scholarly journals The B-Cell Specific Transcription Factor, Oct-2, Promotes Epstein-Barr Virus Latency by Inhibiting the Viral Immediate-Early Protein, BZLF1

2012 ◽  
Vol 8 (2) ◽  
pp. e1002516 ◽  
Author(s):  
Amanda R. Robinson ◽  
Swee Sen Kwek ◽  
Shannon C. Kenney
Keyword(s):  
Transcription Factor ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Immediate Early ◽  
Specific Transcription Factor ◽  
Barr Virus ◽  
Virus Latency ◽  
Early Protein ◽  
Epstein Barr

scholarly journals Epstein-Barr Virus Immediate-Early Proteins BZLF1 and BRLF1 Activate the ATF2 Transcription Factor by Increasing the Levels of Phosphorylated p38 and c-Jun N-Terminal Kinases

2000 ◽  
Vol 74 (3) ◽  
pp. 1224-1233 ◽  
Author(s):  
Amy L. Adamson ◽  
Dayle Darr ◽  
Elizabeth Holley-Guthrie ◽  
Robert A. Johnson ◽  
Amy Mauser ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Epstein Barr Virus ◽  
Viral Latency ◽  
Immediate Early ◽  
Expression Vectors ◽  
Protein Z ◽  
Barr Virus ◽  
Ebv Infection ◽  
Early Protein ◽  
Epstein Barr

ABSTRACT Expression of either Epstein-Barr virus (EBV) immediate-early protein BZLF1 (Z) or BRLF1 (R) is sufficient to convert EBV infection from the latent to lytic form. Disruption of viral latency requires transcriptional activation of the Z and R promoters. The Z and R proteins are transcriptional activators, and each immediate-early protein activates expression of the other immediate-early protein. Z activates the R promoter through a direct binding mechanism. However, R does not bind directly to the Z promoter. In this study, we demonstrate that the ZII element (a cyclic AMP response element site) in the Z promoter is required for efficient activation by R. The ZII element has been shown to be important for induction of lytic EBV infection by tetradecanoyl phorbol acetate and surface immunoglobulin cross-linking and is activated by Z through an indirect mechanism. We demonstrate that both R and Z activate the cellular stress mitogen-activated protein (MAP) kinases, p38 and JNK, resulting in phosphorylation (and activation) of the cellular transcription factor ATF2. Furthermore, we show that the ability of R to induce lytic EBV infection in latently infected cells is significantly reduced by inhibition of either the p38 kinase or JNK pathways. In contrast, inhibition of stress MAP kinase pathways does not impair the ability of Z expression vectors to disrupt viral latency, presumably because expression of Z under the control of a strong heterologous promoter bypasses the need to activate Z transcription. Thus, both R and Z can activate the Z promoter indirectly by inducing ATF2 phosphorylation, and this activity appears to be important for R-induced disruption of viral latency.

scholarly journals Methylation profiling of Epstein-Barr virus immediate-early gene promoters, BZLF1 and BRLF1in tumors of epithelial, NK- and B-cell origins

BMC Cancer ◽  
2012 ◽  
Vol 12 (1) ◽  
Author(s):  
Lili Li ◽  
Xianwei Su ◽  
Gigi Ching Gee Choi ◽  
Ya Cao ◽  
Richard F Ambinder ◽  
...  
Keyword(s):  
B Cell ◽  
Epstein Barr Virus ◽  
Immediate Early Gene ◽  
Early Gene ◽  
Immediate Early ◽  
Gene Promoters ◽  
Barr Virus ◽  
Epstein Barr ◽  
Methylation Profiling

scholarly journals The BRRF1 Early Gene of Epstein-Barr Virus Encodes a Transcription Factor That Enhances Induction of Lytic Infection by BRLF1

2004 ◽  
Vol 78 (10) ◽  
pp. 4983-4992 ◽  
Author(s):  
Gregory K. Hong ◽  
Henri-Jacques Delecluse ◽  
Henri Gruffat ◽  
Thomas E. Morrison ◽  
Wen-Hai Feng ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Epstein Barr Virus ◽  
Cell Types ◽  
Early Gene ◽  
Barr Virus ◽  
Ebv Infection ◽  
Early Protein ◽  
293 Cells ◽  
Latently Infected ◽  
Epstein Barr

