scholarly journals Epstein-Barr Virus Latent Membrane Protein 2a (Lmp2a) Employs the Slp-65 Signaling Module

2001 ◽  
Vol 194 (3) ◽  
pp. 255-264 ◽  
Author(s):  
Niklas Engels ◽  
Mark Merchant ◽  
Rajita Pappu ◽  
Andrew C. Chan ◽  
Richard Longnecker ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Signaling Pathways ◽  
Epstein Barr Virus ◽  
Antigen Receptor ◽  
Adaptor Protein ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

In latently infected B lymphocytes, the Epstein-Barr virus (EBV) suppresses signal transduction from the antigen receptor through expression of the integral latent membrane protein 2A (LMP2A). At the same time, LMP2A triggers B cell survival by a yet uncharacterized maintenance signal that is normally provided by the antigen receptor. The molecular mechanisms are unknown as LMP2A-regulated signaling cascades have not been described so far. Using a novel mouse model we have identified the intracellular adaptor protein Src homology 2 (SH2) domain–containing leukocyte protein (SLP)-65 as a critical downstream effector of LMP2A in vivo. Biochemical analysis of the underlying signaling pathways revealed that EBV infection causes constitutive tyrosine phosphorylation of one of the two SLP-65 isoforms and complex formation between SLP-65 and the protooncoprotein CrkL (CT10 regulator of kinase like). This leads to antigen receptor-independent phosphorylation of Cbl (Casitas B lineage lymphoma) and C3G. In contrast, phospholipase C-γ2 (PLC-γ2) activation is completely blocked. Our data show that in order to establish a latent EBV infection, LMP2A selectively activates or represses SLP-65–regulated signaling pathways.

scholarly journals Epstein-Barr Virus Represses the FoxO1 Transcription Factor through Latent Membrane Protein 1 and Latent Membrane Protein 2A

2006 ◽  
Vol 80 (22) ◽  
pp. 11191-11199 ◽  
Author(s):  
Angharad M. Shore ◽  
Paul C. White ◽  
Rosaline C.-Y. Hui ◽  
Abdelkader Essafi ◽  
Eric W.-F. Lam ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Membrane Protein ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 1 ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) infection is associated with the development of many B-cell lymphomas, including Burkitt's lymphoma, Hodgkin's lymphoma, and posttransplant lymphoproliferative disease. The virus alters a diverse range of cellular molecules, which leads to B-cell growth and immortalization. This study was initiated to investigate the interplay between EBV and a proapoptotic transcription factor target, FoxO1. In this report, we show that EBV infection of B cells leads to the downregulation of FoxO1 expression by phosphatidylinositol 3-kinase-mediated nuclear export, by inhibition of FoxO1 mRNA expression, and by alteration of posttranslational modifications. This repression directly correlates with the expression of the FoxO1 target gene Bcl-6 and inversely correlates with the FoxO1-regulated gene Cyclin D2. Expression of the EBV genes for latent membrane protein 1 and latent membrane protein 2A decreases FoxO1 expression. Thus, our data elucidate distinct mechanisms for the regulation of the proapoptotic transcription factor FoxO1 by EBV.

scholarly journals The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) in latency and cancer

2009 ◽  
Vol 14 (2) ◽  
Author(s):  
Mei-Fong Pang ◽  
Kah-Wai Lin ◽  
Suat-Cheng Peh
Keyword(s):  
Membrane Protein ◽  
Signaling Pathways ◽  
Epstein Barr Virus ◽  
Cellular Transformation ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Cancer Pathogenesis ◽  
Epstein Barr

AbstractEpstein-Barr virus (EBV) is a ubiquitous virus with infections commonly resulting in a latency carrier state. Although the exact role of EBV in cancer pathogenesis remains not entirely clear, it is highly probable that it causes several lymphoid and epithelial malignancies, such as Hodgkin’s lymphoma, NK-T cell lymphoma, Burkitt’s lymphoma, and nasopharyngeal carcinoma. EBV-associated malignancies are associated with a latent form of infection, and several of these EBV-encoded latent proteins are known to mediate cellular transformation. These include six nuclear antigens and three latent membrane proteins. Studies have shown that EBV displays distinct patterns of viral latent gene expression in these lymphoid and epithelial tumors. The constant expression of latent membrane protein 2A (LMP2A) at the RNA level in both primary and metastatic tumors suggests that this protein might be a driving factor in the tumorigenesis of EBV-associated malignancies. LMP2A may cooperate with the aberrant host genome, and thereby contribute to malignant transformation by intervening in signaling pathways at multiple points, especially in the cell cycle and apoptotic pathway. This review summarizes the role of EBV-encoded LMP2A in EBV-associated viral latency and cancers. We will focus our discussions on the molecular interactions of each of the conserved motifs in LMP2A, and their involvement in various signaling pathways, namely the B-cell receptor blockade mechanism, the ubiquitin-mediated (Notch and Wnt) pathways, and the MAPK, PI3-K/Akt, NK-κB and STAT pathways, which can provide us with important insights into the roles of LMP2A in the EBV-associated latency state and various malignancies.

scholarly journals Epstein-Barr virus in Burkitt’s lymphoma: A role for latent membrane protein 2A

Cell Cycle ◽  
2010 ◽  
Vol 9 (5) ◽  
pp. 901-908 ◽  
Author(s):  
Kathryn T. Bieging ◽  
Michelle Swanson-Mungerson ◽  
Alexandra C. Amick ◽  
Richard Longnecker
Keyword(s):  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Burkitt’S Lymphoma ◽  
Latent Membrane Protein ◽  
Burkitt's Lymphoma ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals Immunohistochemical Detection of the Epstein-Barr Virus–Encoded Latent Membrane Protein 2A in Hodgkin's Disease and Infectious Mononucleosis

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1664-1672 ◽  
Author(s):  
G. Niedobitek ◽  
E. Kremmer ◽  
H. Herbst ◽  
L. Whitehead ◽  
C.W. Dawson ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Protein Expression ◽  
Infectious Mononucleosis ◽  
Epstein Barr Virus ◽  
Hodgkin’S Disease ◽  
Latent Membrane Protein ◽  
Immunohistochemical Detection ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Epstein Barr

We describe two new monoclonal antibodies specific for the Epstein-Barr virus (EBV)-encoded latent membrane protein 2A (LMP2A) that are suitable for the immunohistochemical analysis of routinely processed paraffin sections. These antibodies were applied to the immunohistochemical detection of LMP2A in Hodgkin's disease (HD). LMP2A-specific membrane staining was seen in the Hodgkin and Reed-Sternberg (HRS) cells of 22 of 42 (52%) EBV-positive HD cases, but not in 39 EBV-negative HD cases. In lymphoid tissues from patients with acute infectious mononucleosis (IM), interfollicular immunoblasts were shown to express LMP2A. This is the first demonstration of LMP2A protein expression at the single-cell level in EBV-associated lymphoproliferations in vivo. The detection of LMP2A protein expression in HD and IM is of importance in view of the proposed role of this protein for maintaining latent EBV infection and its possible contribution for EBV-associated transformation. Because LMP2A provides target epitopes for EBV-specific cytotoxic T cells, the expression of this protein in HRS cells has implications for the immunotherapeutic approaches to the treatment of HD.

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