LMP1 signaling and activation of NF-κB in LMP1 transgenic mice

Thornburg, Natalie J.; Kulwichit, Wanla; Edwards, Rachel Hood; Shair, Kathy H.Y.; Bendt, Katharine M.; Raab‐Traub, Nancy

doi:10.1038/sj.onc.1209023

Cited by 89 publications

(76 citation statements)

References 50 publications

(42 reference statements)

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“…6 Upper). There are also reports of LMP1 activating the protein kinase B (PKB/Akt) pathway (22). Interestingly, Akt phosphorylation after LMP1 stimulation was inhibited in B cells lacking TRAF5 (Fig.…”

Section: Direct Role Of Traf5 In Lmp1-mediated Jnk Activation and Il-6mentioning

confidence: 94%

TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40

Kraus¹,

Nakano

Bishop

2009

Proc. Natl. Acad. Sci. U.S.A.

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The cytoplasmic signaling protein TNF receptor-associated factor 5 (TRAF5) has been implicated in several biological roles in Tlymphocyte responses. However, a clear connection between in vivo TRAF5 immune cell functions and specific signaling pathways has not been made. This study shows that TRAF5 associated strongly with the viral oncogenic CD40 mimic latent membrane protein 1 (LMP1), in contrast to weaker association with CD40, for which it has been shown to play a modest role. LMP1 uses specific TRAFs differently than CD40, resulting in amplified and dysregulated CD40-like activation of B lymphocytes. When the cytoplasmic domain of LMP1 is expressed as a transgenic replacement for CD40 in mouse B cells, the resulting mouse exhibits measures of B-cell hyperactivity such as splenomegaly, lymphadenopathy, elevated serum IL-6, elevated serum autoantibodies, and abnormal splenic architecture. Thus, in contrast to CD40, TRAF5 may have an important nonredundant role as a positive mediator of LMP1 signaling and functions in B cells. To test this hypothesis, mice were created that express mCD40LMP1 in place of CD40, and are either sufficient or deficient in TRAF5. Results revealed that TRAF5 plays a critical role in LMP1-mediated c-Jun kinase signaling and is required for much of the abnormal phenotype observed in mCD40LMP1 transgenic mice. This is the first report showing a major requirement for TRAF5 in signaling by a specific receptor both in vitro and in vivo, as well as playing an important role in biological function in B lymphocytes.B lymphocyte ͉ latent membrane protein 1 ͉ TNF receptor-associated factor ͉ lymphocyte activation ͉ TNF receptor superfamily T he Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) is a functional mimic of CD40 expressed as a six transmembrane receptor on the cell surface (1). LMP1 selfoligomerizes, resulting in constitutive signaling (1, 2). Although LMP1 can initiate signaling without a ligand, the unique nature of its cytoplasmic domain results in sustained and amplified activation independent of its transmembrane regions. Thus, a hybrid molecule in which the transmembrane domains of LMP1 are replaced with the transmembrane and extracellular portions of CD40 induces B-cell activation that is higher and more prolonged than levels achieved by endogenous CD40 (3-5). Expression of LMP1 by B cells also results in increased survival (5, 6) and class switching (7). The heightened activation state caused by LMP1 expression in mice leads to B-cell hyperactivity, resulting in splenomegaly, lymphadenopathy, and production of elevated serum IL-6 and autoantibodies (4). The amplified and constitutive CD40-like signal provided by LMP1 can also contribute to generation of Reed-Sternberg cells (8) and B-cell lymphoma (9).Like CD40, LMP1 binds and uses cytoplasmic adaptor molecules known as TNF receptor-associated factors (TRAFs). Interestingly, LMP1 uses TRAFs 1, 2, and 3 differently than CD40. TRAFs 1 and 2 cooperate to promote certain CD40-mediated signals to B cells, but TRAF3 inhib...

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Section: Direct Role Of Traf5 In Lmp1-mediated Jnk Activation and Il-6mentioning

confidence: 94%

TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40

Kraus¹,

Nakano

Bishop

2009

Proc. Natl. Acad. Sci. U.S.A.

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“…The primary in vitro transforming protein of EBV is the LMP-1 (Brinkmann and Schulz, 2006). Transgenic mice with LMP-1 under the control of the immunoglobulin promoter develop B-cell lymphoma at an increased frequency (Thornburg et al, 2005). Moreover, LMP-1 is consistently expressed in all EBV-associated cHL cases.…”

Section: Involvement Of the V-rel Protein In Avian Rev-t-induced Retrmentioning

confidence: 99%

“…LMP-1 activates NF-kB (Herrero et al, 1995;Cahir-McFarland et al, 2000), mainly via effects on the NF-kB subunit c-Rel (Thornburg et al, 2005). (Laherty et al, 1992) and prosurvival genes including IAPs, c-FLIP and IL-6 (Keller et al, 2006).…”

Section: Involvement Of the V-rel Protein In Avian Rev-t-induced Retrmentioning

confidence: 99%

Manipulation of the nuclear factor-κB pathway and the innate immune response by viruses

et al. 2006

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“…A previous study proved that LMP1 increased the development of lymphoma in LMP1 transgenic mice through the NF-κB pathway (29). In addition, eIF4E is a direct transcriptional target of NF-κB and is aberrantly regulated in acute myeloid leukemia (30).…”

Section: Discussionmentioning

confidence: 99%

LMP1 promotes nasal NK/T-cell lymphoma cell function by eIF4E via NF-κB pathway

et al. 2015

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Abstract. Nasal natural killer T-cell lymphoma (NKTL) is a highly malignant tumor that is closely associated with EpsteinBarr virus (EBV) infection. Latent membrane protein 1 (LMP1) is encoded by EBV and plays an important role in EBV-induced cell transformation. Therefore, we assessed the function of LMP1 as a stimulant of NKTL progression and the underlying mechanism. A human EBV-positive NKTL cell line (SNK-6) was transfected with pcDNA3.1-LMP1, LV-LMP1 shRNA or LV-eukaryotic translation initiation factor 4E (eIF4E)-shRNA. Then, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to assess the proliferation of SNK-6 cells, and cell migration and invasion were analyzed by Transwell chamber assay. Flow cytometry was used to analyze the cell cycle and apoptosis. The results showed LMP1 was highly expressed in SNK-6 cells compared with control groups. Following pretreatment with LMP1 shRNA, the proliferation of SNK-6 cells was inhibited and resulted in a G0/G1 phase arrest. A reduction in invasion and migration was also observed. LMP1 silencing promoted cell apoptosis. Further mechanistic analysis suggested that LMP1 overexpression induced the expression of eIF4E, while eIF4E-shRNA dramatically attenuated the increase in cell proliferation, invasion, migration and the inhibition of apoptosis triggered by LMP-1 upregulation. Moreover, the effect of LMP1 on eIF4E expression was mediated by the NF-κB pathway. Therefore, this finding may provide a potential target against NKTL.

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LMP1 signaling and activation of NF-κB in LMP1 transgenic mice

Cited by 89 publications

References 50 publications

TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40

TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40

Manipulation of the nuclear factor-κB pathway and the innate immune response by viruses

LMP1 promotes nasal NK/T-cell lymphoma cell function by eIF4E via NF-κB pathway

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