scholarly journals Epstein-Barr Virus Thymidine Kinase Is a Centrosomal Resident Precisely Localized to the Periphery of Centrioles

2007 ◽  
Vol 81 (12) ◽  
pp. 6523-6535 ◽  
Author(s):  
Michael B. Gill ◽  
Jeffery L. Kutok ◽  
Joyce D. Fingeroth
Keyword(s):  
Cell Cycle ◽  
Thymidine Kinase ◽  
Epstein Barr Virus ◽  
Cell Types ◽  
Regulatory Function ◽  
Antigenic Peptides ◽  
Microtubule Organizing Center ◽  
Barr Virus ◽  
Organizing Center ◽  
Epstein Barr

ABSTRACT The thymidine kinase (TK) encoded by Epstein-Barr virus (EBV) differs not only from that of the alphaherpesviruses but also from that of the gamma-2 herpesvirus subfamily. Because cellular location is frequently a determinant of regulatory function, to gain insight into additional role(s) of EBV TK and to uncover how the lymphocryptovirus and rhadinovirus enzymes differ, the subcellular localizations of EBV TK and the related cercopithecine herpesvirus-15 TK were investigated. We show that in contrast to those of the other family members, the gamma-1 herpesvirus TKs localize to the centrosome and even more precisely to the periphery of the centriole, tightly encircling the tubulin-rich centrioles in a microtubule-independent fashion. Centrosomal localization is observed in diverse cell types and occurs whether the protein is expressed independently or in the context of lytic EBV infection. Surprisingly, analysis of mutants revealed that the unique N-terminal domain was not critical for targeting to the centrosome, but rather, peptide sequences located C terminal to this domain were key. This is the first herpesvirus protein documented to reside in the centrosome, or microtubule-organizing center, an amembranous organelle that regulates the structural biology of the cell cycle through control of chromosome separation and cytokinesis. More recently, proteasome-mediated degradation of cell cycle regulatory proteins, production and loading of antigenic peptides onto HLA molecules, and transient homing of diverse virion proteins required for entry and/or egress have been shown to be coordinated at the centrosome. Potential implications of centrosomal localization for EBV TK function are discussed.

Characterization of an Epstein-Barr virus-induced thymidine kinase.

1986 ◽  
Vol 57 (3) ◽  
pp. 1105-1112 ◽  
Author(s):  
M de Turenne-Tessier ◽  
T Ooka ◽  
G de The ◽  
J Daillie
Keyword(s):  
Thymidine Kinase ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals Direct and Indirect Regulation of Cytokine and Cell Cycle Proteins by EBNA-2 during Epstein-Barr Virus Infection

2001 ◽  
Vol 75 (8) ◽  
pp. 3537-3546 ◽  
Author(s):  
Lindsay C. Spender ◽  
Georgina H. Cornish ◽  
Benjamin Rowland ◽  
Bettina Kempkes ◽  
Paul J. Farrell
Keyword(s):  
Cell Cycle ◽  
Epstein Barr Virus ◽  
Transient Transfection ◽  
Cyclin D2 ◽  
Transient Transfection Assay ◽  
Rnase Protection ◽  
Barr Virus ◽  
Tnf Α ◽  
Epstein Barr ◽  
Transfection Assay

ABSTRACT We have studied the pathways of regulation of cytokine and cell cycle control proteins during infection of human B lymphocytes by Epstein-Barr virus (EBV). Among 30 cytokine RNAs analyzed by the RNase protection assay, tumor necrosis factor alpha (TNF-α), granulocyte colony-stimulating factor, lymphotoxin (LT), and LTβ were found to be regulated within 20 h of EBV infection of primary B cells. Similar results were obtained using the estrogen-regulated EBNA-2 cell line EREB2.5, in which RNAs for LT and TNF-α were induced within 6 h of activation of EBNA-2. Expression of Notch also caused an induction of TNF-α RNA. The induction of TNF-α RNA by EBNA-2 was indirect, and constitutive expression of either LMP-1 or c-myc proteins did not substitute for EBNA-2 in induction of TNF-α RNA. Cyclin D2 is also an indirect target of EBNA-2-mediated transactivation. EBNA-2 was found to activate the cyclin D2 promoter in a transient-transfection assay. A mutant of EBNA-2 that does not bind RBP-Jκ retained some activity in this assay, and activation did not depend on the presence of B-cell-specific factors. Deletion analysis of the cyclin D2 promoter revealed that removal of sequences containing E-box c-myc consensus DNA binding sequences did not reduce EBNA-2-mediated activation of the cyclin D2 promoter in the transient-transfection assay. The results indicate that cytokines are an early target of EBNA-2 and that EBNA-2 can regulate cyclin D2 transcription in EBV-infected cells by mechanisms additional to the c-myc pathway.

