Expression of Epstein-Barr Virus Latent Membrane Proteins Leads to Changes in Keratinocyte Cell Adhesion

1999 ◽  
Vol 108 (9) ◽  
pp. 851-859 ◽  
Author(s):  
D. Greg Farwell ◽  
James K. McDougall ◽  
Marc D. Coltrera
Keyword(s):  
Cell Adhesion ◽  
Membrane Proteins ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Keratinocyte Cell ◽  
Epstein Barr

scholarly journals Lactic Acid Downregulates Viral MicroRNA To Promote Epstein-Barr Virus-Immortalized B Lymphoblastic Cell Adhesion and Growth

2018 ◽  
Vol 92 (9) ◽  
Author(s):  
Xiaohui Mo ◽  
Fang Wei ◽  
Yin Tong ◽  
Ling Ding ◽  
Qing Zhu ◽  
...  
Keyword(s):  
Lactic Acid ◽  
Cell Adhesion ◽  
B Cells ◽  
B Cell ◽  
Cancer Progression ◽  
Epstein Barr Virus ◽  
Lactate Production ◽  
Barr Virus ◽  
Viral Microrna ◽  
Epstein Barr

ABSTRACT High plasma lactate is associated with poor prognosis of many malignancies, but its role in virally mediated cancer progression and underlying molecular mechanisms are unclear. Epstein-Barr virus (EBV), the first human oncogenic virus, causes several cancers, including B-cell lymphoma. Here, we report that lactate dehydrogenase A (LDH-A) expression and lactate production are elevated in EBV-immortalized B lymphoblastic cells, and lactic acid (LA; acidic lactate) at low concentration triggers EBV-infected B-cell adhesion, morphological changes, and proliferation in vitro and in vivo . Moreover, LA-induced responses of EBV-infected B cells uniquely occurs in viral latency type III, and it is dramatically associated with the inhibition of global viral microRNAs, particularly the miR-BHRF1 cluster, and the high expression of SMAD3 , JUN , and COL1A genes. The introduction of miR-BHRF1-1 blocks the LA-induced effects of EBV-infected B cells. Thus, this may be a novel mechanism to explain EBV-immortalized B lymphoblastic cell malignancy in an LA microenvironment. IMPORTANCE The tumor microenvironment is complicated, and lactate, which is created by cell metabolism, contributes to an acidic microenvironment that facilitates cancer progression. However, how LA operates in virus-associated cancers is unclear. Thus, we studied how EBV (the first tumor virus identified in humans; it is associated with many cancers) upregulates the expression of LDH-A and lactate production in B lymphoma cells. Elevated LA induces adhesion and the growth of EBV-infected B cells by inhibiting viral microRNA transcription. Thus, we offer a novel understanding of how EBV utilizes an acidic microenvironment to promote cancer development.

scholarly journals Role of NF-κB in Cell Survival and Transcription of Latent Membrane Protein 1-Expressing or Epstein-Barr Virus Latency III-Infected Cells

2004 ◽  
Vol 78 (8) ◽  
pp. 4108-4119 ◽  
Author(s):  
Ellen D. Cahir-McFarland ◽  
Kara Carter ◽  
Andreas Rosenwald ◽  
Jena M. Giltnane ◽  
Sarah E. Henrickson ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Membrane Proteins ◽  
Germinal Center ◽  
Epstein Barr Virus ◽  
Immunoglobulin M ◽  
Barr Virus ◽  
Epstein Barr ◽  
Germinal Center B Cells

ABSTRACT Epstein-Barr virus (EBV) latency III infection converts B lymphocytes into lymphoblastoid cell lines (LCLs) by expressing EBV nuclear and membrane proteins, EBNAs, and latent membrane proteins (LMPs), which regulate transcription through Notch and tumor necrosis factor receptor pathways. The role of NF-κB in LMP1 and overall EBV latency III transcriptional effects was investigated by treating LCLs with BAY11-7082 (BAY11). BAY11 rapidly and irreversibly inhibited NF-κB, decreased mitochondrial membrane potential, induced apoptosis, and altered LCL gene expression. BAY11 effects were similar to those of an NF-κB inhibitor, ΔN-IκBα, in effecting decreased JNK1 expression and in microarray analyses. More than 80% of array elements that decreased with ΔN-IκBα expression decreased with BAY11 treatment. Newly identified NF-κB-induced, LMP1-induced, and EBV-induced genes included pleckstrin, Jun-B, c-FLIP, CIP4, and IκBε. Of 776 significantly changed array elements, 134 were fourfold upregulated in EBV latency III, and 74 were fourfold upregulated with LMP1 expression alone, whereas only 28 were more than fourfold downregulated by EBV latency III. EBV latency III-regulated gene products mediate cell migration (EBI2, CCR7, RGS1, RANTES, MIP1α, MIP1β, CXCR5, and RGS13), antigen presentation (major histocompatibility complex proteins and JAW1), mitogen-activated protein kinase pathway (DUSP5 and p62Dok), and interferon (IFN) signaling (IFN-γRα, IRF-4, and STAT1). Comparison of EBV latency III LCL gene expression to immunoglobulin M (IgM)-stimulated B cells, germinal-center B cells, and germinal-center-derived lymphomas clustered LCLs with IgM-stimulated B cells separately from germinal-center cells or germinal-center lymphoma cells. Expression of IRF-2, AIM1, ASK1, SNF2L2, and components of IFN signaling pathways further distinguished EBV latency III-infected B cells from IgM-stimulated or germinal-center B cells.

scholarly journals Co-Expression of the Epstein-Barr Virus-Encoded Latent Membrane Proteins and the Pathogenesis of Classic Hodgkin Lymphoma

