Induction of Epstein-Barr Virus Latent Membrane Protein 1 by a Lytic Transactivator Rta

Chang, Yao; Lee, Heng-Huan; Chang, Shannon; Hsu, Ting-Yu; Wang, Pei Wen; Chang, Yu Sun; Takada, Kenzo; Tsai, Ching Hwa

doi:10.1128/jvi.78.23.13028-13036.2004

Cited by 37 publications

(40 citation statements)

References 79 publications

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“…A number of studies have demonstrated that LMP1 serves an important role in the EBV lytic cycle (24,45,46). While LMP1 may be expressed in some states of EBV latency, significant induction of full-length LMP1 is frequently observed during virus reactivation into the lytic cycle (13,47,48).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, transfection of cells with an exogenous Rta plasmid has been demonstrated to induce the expression of LMP1 in a variety of epithelial cell lines such as NPC NA, EBV-infected HeLa, 293, P3HR1 and Akata cells (24). The close correlation between the inducible increased expression of LMP1 and the EBV replication cycle indicates that LMP1 expression, as a lytic cycle gene, is under the control of the lytic cycle program (24). In a previous study, lack of LMP1 expression severely impaired virus release into culture supernatants, which resulted in poor infection efficiency.…”

Section: Discussionmentioning

confidence: 99%

“…While LMP1 may be expressed in some states of EBV latency, significant induction of full-length LMP1 is frequently observed during virus reactivation into the lytic cycle (13,47,48). Notably, when EBV reactivation is induced by various stimuli, including cross-linking of surface immunoglobulin, virus superinfection and treatment with phorbol ester, 5-azacytidine, butyrate or histone deacetylase inhibitors, the expression of full-length LMP1 may be significantly increased (13,(22)(23)(24)(25). Furthermore, transfection of cells with an exogenous Rta plasmid has been demonstrated to induce the expression of LMP1 in a variety of epithelial cell lines such as NPC NA, EBV-infected HeLa, 293, P3HR1 and Akata cells (24).…”

Section: Discussionmentioning

confidence: 99%

“…Notably, when EBV reactivation is induced by various stimuli, including cross-linking of surface immunoglobulin, virus superinfection and treatment with phorbol ester, 5-azacytidine, butyrate or histone deacetylase inhibitors, the expression of full-length LMP1 may be significantly increased (13,(22)(23)(24)(25). Furthermore, transfection of cells with an exogenous Rta plasmid has been demonstrated to induce the expression of LMP1 in a variety of epithelial cell lines such as NPC NA, EBV-infected HeLa, 293, P3HR1 and Akata cells (24). The close correlation between the inducible increased expression of LMP1 and the EBV replication cycle indicates that LMP1 expression, as a lytic cycle gene, is under the control of the lytic cycle program (24).…”

Section: Discussionmentioning

confidence: 99%

“…Through its cytoplasmic C-terminal, LMP1 may trigger multiple signal transduction cascades, including the MAPK kinase (MEK)/extracellular signal-regulated kinase (ERK), PI3-K/Akt, c-Jun N-terminal kinase (JNK) and signal transducer and activator of transcription 3 signaling pathways, to alter cell growth and survival (20,21). Furthermore, LMP1 is established as a critical viral protein required for the EBV life cycle (13,(22)(23)(24)(25).Our previous work indicated that EGCG may inhibit the spontaneous reactivation of EBV, which was associated with activation of the MAPK and PI3-K/Akt pathways (26). …”

mentioning

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

(-)-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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hTERT inhibits the Epstein‐Barr virus lytic cycle and promotes the proliferation of primary B lymphocytes: Implications for EBV‐driven lymphomagenesis

