The EBV-Encoded Oncoprotein, LMP1, Induces an Epithelial-to-Mesenchymal Transition (EMT) via its CTAR1 Domain Through Integrin-Mediated ERK-MAPK Signalling
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ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE111340
PROVIDER: PRJNA436714 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The Epstein-Barr virus (EBV)-encoded LMP1 oncogene can induce profound effects on epithelial growth and differentiation including many of the features of the epithelial-to-mesenchymal transition (EMT). To better characterise these effects, we used the well-defined MDCK cell model and found that LMP1 expression in these cells induces EMT as defined by characteristic morphological changes accompanied by loss of E-cadherin, desmosomal cadherin and tight junction protein expression. The induction of the EMT phenotype required a functional CTAR1 domain of LMP1 and studies using pharmacological inhibitors revealed contributions from signalling pathways commonly induced by integrin-ligand interactions: ERK-MAPK, PI3-Kinase and tyrosine kinases, but not TGFbeta. More detailed analysis confirmed the role of integrin and ERK-MAPK signalling in the LMP1-induced EMT and implicated the CTAR1-mediated induction of Slug and Twist in these effects. A key role for beta1 integrin signalling in LMP1-mediated ERK-MAPK and FAK phosphorylation was observed and beta1 integrin activation was found to enhance LMP1-induced cell viability and survival. These findings support an important role for LMP1 in the early stages of NPC pathogenesis through transcriptional reprogramming that enhances tumour cell survival and leads to a more invasive, metastatic phenotype.
2018-06-06 | GSE111340 | GEO
Project description:The Epstein?Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) oncogene can induce profound effects on epithelial growth and differentiation including many of the features of the epithelial-to-mesenchymal transition (EMT). To better characterise these effects, we used the well-defined Madin Darby Canine Kidney (MDCK) epithelial cell model and found that LMP1 expression in these cells induces EMT as defined by characteristic morphological changes accompanied by loss of E-cadherin, desmosomal cadherin and tight junction protein expression. The induction of the EMT phenotype required a functional CTAR1 domain of LMP1 and studies using pharmacological inhibitors revealed contributions from signalling pathways commonly induced by integrin?ligand interactions: extracellular signal-regulated kinases/mitogen-activated protein kinases (ERK-MAPK), PI3-Kinase and tyrosine kinases, but not transforming growth factor beta (TGFβ). More detailed analysis implicated the CTAR1-mediated induction of Slug and Twist in LMP1-induced EMT. A key role for β1 integrin signalling in LMP1-mediated ERK-MAPK and focal adhesion kianse (FAK) phosphorylation was observed, and β1 integrin activation was found to enhance LMP1-induced cell viability and survival. These findings support an important role for LMP1 in disease pathogenesis through transcriptional reprogramming that enhances tumour cell survival and leads to a more invasive, metastatic phenotype.
| S-EPMC5977103 | biostudies-literature
Project description:The Epstein Barr virus (EBV) encoded latent membrane protein-1 (LMP1) is a functional homologue of the tumor necrosis factor receptor family and contributes substantially to the oncogenic potential of EBV through activation of Nuclear Factor-kappaB (NF-kappaB). MicroRNAs (miRNAs) are a class of small RNA molecules that are involved in the regulation of cellular processes such as growth, development, and apoptosis, and have recently been linked to cancer phenotypes. Through miRNA microarray analysis, we demonstrate that LMP1 dysregulates the expression of several cellular miRNAs, including the most highly regulated of these, miR-146a. Quantitative RT-PCR analysis confirmed induced expression of miR-146a by LMP1. Analysis of miR-146a expression in EBV latency type III and type I cell lines revealed substantial expression of miR-146a in type III (which express LMP1) but not in type I cell lines. Reporter studies demonstrated that LMP1 induces miR-146a predominantly through two NF-kappaB binding sites in the miR-146a promoter and identified a role for an OCT-1 site in conferring basal and induced expression. Array analysis of cellular mRNAs expressed in Akata cells transduced with an miR-146a expressing retrovirus identified genes that are directly or indirectly regulated by miR-146a, including a group of interferon responsive genes that are inhibited by miR-146a. Since miR-146a is known to be induced by agents that activate the interferon response pathway (including LMP1), these results suggest that miR-146a functions in a negative feedback loop to modulate the intensity and/or duration of the interferon response. Keywords: microRNA expression modified by EBV encoded oncogene, LMP1 EBV negative Mutu E1dn Cl. 3 cells were transduced with either a control retrovirus (pEhyg) or an LMP1 containing retrovirus (pEhyg-FLAG-LMP1). Cells were selected with hygromycin for approximately 2 weeks afterwhich 5 pairs of RNA preps were carried out on 5 successive days. Arrays GSM255656 and GSM255659 are dye swaps in which LMP1 samples were labeled with Cy3 and control samples were labeled with Cy5.
