Autoactivation of the Epstein-Barr Virus Oncogenic Protein LMP1 during Type II Latency through Opposite Roles of the NF-κB and JNK Signaling Pathways

Goormachtigh, Gautier; Ouk, Tan‐Sothéa; Mougel, Alexandra; Tranchand-Bunel, D.; Masy, E.; Clorennec, Christophe Le; Feuillard, Jean; Bornkamm, Georg W.; Auriault, Claude; Manet, Évelyne; Fafeur, Véronique; Adriaenssens, Eric; Cottet, J

doi:10.1128/jvi.02052-05

Cited by 29 publications

(23 citation statements)

References 70 publications

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“…For quantification of LMP1 mRNA in EBV-infected cells, Qp-EBNA1 was used as a control. Primers for LMP1 and Qp-EBNA1 have been described (34,35). …”

Section: Methodsmentioning

confidence: 99%

Modulation of LMP1 protein expression by EBV-encoded microRNAs

To²,

et al. 2007

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

317

292

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Epstein-Barr virus (EBV) was the first human virus found to encode microRNAs (miRNAs), but the function of these miRNAs has been obscure. Nasopharyngeal carcinoma (NPC) is associated with EBV infection, and the EBV-encoded LMP1 is believed to be a key factor in NPC development. However, detection of LMP1 protein in NPC is variable. Here, we report that EBV-encoded BART miRNAs target the 3 UTR of the LMP1 gene and negatively regulate LMP1 protein expression. These miRNAs also modulate LMP1-induced NF-B signaling and alleviate the cisplatin sensitivity of LMP1-expressing NPC cells. Consistent with a previous study on the NPC C666-1 cell line and C15 xenograft, we found abundant expression of BART miRNAs in NPC tissues. Furthermore, DNA sequencing revealed that the 3 UTR of LMP1 is highly conserved in NPC-derived EBV isolates. The data provide insight into the discrepancy between LMP1 transcript and protein detection in NPC and highlight the role of the EBV miRNAs in regulating LMP1 downstream signaling to promote cancer development. Epstein-Barr virus ͉ nasopharyngeal carcinoma

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“…For quantification of LMP1 mRNA in EBV-infected cells, Qp-EBNA1 was used as a control. Primers for LMP1 and Qp-EBNA1 have been described (34,35). …”

Section: Methodsmentioning

confidence: 99%

Modulation of LMP1 protein expression by EBV-encoded microRNAs

To²,

et al. 2007

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

317

292

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“…This transactivation is dependent on cellular transcription factors and is mediated through several EBNA2-responsive elements at the LMP1 promoter. In the latency II pattern of gene expression, a few transcription factors, including STAT, IRF7, ATF4, ATF2, and NF-B (5,21,31,40,47), have been identified as candidates for LMP1 transactivation. It is becoming apparent that LMP1 transactivation in latency II may require the cooperation of several transcription factors, none of which seem to be absolutely critical in promoter activation.…”

Section: Discussionmentioning

confidence: 99%

“…While a number of EBNA2-independent LMP1 activators have been identified, none of them seem to be critical for LMP1 expression in latency II. Recent data suggest that LMP1 expression in latency II cells is mediated by cell signaling pathways that are activated by LMP1 itself (21,40).The complexity of LMP1 expression is further emphasized in a study by Lam et al (37). This study showed that LMP1 expression levels of individual cells in a clone of EBV lymphoblasts can range over 100-fold.…”

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confidence: 91%

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The p38 Signaling Pathway Upregulates Expression of the Epstein-Barr Virus LMP1 Oncogene

