The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the Tumor Necrosis Factor receptor family

Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.
Cell (Impact Factor: 32.24). 03/1995; 80(3):389-99.
Source: PubMed


The cytoplasmic C-terminus of Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1) is essential for B lymphocyte growth transformation and is now shown to interact with a novel human protein (LMP1-associated protein 1 [LAP1]). LAP1 is homologous to a murine protein, tumor necrosis factor receptor-associated factor 2 (TRAF2), implicated in growth signaling from the p80 TNFR. A second novel protein (EBI6), induced by EBV infection, is the human homolog of a second murine TNFR-associated protein (TRAF1). LMP1 expression causes LAP1 and EBI6 to localize to LMP1 clusters in lymphoblast plasma membranes, and LMP1 coimmunoprecipitates with these proteins. LAP1 binds to the p80 TNFR, CD40, and the lymphotoxin-beta receptor, while EBI6 associates with the p80 TNFR. The interaction of LMP1 with these TNFR family-associated proteins is further evidence for their role in signaling and links LMP1-mediated transformation to signal transduction from the TNFR family.

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    • "Moreover, LMP1 does not reach LCL mRNA or protein levels until $2 weeks postinfection (Price et al., 2012) (Fig. 6.4). LMP1 acts as a constitutively active homologue to the human CD40 membrane protein (Mosialos et al., 1995) and is essential to the transforming capability of EBV (Kaye et al., 1993). Both CD40 and LMP1 signal through the NFkB pathway in a similar fashion (Luftig et al., 2003; Luftig et al., 2004), and inhibition of the NFkB pathway in LCLs results in spontaneous apoptosis (Cahir-McFarland et al., 2000). "
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    ABSTRACT: Epstein-Barr virus (EBV) is an oncogenic human herpesvirus in the γ-herpesvirinae subfamily that contains a 170-180kb double-stranded DNA genome. In vivo, EBV commonly infects B and epithelial cells and persists for the life of the host in a latent state in the memory B-cell compartment of the peripheral blood. EBV can be reactivated from its latent state, leading to increased expression of lytic genes that primarily encode for enzymes necessary to replicate the viral genome and structural components of the virion. Lytic cycle proteins also aid in immune evasion, inhibition of apoptosis, and the modulation of other host responses to infection. In vitro, EBV has the potential to infect primary human B cells and induce cellular proliferation to yield effectively immortalized lymphoblastoid cell lines, or LCLs. EBV immortalization of B cells in vitro serves as a model system for studying EBV-mediated lymphomagenesis. While much is known about the steady-state viral gene expression within EBV-immortalized LCLs and other EBV-positive cell lines, relatively little is known about the early events after primary B-cell infection. It was previously thought that upon latent infection, EBV only expressed the well-characterized latency-associated transcripts found in LCLs. However, recent work has characterized the early, but transient, expression of lytic genes necessary for efficient transformation and delayed responses in the known latency genes. This chapter summarizes these recent findings that show how dynamic and controlled expression of multiple EBV genes can control the activation of B cells, entry into the cell cycle, the inhibition of apoptosis, and innate and adaptive immune responses.
    Full-text · Article · Dec 2014 · Advances in Virus Research
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    • "LMP1 mimics a constitutively active CD40 receptor (Mosialos et al., 1995). LMP1 constitutively aggregates and recruits TRAFs and TRADD leading to activation of NF-kB, a key transcription factor in viral and nonviral lymphomagenesis (Mosialos et al., 1995). NF-kB promotes cell survival by upregulation of the antiapoptotic proteins A20 and BCL-2 and a variety of cellular genes related to B cell proliferation and malignancy. "
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    ABSTRACT: Approximately 12% of all human cancers are caused by oncoviruses. Human viral oncogenesis is complex, and only a small percentage of the infected individuals develop cancer, often many years to decades after the initial infection. This reflects the multistep nature of viral oncogenesis, host genetic variability, and the fact that viruses contribute to only a portion of the oncogenic events. In this review, the Hallmarks of Cancer framework of Hanahan and Weinberg (2000 and 2011) is used to dissect the viral, host, and environmental cofactors that contribute to the biology of multistep oncogenesis mediated by established human oncoviruses. The viruses discussed include Epstein-Barr virus (EBV), high-risk human papillomaviruses (HPVs), hepatitis B and C viruses (HBV and HCV, respectively), human T cell lymphotropic virus-1 (HTLV-1), and Kaposi's sarcoma herpesvirus (KSHV).
    Full-text · Article · Mar 2014 · Cell host & microbe
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    • "LMP-1 is considered the major EBV oncoprotein, acting as an oncogene in rodent fibroblast cells [4,5]. LMP-1 functions as a constitutively active tumor necrosis factor receptor, mimicking an activated CD40 receptor, although structurally different [6,7]. LMP-1 has pleiotropic functions being able to promote B-cell activation, homotypic and heterotypic cell adhesion and the expression of cell surface (i.e. "
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    ABSTRACT: Overcoming cellular senescence is strictly required for virus-driven tumors, including those associated with Epstein-Barr virus (EBV). This critical step is successfully accomplished by EBV through TERT expression and telomerase activation in infected cells. We herein review the complex interplay between EBV and TERT/telomerase in EBV-driven tumorigenesis. Evidence accumulated so far clearly indicates that elucidation of this issue may offer promising opportunities for the design of innovative treatment modalities for EBV-associated malignancies. Indeed, several therapeutic strategies for telomerase inhibition have been developed and are being investigated in clinical trials. In this respect, our recent finding that TERT inhibition sensitizes EBV+ lymphoma cells to antivirals through activation of EBV lytic replication is particularly promising and provides a rationale for the activation of clinical studies aimed at assessing the effects of combination therapies with TERT inhibitors and antivirals for the treatment of EBV-associated malignancies.
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