scholarly journals The Latent Membrane Protein 1 (LMP1) Oncogene of Epstein-Barr Virus Can Simultaneously Induce and Inhibit Apoptosis in B Cells

2012 ◽  
Vol 86 (8) ◽  
pp. 4380-4393 ◽  
Author(s):  
Zachary L. Pratt ◽  
Jingzhu Zhang ◽  
Bill Sugden
Keyword(s):  
B Cells ◽  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 1 ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals Latent Membrane Protein 1 Regulates STAT1 through NF-κB-Dependent Interferon Secretion in Epstein-Barr Virus-Immortalized B Cells

2005 ◽  
Vol 79 (8) ◽  
pp. 4936-4943 ◽  
Author(s):  
Imen Najjar ◽  
Fanny Baran-Marszak ◽  
Christophe Le Clorennec ◽  
Christelle Laguillier ◽  
Olivier Schischmanoff ◽  
...  
Keyword(s):  
B Cells ◽  
Membrane Protein ◽  
Tyrosine Phosphorylation ◽  
Epstein Barr Virus ◽  
Latent Membrane Protein ◽  
Cell Culture Supernatant ◽  
Latent Membrane Protein 1 ◽  
Barr Virus ◽  
Ifn Γ ◽  
Epstein Barr

ABSTRACT Constitutive activation of signal transducer and activator of transcription 1 (STAT1) is a distinctive feature of Epstein-Barr virus (EBV)-immortalized B cells (lymphoblastoid cell lines [LCLs]). The expression of STAT1 in these cells is modulated by the latent membrane protein 1 (LMP1), but the mechanism of STAT1 activation has remained unclear. We demonstrate that the tyrosine phosphorylation of STAT1 in LCLs results from an indirect pathway encompassing an NF-κB-dependent secretion of interferons (IFNs). The cell culture supernatant of LCLs induced tyrosine phosphorylation of STAT1 in cells with no constitutively activated STAT1. Moreover, removal of supernatant from LCLs was sufficient to decrease the phosphorylation of STAT1. Inhibition of NF-κB activity by different pharmacological inhibitors (i.e., parthenolide, MG132 and BAY 11-7082) and by overexpressed mutated IκBα prevented the activation of STAT1. To identify the factors involved, we performed macroarray cDNA profiling with or without inhibition of NF-κB. The expression of several cytokines was NF-κB dependent among those alpha and gamma IFNs (IFN-α and IFN-γ), known activators of STAT1. By real-time PCR and enzyme-linked immunosorbent assay we show that IFN-α and IFN-γ are expressed and released by LCLs in an NF-κB-dependent manner. Finally, the blocking of the IFN-α and IFN-γ by neutralizing antibodies led to the complete inhibition of tyrosine phosphorylation of STAT1. Taken together, our results clearly show that LMP1-induced tyrosine phosphorylation of STAT1 is almost exclusively due to the NF-κB-dependent secretion of IFNs. Whether this response, which is usually considered to be antiviral, is in fact required for the persistence of the virus remains to be elucidated.

Induction of bcl-2 expression by epstein-barr virus latent membrane protein 1 protects infected B cells from programmed cell death

Cell ◽  
1991 ◽  
Vol 65 (7) ◽  
pp. 1107-1115 ◽  
Author(s):  
Sheila Henderson ◽  
Martin Rowe ◽  
Chris Gregory ◽  
Debbie Croom-Carter ◽  
Fred Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
B Cells ◽  
Programmed Cell Death ◽  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 1 ◽  
Barr Virus ◽  
Epstein Barr ◽  
Virus Latent Membrane Protein

scholarly journals Molecular Basis of Cytotoxicity of Epstein-Barr Virus (EBV) Latent Membrane Protein 1 (LMP1) in EBV Latency III B Cells: LMP1 Induces Type II Ligand-Independent Autoactivation of CD95/Fas with Caspase 8-Mediated Apoptosis

2008 ◽  
Vol 82 (13) ◽  
pp. 6721-6733 ◽  
Author(s):  
Christophe Le Clorennec ◽  
Tan-Sothéa Ouk ◽  
Ibtissam Youlyouz-Marfak ◽  
Stéphanie Panteix ◽  
Catherine-Claude Martin ◽  
...  
Keyword(s):  
B Cells ◽  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 1 ◽  
Caspase 8 ◽  
Type Ii ◽  
Barr Virus ◽  
Epstein Barr ◽  
Induced Apoptosis