Johansson

Jansson

Rüetschi

et al. 2010

J Virol

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The Epstein-Barr virus (EBV)-encoded LMP1 oncogene has a role in transformation, proliferation, and metastasis of several EBV-associated tumors. Furthermore, LMP1 is critically involved in transformation and growth of EBV-immortalized B cells in vitro. The oncogenic properties of LMP1 are attributed to its ability to upregulate anti-apoptotic proteins and growth signals. The transcriptional regulation of LMP1 is dependent on the context of cellular and viral proteins present in the cell. Here, we investigated the effect of several signaling pathways on the regulation of LMP1 expression. Inhibition of p38 signaling, using p38-specific inhibitors SB203580 and SB202190, downregulated LMP1 in estrogen-induced EREB2.5 cells. Similarly, p38 inhibition decreased trichostatin A-induced LMP1 expression in P3HR1 cells. Exogenous expression of p38 in lymphoblastoid cell lines (LCLs) led to an increase in LMP1 promoter activity in reporter assays, and this activation was mediated by the previously identified CRE site in the promoter. Inhibition of p38 by SB203580 and p38-specific small interfering RNA (siRNA) also led to a modest decrease in endogenous LMP1 expression in LCLs. Chromatin immunoprecipitation indicated decreased binding of CREB-ATF1 to the CRE site in the LMP1 promoter after inhibition of the p38 pathway in EREB2.5 cells. Taken together, our results suggest that an increase in p38 activation upregulates LMP1 expression. Since p38 is activated in response to stimuli such as stress or possibly primary infection, a transient upregulation of LMP1 in response to p38 may allow the cells to escape apoptosis. Since the p38 pathway itself is activated by LMP1, our results also suggest the presence of an autoregulatory loop in LMP1 upregulation. Epstein-Barr virus (EBV) is a human B-lymphocryptovirusthat infects approximately 90% of the world's adult population and is the causative agent of infectious mononucleosis (IM). EBV is associated with several human malignancies such as Burkitt's lymphoma (BL), Hodgkin's lymphoma (HL), nasopharyngeal carcinoma (NPC), nasal T/NK lymphoma (NL), peripheral T-cell lymphoma, gastric carcinoma, and lymphoproliferative diseases in immunocompromised patients (57). EBV establishes latent infection in human B cells and transforms them in culture. The EBV-encoded LMP1 oncogene is critically involved in the EBV immortalization of B cells and their persistence in vitro, and it has the ability to transform rodent fibroblast and human cell lines in culture (4). LMP1 expression is thought to contribute to the genesis and growth of EBV-associated tumors. The oncogenic ability of LMP1 is attributed to its upregulation of anti-apoptotic proteins and growth signaling pathways (55). LMP1 transcription is regulated by both viral and cellular factors. EBV uses different programs of viral gene expression in order to drive naïve B cells into resting memory cells. These patterns of viral gene expression are referred to as latency types I, II, and III. EBV-associated tumors also exhibit similar patterns o...

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“…On this point, nothing has been known regarding the potential function(s) of UL144 in regulating HCMV latency. However, its pleiotropic functions as an immune-modulating protein, several of which are reminiscent of the latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) (40,43,44), suggest it as a potential candidate.…”

mentioning

confidence: 99%

The Myeloid Transcription Factor GATA-2 Regulates the Viral UL144 Gene during Human Cytomegalovirus Latency in an Isolate-Specific Manner

Poole

Walther

Raven

et al. 2013

J Virol

102

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It is generally accepted that, following primary infection, human cytomegalovirus (HCMV) establishes lifelong latency in CD34؉ progenitor cells and other derivative cells of the myeloid lineage. In this study, we show that the viral UL144 gene is expressed during latent infection in two cell types of the myeloid lineage, CD34؉ and CD14 ؉ monocytes, and that the UL144 protein is functional in latently infected monocytes. However, this latency-associated expression of UL144 occurs only in certain isolates of HCMV and depends on the presence of functional GATA-2 transcription factor binding sites in the UL144 promoter, in contrast to the viral latency-associated gene LUNA, which we also show is regulated by GATA-2 but expressed uniformly during latent infection independent of the virus isolate. Taken together, these data suggest that the HCMV latency-associated transcriptome may be virus isolate specific and dependent on the repertoire of transcription factor binding sites in the promoters of latencyassociated genes.

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Autoactivation of the Epstein-Barr Virus Oncogenic Protein LMP1 during Type II Latency through Opposite Roles of the NF-κB and JNK Signaling Pathways

Cited by 29 publications

References 70 publications

Modulation of LMP1 protein expression by EBV-encoded microRNAs

Modulation of LMP1 protein expression by EBV-encoded microRNAs

The p38 Signaling Pathway Upregulates Expression of the Epstein-Barr Virus LMP1 Oncogene

The Myeloid Transcription Factor GATA-2 Regulates the Viral UL144 Gene during Human Cytomegalovirus Latency in an Isolate-Specific Manner

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