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Yonggang Pei, Shuvomoy Banerjee, Zhiguo Sun, Hem Chandra Jha, Abhik Saha, Erle S Robertson
Epstein-Barr virus (EBV) is considered a ubiquitous herpesvirus with the ability to cause latent infection in humans worldwide. EBV-association is evidently linked to different types of human malignancies, mainly of epithelial and lymphoid origin. Of interest is the EBV nuclear antigen 3C (EBNA3C) which is critical for EBV-mediated immortalization. Recently, EBNA3C was shown to bind the E2F1 transcription regulator. The E2F transcription factors have crucial roles in various cellular functions, including cell cycle, DNA replication, DNA repair, cell mitosis, and cell fate...
August 2016: PLoS Pathogens
C David Wood, Hildegonda Veenstra, Sarika Khasnis, Andrea Gunnell, Helen M Webb, Claire Shannon-Lowe, Simon Andrews, Cameron S Osborne, Michelle J West
Lymphomagenesis in the presence of deregulated MYC requires suppression of MYC-driven apoptosis, often through downregulation of the pro-apoptotic BCL2L11 gene (Bim). Transcription factors (EBNAs) encoded by the lymphoma-associated Epstein-Barr virus (EBV) activate MYC and silence BCL2L11. We show that the EBNA2 transactivator activates multiple MYC enhancers and reconfigures the MYC locus to increase upstream and decrease downstream enhancer-promoter interactions. EBNA2 recruits the BRG1 ATPase of the SWI/SNF remodeller to MYC enhancers and BRG1 is required for enhancer-promoter interactions in EBV-infected cells...
2016: ELife
Jens S Kalchschmidt, Rachael Bashford-Rogers, Kostas Paschos, Adam C T Gillman, Christine T Styles, Paul Kellam, Martin J Allday
Activation-induced cytidine deaminase (AID), the enzyme responsible for induction of sequence variation in immunoglobulins (Igs) during the process of somatic hypermutation (SHM) and also Ig class switching, can have a potent mutator phenotype in the development of lymphoma. Using various Epstein-Barr virus (EBV) recombinants, we provide definitive evidence that the viral nuclear protein EBNA3C is essential in EBV-infected primary B cells for the induction of AID mRNA and protein. Using lymphoblastoid cell lines (LCLs) established with EBV recombinants conditional for EBNA3C function, this was confirmed, and it was shown that transactivation of the AID gene (AICDA) is associated with EBNA3C binding to highly conserved regulatory elements located proximal to and upstream of the AICDA transcription start site...
May 30, 2016: Journal of Experimental Medicine
Sanket Kumar Shukla, Hem Chandra Jha, Darine W El-Naccache, Erle S Robertson
Epstein-Barr virus (EBV), a gamma herpes virus is associated with B-cell malignancies. EBNA-3C is critical for in vitro primary B-cell transformation. Interestingly, the N terminal domain of EBNA3C which contains residues 130-159, interacts with various cellular proteins, such as p53, Mdm2, CyclinD1/Cdk6 complex, and E2F1. In the current reverse genetics study, we deleted the residues 130-159 aa within EBNA3C open reading frame (ORF) by BACmid recombinant engineering methodology. Our experiments demonstrated that deletion of the 130-159 aa showed a reduction in cell proliferation...
April 5, 2016: Oncotarget
Andrea Gunnell, Helen M Webb, C David Wood, Michael J McClellan, Billy Wichaidit, Bettina Kempkes, Richard G Jenner, Cameron Osborne, Paul J Farrell, Michelle J West
In B cells infected by the cancer-associated Epstein-Barr virus (EBV), RUNX3 and RUNX1 transcription is manipulated to control cell growth. The EBV-encoded EBNA2 transcription factor (TF) activates RUNX3 transcription leading to RUNX3-mediated repression of the RUNX1 promoter and the relief of RUNX1-directed growth repression. We show that EBNA2 activates RUNX3 through a specific element within a -97 kb super-enhancer in a manner dependent on the expression of the Notch DNA-binding partner RBP-J. We also reveal that the EBV TFs EBNA3B and EBNA3C contribute to RUNX3 activation in EBV-infected cells by targeting the same element...