ABSTRACT The Epstein-Barr virus (EBV) oncoprotein latent membrane protein 1 (LMP1) is thought to act as the major transforming protein in various cell types, by rerouting the tumor necrosis factor receptor family signaling pathway. Despite this implication in EBV-associated transformation of cells, LMP1 toxicity is a well-known but poorly studied feature, perhaps because it contradicts its role in transformation. We show that LMP1 physiological levels are very heterogeneous and that the highest levels of LMP1 correlate with Fas overexpression and spontaneous apoptosis in lymphoblastoid cell lines (LCLs). To understand the cytotoxic effect of LMP1 in LCLs, we cloned wild-type LMP1 into a doxycycline double-inducible episomal vector pRT-1, with a truncated version of NGFR as a surrogate marker of inducibility. We found that LMP1 overexpression induced apoptosis in LCL B cells, as shown by annexin V labeling, sub-G1 peak, and poly(ADP ribose) polymerase cleavage. Knocking down Fas expression by small interfering RNA abolished LMP1-induced apoptosis. The absence of detectable levels of Fas ligand mRNA suggested a ligand-independent activation of Fas. LMP1 induced Fas overexpression with its relocalization in lipid raft microdomains of the membrane. Fas immunoprecipitation detected FADD (Fas-associated death domain protein) and caspase 8, suggesting a Fas-dependent formation of the death-inducing signaling complex. Caspases 8, 9, 3, and 7 were activated by LMP1. Caspase 8 activation was associated with BID cleavage and truncated-BID mitochondrial relocalization, consistent with type II apoptosis. Therefore, our results are in agreement with a model where LMP1-dependent NF-κB activation induces Fas overexpression and autoactivation that could overwhelm the antiapoptotic effect of NF-κB, revealing an ambivalent function of LMP1 in cell survival and programmed cell death.

scholarly journals Cd40 doesn't Complement The Function Of Epstein-barr Virus (Ebv) Latent Membrane Protein 1 In B Cells Transformation

2012 ◽  
Vol 11 (2) ◽  
pp. 112-116
Author(s):  
Mohammed Nazmul Ahsan ◽  
Anwarul A Akhand
Keyword(s):  
B Cells ◽  
Membrane Protein ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Medical Science ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 1 ◽  
Barr Virus ◽  
Epstein Barr

Objective: Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1) is known to plays important role in B cells growth and transformation. LMP1 is considered to be a functional homologue of the CD40 receptor and they can activate many overlapping signaling pathways. In this study, we compared the function of CD40 with that of LMP1 in B cells transformation. Materials and methods: Expression of CD40L was observed in infected B cells with LMP1 mutated EBV. To observe the expression reverse transcription-PCR were performed. Results: This expression of CD40L did not support proliferation and transformation of B cell. Even in vitro proliferation and transformation of B cell infected with LMP1 deleted EBV supplemented with CD40L were also not observed. Conclusion: Despite many similarities shared between CD40 and LMP1, CD40-CD40L interaction didn’t complement on LMP1 mediated B cells transformation in vitro. DOI: http://dx.doi.org/10.3329/bjms.v11i2.8175 Bangladesh Journal of Medical Science Vol. 11 No. 02 April 2012: 112-116

scholarly journals Latency Type-Dependent Modulation of Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Expression by Type I Interferons in B Cells

2012 ◽  
Vol 86 (8) ◽  
pp. 4701-4707 ◽  
Author(s):  
Daniel Salamon ◽  
Monika Adori ◽  
Dorina Ujvari ◽  
Liang Wu ◽  
Lorand L. Kis ◽  
...  
Keyword(s):  
B Cells ◽  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Latent Membrane Protein ◽  
Type I Interferons ◽  
Latent Membrane Protein 1 ◽  
Type I ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals Latent Membrane Protein 1 of Epstein-Barr Virus Induces CD83 by the NF-κB Signaling Pathway

2003 ◽  
Vol 77 (15) ◽  
pp. 8290-8298 ◽  
Author(s):  
Diana Dudziak ◽  
Arnd Kieser ◽  
Ulrike Dirmeier ◽  
Falk Nimmerjahn ◽  
Susanne Berchtold ◽  
...  
Keyword(s):  
B Cells ◽  
Membrane Protein ◽  
Signaling Pathway ◽  
Epstein Barr Virus ◽  
Target Genes ◽  
Latent Membrane Protein ◽  
Luciferase Reporter ◽  
Latent Membrane Protein 1 ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) infects human resting B cells and transforms them in vitro into continuously growing lymphoblastoid cell lines (LCLs). EBV nuclear antigen 2 (EBNA2) is one of the first viral proteins expressed after infection. It is able to transactivate viral as well as cellular target genes by interaction with cellular transcription factors. EBNA2 target genes can be studied easily by using an LCL (ER/EB2-5) in which wild-type EBNA2 is replaced by an estrogen-inducible EBNA2. Since the cell surface molecule CD83, a member of the immunoglobulin superfamily and a marker for mature dendritic cells, appeared on the surface of ER/EB2-5 cells within 3 h after the addition of estrogen, we analyzed the regulation of CD83 induction by EBV in more detail. Despite its rapid induction, CD83 turned out to be an indirect target gene of EBNA2. We could show that the viral latent membrane protein 1 (LMP1) is responsible for the induction of CD83 by using an LCL expressing a ligand- or antibody-inducible recombinant nerve growth factor receptor-LMP1 fusion protein. The inducibility of the CD83 promoter by LMP1 was mediated by the activation of NF-κB, as seen by use of luciferase reporter assays using the CD83 promoter and LMP1 mutants. Additionally, fusion constructs of the transmembrane domain of LMP1 and the intracellular signaling domain of CD40, TNF-R1, and TNF-R2 likewise transactivated the CD83 promoter via NF-κB. Our studies show that CD83 is also a target of the NF-κB signaling pathway in B cells.

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