. NF-κB p65, but not p50, can activate Qp in vitro, and NF-κB signaling regulates Qp-EBNA1 expression in NPC cells, as well as in other EBV-infected epithelial cells. The introduction of mutations in the putative NF-κB site reduced Qp activation by the NF-κB p65 subunit. Binding of p65 to Qp was shown by chromatin immunoprecipitation (ChIP) analysis, while electrophoretic mobility shift assays (EMSAs) demonstrated that p50 can also bind to Qp. Inhibition of NF-κB signaling by the IκB kinase inhibitor PS-1145 resulted in the downregulation of Qp-EBNA1 expression in C666-1 NPC cells. Since EBNA1 has been reported to block p65 activation by inhibiting IKKα/β through an unknown mechanism, we suggest that, in NPC, NF-κB signaling and EBNA1 may form a regulatory loop which supports EBV latent gene expression, while also limiting NF-κB activity. These findings emphasize the role of NF-κB signaling in the regulation of EBV latency in EBV-associated tumors.
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spelling pubmed-59233742018-05-03 NF-κB Signaling Regulates Epstein–Barr Virus BamHI-Q-Driven EBNA1 Expression Verhoeven, Rob J. A. Tong, Shuang Zong, Jingfeng Chen, Yixin Tsao, Sai-Wah Pan, Jianji Chen, Honglin Cancers (Basel) Article Epstein–Barr virus (EBV) nuclear antigen 1 (EBNA1) is one of the few viral proteins expressed by EBV in nasopharyngeal carcinoma (NPC), most likely because of its essential role in maintaining the viral genome in EBV-infected cells. In NPC, EBNA1 expression is driven by the BamHI-Q promoter (Qp), which is regulated by both cellular and viral factors. We previously determined that the expression of another group of EBV transcripts, BamHI-A rightward transcripts (BARTs), is associated with constitutively activated nuclear factor-κB (NF-κB) signaling in NPC cells. Here, we show that, like the EBV BART promoter, the EBV Qp also responds to NF-κB signaling. NF-κB p65, but not p50, can activate Qp in vitro, and NF-κB signaling regulates Qp-EBNA1 expression in NPC cells, as well as in other EBV-infected epithelial cells. The introduction of mutations in the putative NF-κB site reduced Qp activation by the NF-κB p65 subunit. Binding of p65 to Qp was shown by chromatin immunoprecipitation (ChIP) analysis, while electrophoretic mobility shift assays (EMSAs) demonstrated that p50 can also bind to Qp. Inhibition of NF-κB signaling by the IκB kinase inhibitor PS-1145 resulted in the downregulation of Qp-EBNA1 expression in C666-1 NPC cells. Since EBNA1 has been reported to block p65 activation by inhibiting IKKα/β through an unknown mechanism, we suggest that, in NPC, NF-κB signaling and EBNA1 may form a regulatory loop which supports EBV latent gene expression, while also limiting NF-κB activity. These findings emphasize the role of NF-κB signaling in the regulation of EBV latency in EBV-associated tumors. MDPI 2018-04-16 /pmc/articles/PMC5923374/ /pubmed/29659505 http://dx.doi.org/10.3390/cancers10040119 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Verhoeven, Rob J. A.
Tong, Shuang
Zong, Jingfeng
Chen, Yixin
Tsao, Sai-Wah
Pan, Jianji
Chen, Honglin
NF-κB Signaling Regulates Epstein–Barr Virus BamHI-Q-Driven EBNA1 Expression
title NF-κB Signaling Regulates Epstein–Barr Virus BamHI-Q-Driven EBNA1 Expression
title_full NF-κB Signaling Regulates Epstein–Barr Virus BamHI-Q-Driven EBNA1 Expression
title_fullStr NF-κB Signaling Regulates Epstein–Barr Virus BamHI-Q-Driven EBNA1 Expression
title_full_unstemmed NF-κB Signaling Regulates Epstein–Barr Virus BamHI-Q-Driven EBNA1 Expression
title_short NF-κB Signaling Regulates Epstein–Barr Virus BamHI-Q-Driven EBNA1 Expression
title_sort nf-κb signaling regulates epstein–barr virus bamhi-q-driven ebna1 expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923374/
https://www.ncbi.nlm.nih.gov/pubmed/29659505
http://dx.doi.org/10.3390/cancers10040119
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