Latent Membrane Protein 1 Inhibits Epstein-Barr Virus Lytic Cycle Induction and Progress via Different Mechanisms

Prince, Stuart; Keating, Sinéad E.; Fielding, Ceri Alan; Brennan, Paul; Floettmann, Eike; Rowe, Martin

doi:10.1128/jvi.77.8.5000-5007.2003

Cited by 58 publications

(63 citation statements)

References 55 publications

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“…2B). Furthermore, in line with the known inhibitory effect of LMP-1 on the entry to the lytic cycle (24,25), the percentage of cells entering spontaneously in the lytic cycle decreased from ≈5-8% to 1-2% (Fig. 2B).…”

Section: Resultsmentioning

confidence: 49%

IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter

Kis

Salamon

Persson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Epstein-Barr virus (EBV) is associated with a variety of human tumors. Although the EBV-infected normal B cells in vitro and the EBV-carrying B cell lymphomas in immunodeficient patients express the full set of latent proteins (type III latency), the majority of EBVassociated malignancies express the restricted type I (EBNA-1 only) or type II (EBNA-1 and LMPs) viral program. The mechanisms responsible for these different latent viral gene expression patterns are only partially known. IL-21 is a potent B cell activator and plasma cell differentiation-inducer cytokine produced by CD4 + T cells. We studied its effect on EBV-carrying B cells. In type I Burkitt lymphoma (BL) cell lines and in the conditional lymphoblastoid cell line (LCL) ER/ EB2-5, IL-21 potently activated STAT3 and induced the expression of LMP-1, but not EBNA-2. The IL-21-treated type I Jijoye M13 BL line ceased to proliferate, and this was paralleled by the induction of IRF4 and the down-regulation of BCL6 expression. In the type III LCLs and BL lines, IL-21 repressed the C-promoter-derived and LMP-2A mRNAs, whereas it up-regulated the expression of LMP-1 mRNAs. The IL-21-treated type III cells underwent plasma cell differentiation with the induction of Blimp-1, and high levels of Ig and Oct-2. IL-21 might be involved in the EBNA-2-independent expression of LMP-1 in EBV-carrying type II cells. In light of the fact that IL-21 is already in clinical trials for the treatment of multiple malignancies, the in vivo modulation of EBV gene expression by IL-21 might have therapeutic benefits for the EBV-carrying malignancies.Epstein-Barr virus | IL-21 | lymphoma | STAT3

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Section: Resultsmentioning

confidence: 49%

IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter

Kis

Salamon

Persson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…For instance, LMP1 was reported to inhibit lytic cycle induction via the transcription factor nuclear factor-κB in an EBV-positive Burkitt's lymphoma P3HR1-c16 cell line, which lacks LMP1 and may be activated into a virally productive lytic cycle (52). These findings indicate that in B cells, EBV self-limits its lytic cycle via the transcription factor nuclear factor (NF)-κB.…”

Section: Discussionmentioning

confidence: 79%

“…These findings indicate that in B cells, EBV self-limits its lytic cycle via the transcription factor nuclear factor (NF)-κB. In addition, LMP1 inhibits lytic cycle progress via two distinct NF-κB-independent mechanisms: One associated with the cytosolic C-terminal activating regions and the other with the transmembrane region of LMP1 (52). Additionally, cluster of differentiation (CD) 40-CD40 ligand interactions and viral mimics of activated CD40 and LMP1 suppress virus reactivation, and this regulation of latency by CD40 and LMP1 may have important implications for the balance between EBV and its host in normal or immunocompromised individuals (55).…”

Section: Discussionmentioning

confidence: 96%

“…Other studies have suggested a conflicting model in which LMP1 inhibits lytic cycle progression (52)(53)(54). For instance, LMP1 was reported to inhibit lytic cycle induction via the transcription factor nuclear factor-κB in an EBV-positive Burkitt's lymphoma P3HR1-c16 cell line, which lacks LMP1 and may be activated into a virally productive lytic cycle (52).…”

Section: Discussionmentioning

confidence: 99%

“…It is also speculated that once EBV is reactivated into the lytic cycle, the induced expression of LMP1 is considered to be critical for efficient virus release and infection of new host cells. However, high levels of LMP1 may negatively regulate EBV lytic infection (52)(53)(54). Therefore, EBV has developed a series of strategies to maintain itself in host cells over the host's lifetime, and only periodically produces infectious virons to transmit and infect new host cells.…”

Section: Discussionmentioning

confidence: 99%

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(-)-Epigallocatechin‑3‑gallate inhibition of Epstein‑Barr virus spontaneous lytic infection involves downregulation of latent membrane protein 1

