The c-Jun N-terminal kinase pathway is critical for cell transformation by the latent membrane protein 1 of Epstein–Barr virus

Kutz, Helmut; Reisbach, G.; Schultheiss, Ute; Kieser, Arnd

doi:10.1016/j.virol.2007.09.044

Cited by 32 publications

(29 citation statements)

References 47 publications

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“…JUN pathways play a critical role in malignant transformation. It could be activated in infected cells by herpesviruses such as EBV and KSHV [37,38,39]. The expression of JUN was also found to be upregulated in infected thymuses.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Analysis of Host Responses to Marek's Disease Virus Infection in Chicken Thymus

Qin²,

et al. 2015

Intervirology

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Marek's disease virus (MDV) is a cell-associated alpha-herpesvirus that causes T-cell lymphomas and nervous disorders in chickens. Different from other lymphoid organs, the thymus is the site of T-cell maturation and differentiation. However, the transcriptional response to MDV infection in the chicken thymus is still not known. In this study, we performed genome-wide expression analysis in thymus tissues of RB1B-infected chickens at different time points to investigate the molecular mechanisms of MDV pathogenesis. The number of differentially expressed genes with 2-fold or higher changes (>2) are as follows: 1,250 genes (7 dpi), 834 genes (14 dpi), 1,958 genes (21 dpi), and 2,306 genes (28 dpi). Gene ontology enrichment analysis revealed that the upregulated genes were involved in immune and inflammatory response at 7 dpi; angiogenesis, cytoskeleton organization, cell adhesion, and signal transduction showed different expressions at 21 and 28 dpi. The expression pattern of 18 randomly selected genes was confirmed by real-time RT-PCR. Several differently expressed host genes associated with tumor development are discussed. We identified the global host-gene expression pattern in the thymus of chickens that responded to MDV infection. The present data may provide groundwork for future investigation in the biology and pathogenesis of MDV.

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Section: Discussionmentioning

confidence: 99%

Transcriptional Analysis of Host Responses to Marek's Disease Virus Infection in Chicken Thymus

Qin²,

et al. 2015

Intervirology

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“…As shown in Figure 6, knockdown of RON decreased the phosphorylation of Akt, ERK, JNK, and p38. The data suggest that these downstream signaling pathways, which are critical for LCL growth, 27,28 may be activated by RON in LCLs.…”

Section: The Downstream Signaling Pathways Are Triggered By Ron In Lclsmentioning

confidence: 92%

Requirement for LMP1-induced RON receptor tyrosine kinase in Epstein-Barr virus–mediated B-cell proliferation

Chou

Lin

et al. 2011

Blood

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IntroductionPrimary EBV infection usually is asymptomatic but persists, so that more than 90% of adults worldwide are persistently infected with EBV. 1 However, as the first human tumor virus identified, EBV is associated with several disorders of lymphocytes, including infectious mononucleosis, Burkitt lymphoma, Hodgkin lymphoma, T-cell lymphoma, NK-cell lymphoma, AIDS-associated lymphoma, and posttransplantation lymphoproliferative disorder (PTLD). 1 Being an oncogenic virus, EBV can immortalize primary B cells into lymphoblastoid cell lines (LCLs). EBV-immortalized LCLs are characterized by several features, including aberrant production of cytokines and chemokines, unlimited proliferation, clumping morphology, and display of an EBV latency III phenotype, characteristics similar to those of PTLD. 2 Indeed, LCLs are good in vitro models to understand the pathogenesis of, and to discover novel therapeutic targets for, PTLD.EBV encodes several proteins which mimic or associate with host cellular factors and these factors are well documented in B-cell survival, differentiation, proliferation, and immortalization. 1 (1) The latent membrane protein 1 (LMP1) acts as a constitutively activated CD40 receptor, which provides signals of survival and differentiation in B cells. In LMP1 transgenic mice, constitutively activated LMP1 drives B-cell lymphoma formation, suggesting that LMP1 acts as an oncogene and plays an important role in EBV-mediated tumorigenesis. 1,3 (2) The latent membrane protein 2A (LMP2A) mimics a functional B-cell receptor (BCR). It interacts with Syk and Lyn tyrosine kinases to deliver survival signals through PKC and intracellular calcium. In LMP2A transgenic mice, LMP2A can rescue BCR-lacking B cells from apoptosis, suggesting that the BCR-driven survival signals can be replaced by LMP2A. 4 (3) The Epstein-Barr nuclear antigen 2 (EBNA2) mimics Notch signaling. It interacts with the DNAbinding protein RBPJ/CBP to interfere with Notch-mediated inhibition of B-cell proliferation and differentiation. 1 (4) Zta, a transactivator, mimics a functional and structural AP-1 protein. It plays an important role in regulating cytokine expression by immune cells, such as IL-13. 5 (5) BCRF-1, which is an IL-10 homologue, serves as a growth factor for B cells and suppresses antiviral immune responses. 6 So, we wondered whether any other specific cellular genes are involved in EBV-mediated immortalization. In this study, tyrosine kinases are our target.Among the proteins encoded by the huge human genome, about ninety protein tyrosine kinases (PTKs) have been defined. 7 PTKs are tightly regulated in cells because they play vital roles in crucial biologic functions, such as survival, proliferation, differentiation, and development. 8 Dysregulation of PTK activity is one of the most common mechanisms leading to cellular transformation and cancer formation. 7 Of note, the discovery of PTKs stemmed from the study of an oncogenic virus, Rous sarcoma virus encoding v-src. 9 Generally, viruses can activate PTKs to transf...

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“…The tumor necrosis factor receptor-associated factor (TRAF)-binding domain located within the signaling domain is required for rat fibroblast transformation and upregulates cell cycle markers linked to G1/S-phase transition of the cell cycle (Mainou et al 2005(Mainou et al , 2007. Notably, fibroblast transformation by LMP1 is dependent on the PI3-K/AKT and c-Jun N-terminal kinase (JNK) pathways, but independent of NF-κB (Mainou et al 2005;Kutz et al 2008). Cell immortalization is fostered by LMP1 through telomerase activation via the p16 INK4a /Rb, PI3-K/AKT, and JNK pathways (Ding et al 2007;Yang et al 2014).…”

Section: Transformation Of Epithelial Cells and Fibroblastsmentioning

confidence: 99%

The Latent Membrane Protein 1 (LMP1)

Kieser

Sterz

2015

Current Topics in Microbiology and Immunology

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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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The c-Jun N-terminal kinase pathway is critical for cell transformation by the latent membrane protein 1 of Epstein–Barr virus

Cited by 32 publications

References 47 publications

Transcriptional Analysis of Host Responses to Marek's Disease Virus Infection in Chicken Thymus

Transcriptional Analysis of Host Responses to Marek's Disease Virus Infection in Chicken Thymus

Requirement for LMP1-induced RON receptor tyrosine kinase in Epstein-Barr virus–mediated B-cell proliferation

The Latent Membrane Protein 1 (LMP1)

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