Diagnosis of Nasopharyngeal Carcinoma Using the Epstein-Barr Virus Coded Alkaline Dnase, Membrane Antigen and Thymidine Kinase

1991 ◽  
pp. 353-356
Author(s):  
Edward Littler ◽  
Sally A. Baylis ◽  
Yvonne Connolly ◽  
Margaret J. Conway ◽  
Michael Mackett ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Thymidine Kinase ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals Presence of Human Papillomavirus and Epstein–Barr Virus, but Absence of Merkel Cell Polyomavirus, in Head and Neck Cancer of Non-Smokers and Non-Drinkers

2021 ◽  
Vol 10 ◽  
Author(s):  
Frans J. Mulder ◽  
Faisal Klufah ◽  
Famke M. E. Janssen ◽  
Farzaneh Farshadpour ◽  
Stefan M. Willems ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Human Papillomavirus ◽  
Head And Neck ◽  
Epstein Barr Virus ◽  
Merkel Cell Polyomavirus ◽  
Merkel Cell ◽  
Cell Cycle Proteins ◽  
P53 Expression ◽  
Barr Virus ◽  
Epstein Barr

ObjectiveDetermine the presence and prognostic value of human papillomavirus (HPV), Epstein-Barr virus (EBV), Merkel cell polyomavirus (MCPyV), and cell cycle proteins in head and neck squamous cell carcinoma (HNSCC) of non-smokers and non-drinkers (NSND).MethodsClinical characteristics and tumors of 119 NSND with HNSCC were retrospectively collected and analyzed on tissue microarrays. RNAscope in situ hybridization (ISH) was used to screen for the presence of HPV and MCPyV mRNA. Immunohistochemistry was performed for expression of p16 as surrogate marker for HPV, Large T-antigen for MCPyV, and cell cycle proteins p53 and pRb. Positive virus results were confirmed with polymerase chain reaction. For EBV, EBV encoded RNA ISH was performed. Differences in 5-year survival between virus positive and negative tumors were determined by log rank analysis.ResultsAll oropharyngeal tumors (OPSCC) (n = 10) were HPV-positive, in addition to one oral (OSCC) and one nasopharyngeal tumor (NPSCC). The other three NPSCC were EBV-positive. MCPyV was not detected. Patients with HPV or EBV positive tumors did not have a significantly better 5-year disease free or overall survival. Over 70% of virus negative OSCC showed mutant-type p53 expression.ConclusionIn this cohort, all OPSCC and NPSCC showed HPV or EBV presence. Besides one OSCC, all other oral (n = 94), hypopharyngeal (n = 1), and laryngeal (n = 9) tumors were HPV, EBV, and MCPyV negative. This argues against a central role of these viruses in the ethiopathogenesis of tumors outside the oro- and nasopharynx in NSND. So, for the majority of NSND with virus negative OSCC, more research is needed to understand the carcinogenic mechanisms in order to consider targeted therapeutic options.

scholarly journals Radiosensitization Effect of Nedaplatin on Nasopharyngeal Carcinoma Cells in Different Status of Epstein-Barr Virus Infection

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Li Yin ◽  
Jing Wu ◽  
Jianfeng Wu ◽  
Jinjun Ye ◽  
Xuesong Jiang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Nasopharyngeal Carcinoma ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Cycle Arrest ◽  
M Phase ◽  
Epstein Barr ◽  
Mts Assay

This study aims to evaluate the radiosensitization effect of nedaplatin on nasopharyngeal carcinoma (NPC) cell lines with different Epstein-Barr virus (EBV) status. Human NPC cell lines CNE-2 (EBV-negative) and C666 (EBV-positive) were treated with 0–100 μg/mL nedaplatin, and inhibitory effects on cell viability and IC50were calculated by MTS assay. We assessed changes in radiosensitivity of cells by MTS and colony formation assays, and detected the apoptosis index and changes in cell cycle by flow cytometry. MTS assay showed that nedaplatin caused significant cytotoxicity in CNE-2 and C666 cells in a time- and dose-dependent manner. After 24 h, nedaplatin inhibited growth of CNE-2 and C666 cells with IC50values of 34.32 and 63.69 μg/mL, respectively. Compared with radiation alone, nedaplatin enhanced the radiation effect on both cell lines. Nedaplatin markedly increased apoptosis and cell cycle arrest in G2/M phase. Nedaplatin radiosensitized human NPC cells CNE-2 and C666, with a significantly greater effect on the former. The mechanisms of radiosensitization include induction of apoptosis and enhancement of cell cycle arrest in G2/M phase.

scholarly journals Rewiring of B cell receptor signaling by Epstein–Barr virus LMP2A