June 2, 2016: Nucleic Acids Research
Jens S Kalchschmidt, Adam C T Gillman, Kostas Paschos, Quentin Bazot, Bettina Kempkes, Martin J Allday
It is well established that Epstein-Barr virus nuclear antigen 3C (EBNA3C) can act as a potent repressor of gene expression, but little is known about the sequence of events occurring during the repression process. To explore further the role of EBNA3C in gene repression-particularly in relation to histone modifications and cell factors involved-the three host genes previously reported as most robustly repressed by EBNA3C were investigated. COBLL1, a gene of unknown function, is regulated by EBNA3C alone and the two co-regulated disintegrin/metalloproteases, ADAM28 and ADAMDEC1 have been described previously as targets of both EBNA3A and EBNA3C...
January 2016: PLoS Pathogens
Anqi Wang, Rene Welch, Bo Zhao, Tram Ta, Sündüz Keleş, Eric Johannsen
UNLABELLED: Latent infection of B lymphocytes by Epstein-Barr virus (EBV) in vitro results in their immortalization into lymphoblastoid cell lines (LCLs); this latency program is controlled by the EBNA2 viral transcriptional activator, which targets promoters via RBPJ, a DNA binding protein in the Notch signaling pathway. Three other EBNA3 proteins (EBNA3A, EBNA3B, and EBNA3C) interact with RBPJ to regulate cell gene expression. The mechanism by which EBNAs regulate different genes via RBPJ remains unclear...
March 2016: Journal of Virology
Lingling Sun, Zhenzhen Zhao, Song Liu, Xia Liu, Zhifu Sun, Bing Luo
Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is the only viral protein expressed in all EBV-positive tumors as it is essential for the maintenance, replication and transcription of the virus genome. According to the polymorphism of residue 487 in EBNA1 gene, EBV isolates can be classified into five subtypes: P-ala, P-thr, V-val, V-leu and V-pro. Whether these EBNA1 subtypes contribute to different tissue tropism of EBV and are consequently associated with certain malignancies remain to be determined. To elucidate the relationship, one hundred and ten EBV-positive lymphoma tissues of different types from Northern China, a non-NPC endemic area, were tested for the five subtypes by nested-PCR and DNA sequencing...
2015: PloS One
Martin J Allday, Quentin Bazot, Robert E White
Epstein-Barr virus nuclear antigens EBNA3A , EBNA3B and EBNA3C are a family of three large latency-associated proteins expressed in B cells induced to proliferate by the virus. Together with the other nuclear antigens (EBNA-LP, EBNA2 and EBNA1), they are expressed from a polycistronic transcription unit that is probably unique to B cells. However, compared with the other EBNAs, hitherto the EBNA3 proteins were relatively neglected and their roles in EBV biology rather poorly understood. In recent years, powerful new technologies have been used to show that these proteins are central to the latency of EBV in B cells, playing major roles in reprogramming the expression of host genes affecting cell proliferation, survival, differentiation and immune surveillance...
2015: Current Topics in Microbiology and Immunology
Hem Chandra Jha, Sanket Kumar Shukla, Jie Lu, Mahadesh Prasad Aj, Shuvomoy Banerjee, Erle S Robertson
Epstein-Barr virus (EBV) is an oncogenic gammaherpes virus which is linked to pathogenesis of several human lymphatic malignancies. The EBV essential latent antigen EBNA3C is critical for efficient conversion of primary human B-lymphocytes to lymphoblastic cell lines and for continued LCL growth. EBNA3C, an EBV latent antigen with oncogenic potential can bind and regulate the functions of a wide range of cellular transcription factors. In our current reverse genetics study, we deleted the full length EBNA3C, and independently the RBP-Jκ and Nm23-H1 binding sites within EBNA3C using BACmid recombinant engineering methodology...