ABSTRACT The switch from the latent to the lytic form of Epstein-Barr virus (EBV) infection is mediated by expression of the viral immediate-early (IE) proteins, BZLF1 (Z) and BRLF1 (R). An EBV early protein, BRRF1 (Na), is encoded by the opposite strand of the BRLF1 intron, but the function of this nuclear protein in the viral life cycle is unknown. Here we demonstrate that Na enhances the R-mediated induction of lytic EBV infection in 293 cells latently infected with a recombinant EBV (R-KO) defective for the expression of both R and Na. Na also enhances R-induced lytic infections in a gastric carcinoma line (AGS) carrying the R-KO virus, although it has no effect in a Burkitt lymphoma line (BL-30) stably infected with the same mutant virus. We show that Na is a transcription factor that increases the ability of R to activate Z expression from the R-KO viral genome in 293 cells and that Na by itself activates the Z promoter (Zp) in EBV-negative cells. Na activation of Zp requires a CRE motif (ZII), and a consensus CRE motif is sufficient to transfer Na responsiveness to the heterologous E1b promoter. Furthermore, we show that Na enhances the transactivator function of a Gal4-c-Jun fusion protein but does not increase the transactivator function of other transcription factors (including ATF-1, ATF-2, and CREB) known to bind CRE motifs. Na expression in cells results in increased levels of a hyperphosphorylated form of c-Jun, suggesting a mechanism by which Na activates c-Jun. Our results indicate that Na is a transcription factor that activates the EBV Zp IE promoter through its effects on c-Jun and suggest that Na cooperates with BRLF1 to induce the lytic form of EBV infection in certain cell types.

scholarly journals c-Myc Represses Transcription of Epstein-Barr Virus Latent Membrane Protein 1 Early after Primary B Cell Infection

2017 ◽  
Vol 92 (2) ◽  
Author(s):  
Alexander M. Price ◽  
Joshua E. Messinger ◽  
Micah A. Luftig
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
Membrane Protein ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Latent Membrane Protein ◽  
Cell Infection ◽  
Barr Virus ◽  
Epstein Barr ◽  
Factor C

ABSTRACTRecent evidence has shown that the Epstein-Barr virus (EBV) oncogene LMP1 is not expressed at high levels early after EBV infection of primary B cells, despite its being essential for the long-term outgrowth of immortalized lymphoblastoid cell lines (LCLs). In this study, we found that expression of LMP1 increased 50-fold between 7 days postinfection and the LCL state. Metabolic labeling of nascent transcribed mRNA indicated that this was primarily a transcription-mediated event. EBNA2, the key viral transcription factor regulating LMP1, and CTCF, an important chromatin insulator, were recruited to the LMP1 locus similarly early and late after infection. However, the activating histone H3K9Ac mark was enriched at the LMP1 promoter in LCLs relative to that in infected B cells early after infection. We found that high c-Myc activity in EBV-infected lymphoma cells as well as overexpression of c-Myc in an LCL model system repressed LMP1 transcription. Finally, we found that chemical inhibition of c-Myc both in LCLs and early after primary B cell infection increased LMP1 expression. These data support a model in which high levels of endogenous c-Myc activity induced early after primary B cell infection directly repress LMP1 transcription.IMPORTANCEEBV is a highly successful pathogen that latently infects more than 90% of adults worldwide and is also causally associated with a number of B cell malignancies. During the latent life cycle, EBV expresses a set of viral oncoproteins and noncoding RNAs with the potential to promote cancer. Critical among these is the viral latent membrane protein LMP1. Prior work suggests that LMP1 is essential for EBV to immortalize B cells, but our recent work indicates that LMP1 is not produced at high levels during the first few weeks after infection. Here we show that transcription of the LMP1 gene can be negatively regulated by a host transcription factor, c-Myc. Ultimately, understanding the regulation of EBV oncogenes will allow us to better treat cancers that rely on these viral products for survival.

scholarly journals Nucleoprotein Structure of Immediate-Early Promoters Zp and Rp and of oriLyt of Latent Epstein-Barr Virus Genomes

2002 ◽  
Vol 76 (8) ◽  
pp. 4113-4118 ◽  
Author(s):  
Hans Helmut Niller ◽  
Daniel Salamon ◽  
Jörg Uhlig ◽  
Stefanie Ranf ◽  
Marcus Granz ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
Initiation Site ◽  
Transient Transfection ◽  
Immediate Early ◽  
Barr Virus ◽  
Latently Infected ◽  
Epstein Barr ◽  
Virus Genomes

ABSTRACT Genomic footprints across Rp, Zp, and oriLyt of Epstein-Barr virus (EBV) have been conducted in a panel of latently infected B-cell lines. Close protein-base contacts were found about 360 nucleotides upstream of the Zp initiation site. Gel shifts and transient transfection assays indicated that an Sp1-NF1 locus may serve as a repressive transcriptional element against Zp induction from latent EBV genomes.

scholarly journals Epstein-Barr Virus Represses the FoxO1 Transcription Factor through Latent Membrane Protein 1 and Latent Membrane Protein 2A