2020 ◽  
Vol 117 (42) ◽  
pp. 26318-26327
Author(s):  
Kamonwan Fish ◽  
Federico Comoglio ◽  
Arthur L. Shaffer ◽  
Yanlong Ji ◽  
Kuan-Ting Pan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Barr Virus ◽  
Human B Cells ◽  
Bcr Signaling ◽  
Epstein Barr

Epstein–Barr virus (EBV) infects human B cells and reprograms them to allow virus replication and persistence. One key viral factor in this process is latent membrane protein 2A (LMP2A), which has been described as a B cell receptor (BCR) mimic promoting malignant transformation. However, how LMP2A signaling contributes to tumorigenesis remains elusive. By comparing LMP2A and BCR signaling in primary human B cells using phosphoproteomics and transcriptome profiling, we identified molecular mechanisms through which LMP2A affects B cell biology. Consistent with the literature, we found that LMP2A mimics a subset of BCR signaling events, including tyrosine phosphorylation of the kinase SYK, the calcium initiation complex consisting of BLNK, BTK, and PLCγ2, and its downstream transcription factor NFAT. However, the majority of LMP2A-induced signaling events markedly differed from those induced by BCR stimulation. These included differential phosphorylation of kinases, phosphatases, adaptor proteins, transcription factors such as nuclear factor κB (NF-κB) and TCF3, as well as widespread changes in the transcriptional output of LMP2A-expressing B cells. LMP2A affected apoptosis and cell-cycle checkpoints by dysregulating the expression of apoptosis regulators such as BCl-xL and the tumor suppressor retinoblastoma-associated protein 1 (RB1). LMP2A cooperated with MYC and mutant cyclin D3, two oncogenic drivers of Burkitt lymphoma, to promote proliferation and survival of primary human B cells by counteracting MYC-induced apoptosis and by inhibiting RB1 function, thereby promoting cell-cycle progression. Our results indicate that LMP2A is not a pure BCR mimic but rather rewires intracellular signaling in EBV-infected B cells that optimizes cell survival and proliferation, setting the stage for oncogenic transformation.

scholarly journals Determination of Epstein-Barr Virus–Infected Lymphocyte Cell Types in Peripheral Blood Mononuclear Cells as a Valuable Diagnostic Tool in Hematological Diseases

2019 ◽  
Vol 6 (5) ◽  
Author(s):  
Peiling Zhang ◽  
Chen Zeng ◽  
Jiali Cheng ◽  
Jing Zhou ◽  
Jia Gu ◽  
...  
Keyword(s):  
Infected Cell ◽  
B Cell ◽  
Peripheral Blood Mononuclear Cells ◽  
Epstein Barr Virus ◽  
Nk Cell ◽  
Cell Types ◽  
Cell Type ◽  
Peripheral Blood Mononuclear ◽  
Barr Virus ◽  
Epstein Barr

Abstract Background High loads of Epstein-Barr virus (EBV) in peripheral blood mononuclear cells (PBMCs) can be indicative of a broad spectrum of diseases, ranging from asymptomatic infection to fatal cancers. Methods We retrospectively investigated the EBV-infected cell types in PBMCs among 291 patients. Based on EBV-infected cell types, the clinical features and prognoses of 93 patients with EBV-associated (EBV+) T/natural killer (NK)–cell lymphoproliferative diseases (LPDs) T/NK-LPDs) were investigated over a 5-year period. Results Although B-cell-type infection was found in immunocompromised patients and patients with asymptomatic high EBV carriage, infectious mononucleosis, EBV+ B-cell LPDs and B-cell lymphomas, T-cell, NK-cell or multiple-cell-type infection in immunocompetent hosts were highly suggestive of EBV+ T/NK-LPDs, EBV+ T/NK-cell lymphomas, and aggressive NK-cell leukemia. Patients with non–B-cell infection had a poorer prognosis than those with B-cell-type infection. In our cohort, 79.6% of patients with EBV+ T/NK-LPDs were >18 years old, and NK cells were identified as EBV-infected cell type in 54.8%. Nearly half of patients with EBV+ T/NK-LPDs had genetic defects associated with immunodeficiency. However, hemophagocytic lymphohistiocytosis, and not genetic defects, was the only parameter correlated with poor prognosis of EBV+ T/NK-LPDs. Conclusions Determination of EBV-infected cell types among PBMCs is a valuable tool for the differential diagnosis of EBV+ hematological diseases. In this study, determination of Epstein-Barr virus-infected cell types in peripheral blood mononuclear cells of 291 patients with high Epstein-Barr virus loads were retrospectively investigated, which indicate it is a valuable tool for Epstein-Barr virus-associated hematological diseases.

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