Id1 Interacts and Stabilizes the Epstein-Barr Virus Latent Membrane Protein 1 (LMP1) in Nasopharyngeal Epithelial Cells

Hau, Pok Man; Tsang, Chi Man; Yip, Yim Ling; Huen, Michael S. Y.; Tsao, Sai Wah

doi:10.1371/journal.pone.0021176

Cited by 16 publications

(18 citation statements)

References 45 publications

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“…LMP1 protein in the cell may be unstable and easily degraded. Notably, LMP1 is reported to be degraded rapidly through the ubiquitin/proteasome-dependent pathway (67), and LMP1 degradation is specifically regulated in NPC cells (45). Furthermore, since LMP1 mRNA levels are low in C666-1 cells, LMP1 may be regulated prior to its translation.…”

Section: Discussionmentioning

confidence: 99%

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Induction of Epstein-Barr Virus Oncoprotein LMP1 by Transcription Factors AP-2 and Early B Cell Factor

Murata

Noda

Narita

et al. 2016

J Virol

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Latent membrane protein 1 (LMP1) is a major oncogene essential for primary B cell transformation by Epstein-Barr virus (EBV).Previous studies suggested that some transcription factors, such as PU.1, RBP-J, NF-B, and STAT, are involved in this expression, but the underlying mechanism is unclear. Here, we identified binding sites for PAX5, AP-2, and EBF in the proximal LMP1 promoter (ED-L1p). We first confirmed the significance of PU.1 and POU domain transcription factor binding for activation of the promoter in latency III. We then focused on the transcription factors AP-2 and early B cell factor (EBF). Interestingly, among the three AP-2-binding sites in the LMP1 promoter, two motifs were also bound by EBF. Overexpression, knockdown, and mutagenesis in the context of the viral genome indicated that AP-2 plays an important role in LMP1 expression in latency II in epithelial cells. In latency III B cells, on the other hand, the B cell-specific transcription factor EBF binds to the ED-L1p and activates LMP1 transcription from the promoter. IMPORTANCE Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is crucial for B cell transformation and oncogenesis of other EBVrelated malignancies, such as nasopharyngeal carcinoma and T/NK lymphoma.Its expression is largely dependent on the cell type or condition, and some transcription factors have been implicated in its regulation. However, these previous reports evaluated the significance of specific factors mostly by reporter assay. In this study, we prepared point-mutated EBV at the binding sites of such transcription factors and confirmed the importance of AP-2, EBF, PU.1, and POU domain factors. Our results will provide insight into the transcriptional regulation of the major oncogene LMP1. The Epstein-Barr virus (EBV) is a human gammaherpesvirus that mainly infects and establishes latent infection in B lymphocytes, but it can also infect other types of cells, including NK, T, and epithelial cells. EBV infection has been implicated as a causal factor in a variety of malignancies, and the expression pattern of viral latent genes varies depending on the tissue of origin and the state of the tumors. Neoplasms such as Burkitt lymphomas or gastric carcinomas express only EBV-encoded small RNA (EBER) and EBV nuclear antigen 1 (EBNA1) (type I latency), whereas some Hodgkin lymphomas, nasopharyngeal carcinomas (NPC), and NK/T lymphomas express EBER, EBNA1, latent membrane protein 1 (LMP1), and LMP2 genes (type II latency). In addition to the type II genes, EBNA2, EBNA3, and EBNA-LP are also expressed in immunosuppression-related lymphomas or lymphoblastoid cell lines (LCLs; type III latency). LMP1 constitutively activates cellular signaling through NF-B, mitogen-activated protein, JAK/STAT, and AKT and is believed to be a major oncogene encoded by EBV (1-11).Two promoters regulate LMP1 gene transcription, with mechanisms that differ between type II and type III infection. In latency III in B lymphocytes, LMP1 transcription from the proximal ED-L1 promoter is acti...