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 285 ◽  
Author(s):  
Katerina Vrzalikova ◽  
Maha Ibrahim ◽  
Eszter Nagy ◽  
Martina Vockerodt ◽  
Tracey Perry ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Epstein Barr Virus ◽  
Tumour Cells ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Classic Hodgkin Lymphoma ◽  
Epstein Barr ◽  
Cellular Transcription

The Epstein-Barr virus (EBV) is present in the tumour cells of a subset of patients with classic Hodgkin lymphoma (cHL), yet the contribution of the virus to the pathogenesis of these tumours remains only poorly understood. The EBV genome in virus-associated cHL expresses a limited subset of genes, restricted to the non-coding Epstein-Barr virus-encoded RNAs (EBERs) and viral miRNA, as well as only three virus proteins; the Epstein-Barr virus nuclear antigen-1 (EBNA1), and the two latent membrane proteins, known as LMP1 and LMP2, the latter of which has two isoforms, LMP2A and LMP2B. LMP1 and LMP2A are of particular interest because they are co-expressed in tumour cells and can activate cellular signalling pathways, driving aberrant cellular transcription in infected B cells to promote lymphomagenesis. This article seeks to bring together the results of recent studies of the latent membrane proteins in different B cell systems, including experiments in animal models as well as a re-analysis of our own transcriptional data. In doing so, we summarise the potentially co-operative and antagonistic effects of the LMPs that are relevant to B cell lymphomagenesis.

scholarly journals Epithelial Cell Adhesion to Extracellular Matrix Proteins Induces Tyrosine Phosphorylation of the Epstein-Barr Virus Latent Membrane Protein 2: a Role for C-Terminal Src Kinase

1999 ◽  
Vol 73 (6) ◽  
pp. 4767-4775 ◽  
Author(s):  
Frank Scholle ◽  
Richard Longnecker ◽  
Nancy Raab-Traub
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cells ◽  
Tyrosine Phosphorylation ◽  
Epstein Barr Virus ◽  
Latent Membrane Protein ◽  
Src Family Kinases ◽  
Barr Virus ◽  
Epstein Barr ◽  
Latent Membrane Protein 2

ABSTRACT The Epstein-Barr virus (EBV) latent membrane protein 2 (LMP2) is expressed in latently EBV-infected B cells, where it forms patches in the plasma membrane and interferes with B-cell receptor signal transduction through dominant-negative effects on protein kinases. LMP2 transcripts are detected in nasopharyngeal carcinoma, an epithelial-cell malignancy. In this study the function of LMP2A in epithelial cells was investigated. LMP2A was found to coprecipitate with protein kinase activities and to become phosphorylated in in vitro kinase assays. Analysis of LMP2A deletion mutants demonstrated that tyrosines implicated in interacting with Src family kinase SH2 domains and the SH2 domain of Csk, as well as the LMP2A immunoreceptor tyrosine-based activation motif, are important for its phosphorylation in epithelial cells. LMP2A tyrosine phosphorylation was triggered by cell adhesion to extracellular-matrix (ECM) proteins. Src family kinases, whose involvement in cell-ECM signaling and LMP2A phosphorylation in B lymphocytes has been well established, were found not to be responsible for LMP2A phosphorylation in epithelial cells. Instead, coexpression of Csk, a negative Src regulator, and LMP2A led to an increase in LMP2A phosphorylation both in nonadherent cells and upon cell adhesion. Csk also phosphorylated LMP2A in vitro. These results suggest that LMP2A has a different role in epithelial cells, where it interacts with cell adhesion-initiated signaling pathways. Although tyrosine phosphorylation of LMP2A occurs in both cell types, different protein kinases seem to be used: Src family kinases in B lymphocytes and Csk in epithelial cells.

scholarly journals MUC1 Induced by Epstein-Barr Virus Latent Membrane Protein 1 Causes Dissociation of the Cell-Matrix Interaction and Cellular Invasiveness via STAT Signaling

2006 ◽  
Vol 81 (4) ◽  
pp. 1554-1562 ◽  
Author(s):  
Satoru Kondo ◽  
Tomokazu Yoshizaki ◽  
Naohiro Wakisaka ◽  
Toshiyuki Horikawa ◽  
Shigeyuki Murono ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Membrane Protein ◽  
Tumor Cells ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 1 ◽  
Barr Virus ◽  
Epstein Barr ◽  
Cellular Invasiveness

ABSTRACT Disruption of cellular adhesion is an essential pathobiologic step leading to tumor dissemination. Mucin 1 (MUC1) is a mucinous glycoprotein expressed at the surfaces of epithelial cells in many tissues and their carcinomas. MUC1 plays crucial roles in tumor invasion and metastasis, especially in opposing cell adhesion. We have shown that virus infection, specifically by the human tumor virus Epstein-Barr virus (EBV) induces a spectrum of cellular invasiveness and metastasis factors. Here we show that expression of MUC1 is increased in diverse latently EBV-infected cell lines that express latent membrane protein 1 (LMP1), the main viral oncoprotein, and that the level of MUC1 was suppressed by expression of a dominant-negative mutant of LMP1. Expression of LMP1 in EBV-negative nasopharyngeal cell lines induces expression of MUC1 through activation of the MUC1 promoter via binding of STAT1 and STAT3. Finally, LMP1 reduces cell adhesion ability, which is restored by inhibition of MUC1 expression with MUC1 small interfering RNA (siRNA). In addition, LMP1 increases cell invasiveness, which is suppressed by MUC1 siRNA. Thus, LMP1 induces MUC1, a factor important in an early step of detachment and release of tumor cells, which along with induction of other invasiveness and angiogenic factors may combine to act in a complex sequential process that culminates in metastasis of EBV-infected tumor cells.

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