Terrin

Dolcetti

Corradini

et al. 2007

Intl Journal of Cancer

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Transformation of primary B lymphocytes by Epstein-Barr Virus (EBV) requires the establishment of a latent infection, the expression of several latent viral proteins and a sustained telomerase activity. We investigated the interplay between the activation of human telomerase reverse transcriptase (hTERT), the catalytic rate-limiting component of the telomerase complex, and the expression of latent/lytic EBV genes during the establishment of a stably latent EBV infection of normal B lymphocytes. Cell cultures at early passages after EBV infection greatly differed in their timing of hTERT expression and telomerase activation. Induction of hTERT was dependent on the balance between latent and lytic EBV gene expression, being positively associated with a high ratio of latent/lytic isoforms of latent membrane protein 1, and negatively associated with the expression of BZLF1 gene, the main activator of the viral lytic cycle. In turn, hTERT expression was followed by a decrease in EBV lytic gene expression and virus production. Ectopic expression of hTERT in BZLF1-positive B cell cultures resulted in BZLF1 down-regulation, increased resistance to lytic cycle induction, and enhanced in vitro growth properties, whereas hTERT inhibition by siRNA triggered the activation of the EBV lytic cycle. These findings indicate that hTERT contributes by multiple mechanisms to the EBV-driven transformation of B lymphocytes and suggest that hTERT may constitute a therapeutic target for EBV-associated B cell lymphomas. ' 2007 Wiley-Liss, Inc. Key words: hTERT; EBV latent infection; B lymphocytesEpstein-Barr virus (EBV) is closely associated with a broad spectrum of malignancies in vivo, and EBV infection of resting B cells in vitro results in the generation of immortalized, continuously proliferating lymphoblastoid cell lines (LCLs). Similar to other gammaherpesviruses, EBV has both latent and lytic stages in its life cycle. Viral replication is triggered by the expression of the BZLF1 gene, which initiates a cascade of viral lytic gene expression that culminates in the release of infectious virus and the death of host cells.1 In vitro grown LCLs, like most of the EBV-related tumors associated with immune suppression, harbor EBV mainly in its latent state and express several latent proteins, including 6 nuclear antigens (EBNAs) and 3 latent membrane proteins (LMP1, LMP2A and LMP2B). Expression of LMP1 is key to the ability of EBV to transform B cells.2 LMP1 functions as a constitutively active tumor necrosis factor receptor, and triggers multiple cell signaling pathways in a ligand-independent manner. 3-6Notably, LMP1 is also expressed early during EBV replication, being activated by the lytic transactivator protein Rta.7 In addition, the LMP1 gene of several EBV strains also contains a late lytic cycle promoter, EDL1A, driving the expression of an amino-terminally truncated form of LMP1, the lytic LMP1 (lyLMP1), 8,9 which can affect the ability of LMP1 to activate cell signaling pathways. 9,10Expression of latent EBV proteins is not s...

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Roles of lytic viral infection and IL‐6 in early versus late passage lymphoblastoid cell lines and EBV‐associated lymphoproliferative disease

Jones

Seaman²,

Feng³

et al. 2007

Intl Journal of Cancer

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Lytically infected EBV-positive lymphoblastoid cells enhance the growth of early-passage, but not late-passage, EBV-immortalized lymphoblastoid cell lines (LCLs) in SCID mice and have enhanced IL-6 secretion. Here, we have examined the importance of IL-6 for the growth of early-passage LCLs (EPL) in SCID mice, identified lytic EBV proteins that activate IL-6 production and compared viral and cellular differences between early versus late passage LCLs (LPL). IL-6 was required for efficient growth of EPL in SCID mice. The EBV immediate-early (IE) proteins, BRLF1 and BZLF1, each induced IL-6 secretion when transfected into 293 and BJAB cells. Interestingly, the combination of BZLF1 and the latent EBV protein, LMP-1, induced much more IL-6 expression in both 293 and BJAB cells than either protein alone. Both BZLF1 and BRLF1 also enhanced IL-10 production in 293 cells. In comparison to the EPL, LPL had much reduced expression of early lytic viral proteins and cellular IL-6. In contrast, expression of cellular IL-10 was similar in EPL versus LPL, while VEGF secretion was increased in late-passage LCLs. These results suggest that both BRLF1 and BZLF1 contribute to IL-6 secretion in lytically infected cells and that lytically infected cells may promote early lymphoproliferative disease in patients through enhanced IL-6 production. ' 2007 Wiley-Liss, Inc.

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Induction of Epstein-Barr Virus Latent Membrane Protein 1 by a Lytic Transactivator Rta

Cited by 37 publications

References 79 publications

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

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

hTERT inhibits the Epstein‐Barr virus lytic cycle and promotes the proliferation of primary B lymphocytes: Implications for EBV‐driven lymphomagenesis

Roles of lytic viral infection and IL‐6 in early versus late passage lymphoblastoid cell lines and EBV‐associated lymphoproliferative disease

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