2010-05-26 | E-GEOD-10105 | biostudies-arrayexpress
Project description:The Epstein Barr virus (EBV) encoded latent membrane protein-1 (LMP1) is a functional homologue of the tumor necrosis factor receptor family and contributes substantially to the oncogenic potential of EBV through activation of Nuclear Factor-kappaB (NF-kappaB). MicroRNAs (miRNAs) are a class of small RNA molecules that are involved in the regulation of cellular processes such as growth, development, and apoptosis, and have recently been linked to cancer phenotypes. Through miRNA microarray analysis, we demonstrate that LMP1 dysregulates the expression of several cellular miRNAs, including the most highly regulated of these, miR-146a. Quantitative RT-PCR analysis confirmed induced expression of miR-146a by LMP1. Analysis of miR-146a expression in EBV latency type III and type I cell lines revealed substantial expression of miR-146a in type III (which express LMP1) but not in type I cell lines. Reporter studies demonstrated that LMP1 induces miR-146a predominantly through two NF-kappaB binding sites in the miR-146a promoter and identified a role for an OCT-1 site in conferring basal and induced expression. Array analysis of cellular mRNAs expressed in Akata cells transduced with an miR-146a expressing retrovirus identified genes that are directly or indirectly regulated by miR-146a, including a group of interferon responsive genes that are inhibited by miR-146a. Since miR-146a is known to be induced by agents that activate the interferon response pathway (including LMP1), these results suggest that miR-146a functions in a negative feedback loop to modulate the intensity and/or duration of the interferon response. Keywords: microRNA expression modified by EBV encoded oncogene, LMP1
2008-01-09 | GSE10105 | GEO
Project description:Undifferentiated nasopharyngeal carcinoma (NPC) is 100% associated with Epstein-Barr virus (EBV) infection, and biopsies display variable levels of expression of the viral oncoprotein, latent membrane protein 1 (LMP1). Emerging evidence suggests an important role for cancer-associated fibroblasts (CAFs) in the NPC tumour microenvironment, yet the interaction between the virus, its latent gene products and the recruitment and activation of CAFs in the NPC tumour stroma remains unclear. This short review will discuss the current evidence for the importance of CAFs in NPC pathogenesis and outline a putative role for the EBV-encoded oncoprotein, LMP1, in governing tumour-stromal interactions.
| S-EPMC7168608 | biostudies-literature
Project description:Extracellular vesicles (EV) mediate intercellular communication events and alterations in normal vesicle content contribute to function and disease initiation or progression. The ability to package a variety of cargo and transmit molecular information between cells renders EVs important mediators of cell to cell crosstalk. Latent membrane protein 1 (LMP1) is a chief viral oncoprotein expressed in most Epstein-Barr virus (EBV)-associated cancers and is released from cells at high levels in EVs. LMP1 containing EVs have been demonstrated to promote cell growth, migration, differentiation, and regulate immune cell function. Despite these significant changes in recipient cells induced by LMP1 modified EVs, the mechanism how this viral oncogene modulates the recipient cells towards these phenotypes is not well understood. We hypothesize that LMP1 alters EV content and following uptake of the LMP1-modified EVs by the recipient cells results in the activation of cell signaling pathways and increased gene expression which modulates the biological properties of recipient cell towards a new phenotype. Our results show that LMP1 expression alters the EV protein and microRNA content packaged into EVs.
2020-11-03 | PXD021914 | Pride
Project description:RNA-seq was used to characterize the LMP1 TES domain-mediated regulation of B-cell genome wide target genes. We created an inducible stable EBV-negative BL41 Burkitt Lymphoma cell line expressing LMP1 wildtype, TES1 functional only, TES2 functional only and TES1/2 non-functional. wildtype EBV-negative BL41 (no LMP1 transgene) cells were also subjected to CD40L (recombinant CD40 ligand) to study the B-cell target gene regulation in comparison to LMP1 wildtype-mediated.
2023-04-25 | GSE228158 | GEO
Project description: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-kappaB 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.
| S-EPMC2042179 | biostudies-literature
Project description:Expression of mRNAs in an EBV-positive B-cell strain, 28-2. 28-2 are infected with a derivative of the B-958 strain of EBV, which expresses eGFP constitutively and LMP1 fused to mRFP from its native promoter. Single cells were sorted by flow cytometry for their levels of LMP1-mRFP (5% expressing the lowest levels of LMP1-mRFP or 5% expressing the highest levels of LMP1-mRFP) Two-condition experiment: Low v. High LMP1-mRFP expression. Biological replicates: 3 Low LMP1-mRFP, 3 High LMP1-mRFP. Samples were normalized to the expression of mRNAs in a pool of unsorted 28-2 cells.
2012-02-01 | E-GEOD-33673 | biostudies-arrayexpress
Project description:Expression of miRNAs in an EBV-positive B-cell strain, 28-2. 28-2 are infected with a derivative of the B-958 strain of EBV, which expresses eGFP constitutively and LMP1 fused to mRFP from its native promoter. Single cells were sorted by flow cytometry for their levels of LMP1-mRFP (5% expressing the lowest levels of LMP1-mRFP or 5% expressing the highest levels of LMP1-mRFP) Two-condition experiment: Low v. High LMP1-mRFP expression. Biological replicates: 3 Low LMP1-mRFP, 3 High LMP1-mRFP. Samples were normalized to the expression of miRNAs in a pool of unsorted 28-2 cells.
2012-02-01 | E-GEOD-33972 | biostudies-arrayexpress