October 6, 2015: Oncotarget
Justyna Nowakowska, Claudia Stuehler, Adrian Egli, Manuel Battegay, Georg Rauser, Glenn Robert Bantug, Christian Brander, Christoph Hess, Nina Khanna
BACKGROUND AIMS: Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorders (PTLD) belong to the most dreaded complications of immunosuppression. The efficacy of EBV-specific T-cell transfer for PTLD has been previously shown, yet the optimal choice of EBV-derived antigens inducing polyclonal CD4(+) and CD8(+) T cells that cover a wide range of human leukocyte antigen types and efficiently control PTLD remains unclear. METHODS: A pool of 125 T-cell epitopes from seven latent and nine lytic EBV-derived proteins (EBVmix) and peptide pools of EBNA1, EBNA3c, LMP2a and BZLF1 were used to determine T-cell frequencies and to isolate T cells through the use of the interferon (IFN)-γ cytokine capture system...
September 2015: Cytotherapy
Quentin Bazot, Kostas Paschos, Lenka Skalska, Jens S Kalchschmidt, Gillian A Parker, Martin J Allday
We show that two host-encoded primary RNAs (pri-miRs) and the corresponding microRNA (miR) clusters--widely reported to have cell transformation-associated activity--are regulated by EBNA3A and EBNA3C. Utilising a variety of EBV-transformed lymphoblastoid cell lines (LCLs) carrying knockout-, revertant- or conditional-EBV recombinants, it was possible to demonstrate unambiguously that EBNA3A and EBNA3C are both required for transactivation of the oncogenic miR-221/miR-222 cluster that is expressed at high levels in multiple human tumours--including lymphoma/leukemia...
July 2015: PLoS Pathogens
Marco Neves, Joana Marinho-Dias, Joana Ribeiro, Marlene Esteves, Elsa Maltez, Inês Baldaque, Eduardo Breda, Eurico Monteiro, Rui Medeiros, Hugo Sousa
Variations in the genome sequence of Epstein-Barr Virus (EBV) are thought to lead to differential interaction with host cells, immune evasion, and transformation. The discussion regarding EBV strains as having a geographic or disease-association has been increasing and the majority of studies are performed in Asiatic populations. We developed a case-control study with 139 individuals, including 96 subjects with different malignancies and 43 healthy individuals, from the North region of Portugal. We have used PCR protocols for the characterization of EBV strains (type A or B) based on EBNA3C genome variation and for the LMP1 30bp-deletion variants (wt-LMP1 or del-LMP1)...
August 2015: Journal of Medical Virology
Ayako Arai
Epstein-Barr virus (EBV) infects human beings and latently persists in B-cells throughout life. EBV infection renders B cells immortal. In immunocompetent individuals, the expansion of EBV-infected B-cells is suppressed by cytotoxic T lymphocytes (CTL). However, once immunosuppression-induced CTL dysfunction or accelerated proliferation of infected cells due to gene mutation accumulation occurs, the infected cells proliferate leading to B-cell neoplasms. The products of the viral genome, i.e. LMP1, EBNA2, EBNA3A, and EBNA3C, are indispensable for transformation of infected B-cells...
March 2015: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Makoto Ohashi, Amy M Holthaus, Michael A Calderwood, Chiou-Yan Lai, Bryan Krastins, David Sarracino, Eric Johannsen
The Epstein-Barr virus (EBV) nuclear proteins EBNA3A, EBNA3B, and EBNA3C interact with the cell DNA binding protein RBPJ and regulate cell and viral genes. Repression of the CDKN2A tumor suppressor gene products p16(INK4A) and p14(ARF) by EBNA3A and EBNA3C is critical for EBV mediated transformation of resting B lymphocytes into immortalized lymphoblastoid cell lines (LCLs). To define the composition of endogenous EBNA3 protein complexes, we generated lymphoblastoid cell lines (LCLs) expressing flag-HA tagged EBNA3A, EBNA3B, or EBNA3C and used tandem affinity purification to isolate each EBNA3 complex...