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Section: Discussionmentioning

confidence: 99%

“…HEK293EBV-BAC and HeLa-CR2/GFP-EBV (32) cells were maintained in Dulbecco modified Eagle medium (Sigma) supplemented with 10% fetal bovine serum. Akata(Ϫ), C666-1 (45), and LCLs were maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum. Antibodies against SP1 and PAX5 were obtained from Santa Cruz Biotechnology.…”

Section: Methodsmentioning

confidence: 99%

Induction of Epstein-Barr Virus Oncoprotein LMP1 by Transcription Factors AP-2 and Early B Cell Factor

Murata

Noda

Narita

et al. 2016

J Virol

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“…Ubiquitination and proteasome-dependent degradation of LMP1 is further dependent on the TRAF-binding site within the carboxy-terminus of LMP1 (Rothenberger et al 2003;Hau et al 2011). Mutation of the amino-terminus showed that this domain does not contribute critical signals for B cell transformation (Izumi et al 1994;Dirmeier et al 2003).…”

Section: Amino-terminus and Transmembrane Domainmentioning

confidence: 99%

The Latent Membrane Protein 1 (LMP1)

Kieser

Sterz

2015

Current Topics in Microbiology and Immunology

123

127

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Almost exactly twenty years after the discovery of Epstein-Barr virus (EBV), the latent membrane protein 1 (LMP1) entered the EBV stage, and soon thereafter, it was recognized as the primary transforming gene product of the virus. LMP1 is expressed in most EBV-associated lymphoproliferative diseases and malignancies, and it critically contributes to pathogenesis and disease phenotypes. Thirty years of LMP1 research revealed its high potential as a deregulator of cellular signal transduction pathways leading to target cell proliferation and the simultaneous subversion of cell death programs. However, LMP1 has multiple roles beyond cell transformation and immortalization, ranging from cytokine and chemokine induction, immune modulation, the global alteration of gene and microRNA expression patterns to the regulation of tumor angiogenesis, cell-cell contact, cell migration, and invasive growth of tumor cells. By acting like a constitutively active receptor, LMP1 recruits cellular signaling molecules associated with tumor necrosis factor receptors such as tumor necrosis factor receptor-associated factor (TRAF) proteins and TRADD to mimic signals of the costimulatory CD40 receptor in the EBV-infected B lymphocyte. LMP1 activates NF-κB, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3-K), IRF7, and STAT pathways. Here, we review LMP1's molecular and biological functions, highlighting the interface between LMP1 and the cellular signal transduction network as an important factor of virus-host interaction and a potential therapeutic target.

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“…TRAFs are thought to interact with CD 40 to nuclear factor (NF)-κB and c-Jun kinase (JNK) activation. Similar to CD 40 , LMP1 also binds TRAFs which are then thought to interact with kinases such as NF-κB-inducing kinase that ultimately promote activation of NF-κB (33)(34)(35)(36)(37)(38). However, further investigation on the exact interaction between LMP1 and miRNA-146a is still needed.…”

Section: Discussionmentioning

confidence: 99%

Expression of miRNA-146a in nasopharyngeal carcinoma is upregulated by Epstein-Barr virus latent membrane protein 1

et al. 2012

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We aimed to investigate the relationship between miRNA-146a and latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) in nasopharyngeal carcinoma (NPC). The expression levels of LMP1 in 40 cases of NPC, 28 cases of chronic nasopharyngitis and NPC cell lines CNE1 and CNE1-GL (in which LMP1 was stably transfected) were detected by immunohistochemical staining. The expression of miRNA-146a in 16 cases of NPC, 13 cases of chronic nasopharyngitis and cell lines was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. A plasmid containing the luciferase gene under the control of miRNA-146a promoter (pri-miRNA-146a) was constructed and transfected into NPC cells, and the luciferase activity was detected. LMP1 was positive in 17.9% (5/28) of chronic nasopharyngitis cases and 62.5% (25/40) of NPC cases (P<0.01). The miRNA-146a levels in NPC were significantly higher than that in chronic nasopharyngitis (P<0.01), and were higher in CNE1-GL cells than those in CNE1 cells (p<0.01). The expression of miRNA-146a in human NPC was elevated by EBV-associated antigen LMP1, probably through the activation of the miRNA-146a promoter.

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Id1 Interacts and Stabilizes the Epstein-Barr Virus Latent Membrane Protein 1 (LMP1) in Nasopharyngeal Epithelial Cells

Cited by 16 publications

References 45 publications

Induction of Epstein-Barr Virus Oncoprotein LMP1 by Transcription Factors AP-2 and Early B Cell Factor

Induction of Epstein-Barr Virus Oncoprotein LMP1 by Transcription Factors AP-2 and Early B Cell Factor

The Latent Membrane Protein 1 (LMP1)

Expression of miRNA-146a in nasopharyngeal carcinoma is upregulated by Epstein-Barr virus latent membrane protein 1

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