2006 ◽  
Vol 80 (22) ◽  
pp. 11191-11199 ◽  
Author(s):  
Angharad M. Shore ◽  
Paul C. White ◽  
Rosaline C.-Y. Hui ◽  
Abdelkader Essafi ◽  
Eric W.-F. Lam ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Membrane Protein ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 1 ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) infection is associated with the development of many B-cell lymphomas, including Burkitt's lymphoma, Hodgkin's lymphoma, and posttransplant lymphoproliferative disease. The virus alters a diverse range of cellular molecules, which leads to B-cell growth and immortalization. This study was initiated to investigate the interplay between EBV and a proapoptotic transcription factor target, FoxO1. In this report, we show that EBV infection of B cells leads to the downregulation of FoxO1 expression by phosphatidylinositol 3-kinase-mediated nuclear export, by inhibition of FoxO1 mRNA expression, and by alteration of posttranslational modifications. This repression directly correlates with the expression of the FoxO1 target gene Bcl-6 and inversely correlates with the FoxO1-regulated gene Cyclin D2. Expression of the EBV genes for latent membrane protein 1 and latent membrane protein 2A decreases FoxO1 expression. Thus, our data elucidate distinct mechanisms for the regulation of the proapoptotic transcription factor FoxO1 by EBV.

scholarly journals Study On the Mechanism of LMP2A Maintaining Epstein-barr Virus Latency Infection Through Interaction With CXCR4

2021 ◽  
Author(s):  
Ni Qin ◽  
Yan Zhang ◽  
Lin Xu ◽  
Wen Liu ◽  
Bing Luo
Keyword(s):  
Gastric Cancer ◽  
Epstein Barr Virus ◽  
Human Tumor ◽  
Signal Pathways ◽  
Barr Virus ◽  
Virus Latency ◽  
Early Protein ◽  
Tumor Virus ◽  
Epstein Barr ◽  
And Migration

Abstract Epstein-Barr virus (EBV) belongs to the γ-herpesvirus subfamily and is the first human tumor virus to be discovered. The global adult infection rate exceeds 90%. EBV can participate in the regulation of multiple genes and multiple signal pathways through its latent genes. Many studies have reported that CXCR4 is involved in the development of gastric cancer, but there are few studies on the specific mechanism of its role in EBV-associated gastric cancer (EBVaGC). In this study, we explored the mechanism by which EBV-encoded products maintain EBV latent infection through interaction with CXCR4, and the role of CXCR4 in EBV positive cells. The results show that there is a positive feedback between the EBV-encoded products and CXCR4, and LMP2A can activate CXCR4 through the NF-κB pathway. In addition, CXCR4 can be fed back to LMP2A and EBNA1 through the ERK signaling pathway. At the same time, CXCR4 can promote the proliferation and migration of EBV-positive cells, reduce the expression of the immediate early protein BZLF1, and play an important role in maintaining the incubation period of EBV infection. These findings are conducive to the further targeted therapy of EBVaGC.

scholarly journals Epstein-Barr Virus Immediate-Early Protein BZLF1 Is SUMO-1 Modified and Disrupts Promyelocytic Leukemia Bodies

2001 ◽  
Vol 75 (5) ◽  
pp. 2388-2399 ◽  
Author(s):  
Amy L. Adamson ◽  
Shannon Kenney
Keyword(s):  
Cell Lines ◽  
Transcriptional Activation ◽  
Epstein Barr Virus ◽  
Promyelocytic Leukemia ◽  
Lytic Replication ◽  
Immediate Early ◽  
Barr Virus ◽  
Early Protein ◽  
Pml Bodies ◽  
Epstein Barr

ABSTRACT Although the immediate-early proteins of both herpes simplex virus (HSV) and cytomegalovirus (CMV) are known to modify promyelocytic leukemia (PML) (ND10) bodies in the nucleus of the host cell, it has been unclear whether lytic infection with gamma herpesviruses induces a similar effect. The PML protein is induced by interferon, involved in major histocompatibility complex class I presentation, and necessary for certain types of apoptosis. Therefore, it is likely that PML bodies function in an antiviral capacity. SUMO-1 modification of PML is known to be required for the formation of PML bodies. To examine whether Epstein-Barr virus (EBV) lytic replication interferes with PML bodies, we expressed the EBV immediate-early genes BZLF1 (Z) and BRLF1 (R) in EBV-positive cell lines and examined PML localization. Both Z and R expression resulted in PML dispersion in EBV-positive cells. Z but not R expression is sufficient to disrupt PML bodies in EBV-negative cell lines. We show that dispersion of PML bodies by Z requires a portion of the transcriptional activation domain of Z but not the DNA-binding function. As was previously reported for the HSV-1 ICP0 and CMV IE1 proteins, Z reduces the amount of SUMO-1-modified PML. We also found that Z itself is SUMO-1 modified (through amino acid 12) and that Z competes with PML for limiting amounts of SUMO-1. These results suggest that disruption of PML bodies is important for efficient lytic replication of EBV. Furthermore, Z may potentially alter the function of a variety of cellular proteins by inhibiting SUMO-1 modification.

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