April 2015: PLoS Pathogens
Hem C Jha, Karren Yang, Darine W El-Naccache, Zhiguo Sun, Erle S Robertson
In multicellular organisms p53 maintains genomic integrity through activation of DNA repair, and apoptosis. EBNA3C can down regulate p53 transcriptional activity. Aurora kinase (AK) B phosphorylates p53, which leads to degradation of p53. Aberrant expression of AK-B is a hallmark of numerous human cancers. Therefore changes in the activities of p53 due to AK-B and EBNA3C expression is important for understanding EBV-mediated cell transformation. Here we show that the activities of p53 and its homolog p73 are dysregulated in EBV infected primary cells which can contribute to increased cell transformation...
March 20, 2015: Oncotarget
Pankaj Kumar, Masanao Murakami, Rajeev Kaul, Abhik Saha, Qiliang Cai, Erle S Robertson
Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus associated with a large number of lymphoid and epithelial malignancies. As a successful pathogen it has co-evolved with its human host for millions of years. EBV has the unique ability to establish life-long latent infection in primary human B lymphocytes. During latent infection, a small subset of viral proteins is expressed. These proteins are essential for maintenance of the EBV genome as well as the deregulation of various signaling pathways that facilitate the proliferation and survival of the infected cells...
January 2009: Future Virology
Xiaojun Yu, Marta Ilecka, Emmalene J Bartlett, Viktor Schneidt, Rauf Bhat, Josef Mautner, Regina Feederle, Henri-Jacques Delecluse
The treatment of non-Hodgkin lymphomas has benefited enormously from the introduction of monoclonal antibody-based therapies. However, the efficacy of these treatments varies with lymphoma subtypes and typically decreases with subsequent relapses. Here, we report on antigen-armed antibodies (AgAbs) as a potential treatment of B-cell lymphoma. AgAbs include antigens from ubiquitous pathogens, such as Epstein-Barr virus (EBV), that persist in their host and elicit strong lifelong T-cell responses. They act as vectors by introducing antigen directly into tumor cells to induce an antigen-specific CD4(+) T-cell response against these cells...
March 5, 2015: Blood
Stefanie C S Schmidt, Sizun Jiang, Hufeng Zhou, Bradford Willox, Amy M Holthaus, Peter V Kharchenko, Eric C Johannsen, Elliott Kieff, Bo Zhao
Epstein-Barr Virus (EBV) conversion of B-lymphocytes to Lymphoblastoid Cell Lines (LCLs) requires four EBV nuclear antigen (EBNA) oncoproteins: EBNA2, EBNALP, EBNA3A, and EBNA3C. EBNA2 and EBNALP associate with EBV and cell enhancers, up-regulate the EBNA promoter, MYC, and EBV Latent infection Membrane Proteins (LMPs), which up-regulate BCL2 to protect EBV-infected B-cells from MYC proliferation-induced cell death. LCL proliferation induces p16(INK4A) and p14(ARF)-mediated cell senescence. EBNA3A and EBNA3C jointly suppress p16(INK4A) and p14(ARF), enabling continuous cell proliferation...
January 13, 2015: Proceedings of the National Academy of Sciences of the United States of America
Nivedita Gaur, Jaya Gandhi, Erle S Robertson, Subhash C Verma, Rajeev Kaul
Epithelial-mesenchymal transition is an important mechanism in cancer invasiveness and metastasis. We had previously reported that cancer cells expressing Epstein-Barr virus (EBV) latent viral antigens EBV nuclear antigen EBNA3C and/ or EBNA1 showed higher motility and migration potential and had a propensity for increased metastases when tested in nude mice model. We now show that both EBNA3C and EBNA1 can modulate cellular pathways critical for epithelial to mesenchymal transition of cancer cells. Our data confirms that presence of EBNA3C or EBNA1 result in upregulation of transcriptional repressor Slug and Snail, upregulation of intermediate filament of mesenchymal origin vimentin, upregulation of transcription factor TCF8/ZEB1, downregulation as well as disruption of tight junction zona occludens protein ZO-1, downregulation of cell adhesion molecule E-cadherin, and nuclear translocation of β-catenin...
April 2015: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
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