Liu

Tang

et al. 2017

Exp Ther Med

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Abstract. The Epstein-Barr virus (EBV) lytic cycle contributes to the development of EBV-associated diseases. EBV-encoded latent membrane protein 1 (LMP1) is key to EBV lytic replication, and our previous work indicated that epigallocatechin-3-gallate (EGCG) inhibited constitutive EBV lytic infection through the suppression of LMP1-activated phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase kinase/extracellular signal-related protein kinase 1/2 signaling. The present study demonstrated that LMP1 in CNE-LMP1 constructed cells significantly induced the expression of the EBV lytic proteins BZLF1 (P<0.001) and BMRF1 (P<0.05) compared with CNE1 cells. Following treatment with a specific DNAzyme that targets LMP1, significantly reduced protein expression levels of BZLF1 and BMRF1 in EBV-associated epithelial carcinoma CNE1-LMP1 cells (P<0.001 and P<0.01, respectively) and lymphoma B95.8 cells (both P<0.01) were observed. Furthermore, EGCG significantly inhibited the mRNA and protein expression levels of LMP1 (P<0.05) in an apparent dose-dependent manner in CNE1-LMP1 and B95.8 cells. Thus, the present findings indicated that the molecular mechanism underlying EGCG inhibition of EBV lytic infection involves downregulation of LMP1. IntroductionEpstein-Barr virus (EBV) is a human herpes virus that infects over 90% of the human population worldwide (1). EBV is suggested to be an environmental factor associated with the development of several human malignancies, including nasopharyngeal carcinoma (NPC), Burkitt's lymphoma, Hodgkin's disease (HD), gastric cancer, natural killer/T-cell lymphoma, acquired immune deficiency syndrome-and transplantation-associated lymphoma (2,3), breast carcinoma, and hepatocellular carcinoma (4,5). EBV, as all other herpes viruses, may establish a latent or lytic infection in host cells (6). Notably, studies suggest that EBV reactivation into a lytic cycle may contribute to the pathogenesis of malignancies (7,8). EBV lytic infection in vivo has been identified by elevated antibody titers against EBV lytic antigens and by increased viral DNA load in the serum/plasma, and these observations correspond with advanced cancer stages, poor prognosis or tumor recurrence following therapy (9,10). Additionally, serological studies have indicated that EBV lytic infection may occur months or years prior to a clinical diagnosis of NPC, HD or Burkitt's lymphoma, which suggests EBV lytic infection may be a risk factor for cancer development (11-13).Green tea contains (-)-epigallocatechin-3-gallate (EGCG), which is reported to have antioxidant, antibacterial and antitumor effects (14,15). EGCG has been indicated to modulate multiple signaling pathways, including the phosphoinositide 3-kinase (PI3-K)/Akt and mitogen-activated protein kinase (MAPK) signaling pathways, which may enable it to exert its cancer chemopreventive and therapeutic effects (16,17).EBV encoded latent membrane protein 1 (LMP1), which is considered to have oncogenic properties, has been identified in 90% of patients with NPC...

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The role of oxidative stress in EBV lytic reactivation, radioresistance and the potential preventive and therapeutic implications

Luo

et al. 2017

Intl Journal of Cancer

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Epstein-Barr virus (EBV) is an important cancer causing virus. Cancer associated with EBV account for approximately 1.5% of all cancers, and represent 1.8% of all cancer deaths worldwide. EBV reactivation plays an important role in the development of EBV-related diseases and is closely related with patients' survival and clinical stages of EBV-related cancers. The therapy regarding to EBV-related cancers is very urgent, especially in endemic areas. Generating oxidative stress is a critical mechanism by which host cells defend against infection by virus. In addition, ROS-mediated oxidative stress plays a significant but paradoxical role acting as a "double-edged sword" to regulate cellular response to radiation, which is the main therapy strategy for EBV-related cancers, especially nasopharyngeal carcinoma. Therefore, in this review we primarily discuss the possible interplay among the oxidative stress, EBV lytic reactivation and radioresistance. Understanding the role of oxidative stress in EBV lytic reactivation and radioresistance will assist in the development of effective strategies for prevention and treatment of EBV-related cancers.

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Latent Membrane Protein 1 Inhibits Epstein-Barr Virus Lytic Cycle Induction and Progress via Different Mechanisms

Cited by 58 publications

References 55 publications

IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter

IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter

(-)-Epigallocatechin‑3‑gallate inhibition of Epstein‑Barr virus spontaneous lytic infection involves downregulation of latent membrane protein 1

The role of oxidative stress in EBV lytic reactivation, radioresistance and the potential preventive and therapeutic implications

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