scholarly journals Activation of the ERK signal transduction pathway by Epstein–Barr virus immediate-early protein Rta

2008 ◽  
Vol 89 (10) ◽  
pp. 2437-2446 ◽  
Author(s):  
Yu-Hsiu Lee ◽  
Ya-Fang Chiu ◽  
Wen-Hung Wang ◽  
Li-Kwan Chang ◽  
Shih-Tung Liu
Keyword(s):  
Signal Transduction ◽  
Epstein Barr Virus ◽  
Signal Transduction Pathway ◽  
Early Gene ◽  
Immediate Early ◽  
Transduction Pathway ◽  
Binding Studies ◽  
Barr Virus ◽  
Early Protein ◽  
Epstein Barr

BRCA1-associated protein 2 (BRAP2) is known to interact with the kinase suppressor of Ras 1 (KSR1), inhibiting the ERK signal transduction cascade. This study found that an Epstein–Barr virus (EBV) immediate-early protein, Rta, is a binding partner of BRAP2 in yeast and confirmed the binding in vitro by a glutathione S-transferase pull-down assay and in vivo by co-immunoprecipitation in 293(maxi-EBV) cells. Binding studies also showed that Rta and KSR1 interacted with the C-terminal 202 aa region in BRAP2. Additionally, Rta appeared to prevent the binding of KSR1 to BRAP2, activating the ERK signal transduction pathway and the transcription of an EBV immediate-early gene, BZLF1. Activation of the ERK signal transduction pathway by Rta may be critical for the maintenance of the lytic state of EBV.

scholarly journals Divergent Requirements for the MAPKERK Signal Transduction Pathway during Initial Virus Infection of Quiescent Primary B Cells and Disruption of Epstein-Barr Virus Latency by Phorbol Esters

1999 ◽  
Vol 73 (10) ◽  
pp. 8913-8916 ◽  
Author(s):  
Mandy Fenton ◽  
Alison J. Sinclair
Keyword(s):  
Signal Transduction ◽  
Epstein Barr Virus ◽  
Phorbol Esters ◽  
Signal Transduction Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Transduction Pathway ◽  
Barr Virus ◽  
Virus Latency ◽  
Mitogen Activated Protein ◽  
Epstein Barr

ABSTRACT Quiescent primary B lymphocytes and Epstein-Barr virus (EBV)-immortalized lymphoblastoid cell lines express components of the extracellular response kinase arm of the mitogen-activated protein kinase (MAPKERK) signal transduction pathway and transmit signals through the pathway when exposed to appropriate stimuli. Although the MAPKERK pathway is activated following infection with EBV, MAPK/ERK kinase (MEK1) activity is not required to drive the proliferation of infected cells. However, MEK1 contributes to EBV latency control.

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 Identification of Protein Tyrosine Kinases Required for B-Cell- Receptor-Mediated Activation of an Epstein-Barr Virus Immediate-Early Gene Promoter

2004 ◽  
Vol 78 (16) ◽  
pp. 8543-8551 ◽  
Author(s):  
Sandra Lavens ◽  
Emmanuel A. Faust ◽  
Fang Lu ◽  
Michele Jacob ◽  
Messele Leta ◽  
...  
Keyword(s):  
Signal Transduction ◽  
B Cell ◽  
Tyrosine Kinases ◽  
Epstein Barr Virus ◽  
Cell Receptor ◽  
Lytic Cycle ◽  
Protein Tyrosine Kinases ◽  
Early Gene ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT Epstein-Barr Virus (EBV) is a potentially oncogenic herpesvirus that infects >90% of the world's population. EBV exists predominantly as a latent infection in B lymphocytes, with periodic lytic-cycle reactivation essential for cellular and host transmission. Viral reactivation can be stimulated by ligand-induced activation of B-cell-receptor (BCR)-coupled signaling pathways. The critical first step in the transition from latency to the lytic cycle is the expression of the viral immediate-early gene BZLF1 through the transcription activation of its promoter, Zp. However, the BCR-coupled signal transduction cascade(s) leading to the induction of Zp and the expression of the BZLF1 gene product, Zta, is currently unclear. A major obstacle to delineating the relevant signal transduction events has been the lack of a model of EBV infection that is amenable to genetic manipulation. The use of the avian B-cell line DT40 has proven to be a powerful tool for delineating BCR-mediated signal transduction pathways that appear to be highly conserved between avian and mammalian systems. We demonstrate that the DT40 cell line is a robust and genetically tractable system for the study of BCR-mediated signaling pathways leading to transcriptional activation of BZLF1. Using this system, we demonstrate that activation of Zp requires the BCR-coupled protein tyrosine kinases Syk and Btk and that it is positively regulated by Lyn. Thus, the use of DT40 cells has allowed us to delineate the early signaling components required for BCR-dependent reactivation of latent EBV, and this system is likely to prove useful for further dissection of the downstream signaling cascades involved.

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.

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