TRAF6 is a critical mediator of signal transduction by the viral oncogene latent membrane protein 1

Schultheiss, Ute; Püschner, Stephanie; Kremmer, Elisabeth; Mak, Tak W.; Engelmann, Hartmut; Hammerschmidt, Wolfgang; Kieser, Arnd

doi:10.1093/emboj/20.20.5678

Cited by 113 publications

(198 citation statements)

References 70 publications

Supporting

Mentioning

170

Contrasting

Unclassified

Order By: Relevance

“…Our data that both CTAR1 and CTAR2 domains of LMP1 regulate miR-29b through p38 MAP kinase are consistent with a previous study showing that both these domains have an important role in p38 MAP kinase induction (Schultheiss et al, 2001). This adds to the growing evidence of the role of MAP kinases and their downstream transcription factor targets in the regulation of miR (O'Connell et al, 2007;Rahadiani et al, 2008).…”

Section: Ebv Lmp1 Regulates Tcl1 Through Mir-29bsupporting

confidence: 93%

Section: Identification Of Lmp1 Domains Responsible For Tcl1 Reductiosupporting

confidence: 84%

“…(RaabTraub, 2001;Schultheiss et al, 2001). The results in Supplementary Figure 6 that wt LMP1 but not mutated LMP1 activates p38 MAP kinase are consistent with previous data (Schultheiss et al, 2001). The parental, vector-transfected and LMP1-expressing U2932 cells were treated with p38 MAP kinase-specific inhibitor, SB203580 (20 mM) for 24 and 48 h. These samples were tested for TCL1 expression.…”

Section: Identification Of Lmp1 Domains Responsible For Tcl1 Reductiosupporting

confidence: 82%

See 2 more Smart Citations

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

et al. 2009

View full text Add to dashboard Cite

Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1) is noted for its transforming potential. Yet, it also acts as a cytostatic and growth-relenting factor in Burkitt's lymphoma (BL) cells. The underlying molecular mechanisms of the growth inhibitory property of LMP1 have remained largely unknown. In this study, we show that LMP1 negatively regulates a major oncogene, TCL1, in diffuse large B-cell lymphoma (DLBCL) and BL cells. MicroRNA (miR) profiling of LMP1 transfectants showed that among others, miR-29b, is upregulated. LMP1 diminished TCL1 by inducing miR29b through C-terminus activation region 1 (CTAR1) and CTAR2. miR-29b locked nucleic acid (LNA) antisense oligonucleotide transfection into LMP1-expressing cells reduced miR-29b expression and consequently reconstituted TCL1, suggesting that LMP1 negatively regulates TCL1 through miR-29b upregulation. The miR-29b increase by LMP1 was due to an increase in the cluster pri-miR-29b1-a transcription, derived from human chromosome 7. Using pharmacological inhibitors, we found that p38 mitogen-activated protein kinase-activating function of LMP1 is important for this effect. The ability of LMP1 to negatively regulate TCL1 through miR-29b might underlie its B-cell lymphoma growth antagonistic property. As LMP1 is also important for B-cell transformation, we suggest that the functional dichotomy of this viral protein may depend on a combination of levels of its expression, lineage and differentiation of the target cells and regulation of miRs, which then directs the outcome of the cellular response.

show abstract

Section: Ebv Lmp1 Regulates Tcl1 Through Mir-29bsupporting

confidence: 93%

Section: Identification Of Lmp1 Domains Responsible For Tcl1 Reductiosupporting

confidence: 84%

Section: Identification Of Lmp1 Domains Responsible For Tcl1 Reductiosupporting

confidence: 82%

See 1 more Smart Citation

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

et al. 2009

View full text Add to dashboard Cite

show abstract

“…To date, no specific investigation of the role of TRAF5 in LMP1 signal transduction in B cells has been reported. TRAF6 does not appear to interact directly with LMP1 in B cells [21] or MEFs [27]. However, TRAF6 is required for signals through LMP1 in MEFs and epithelial cells [20,27].…”

Section: Lmp1mentioning

confidence: 97%

“…TRAF6 does not appear to interact directly with LMP1 in B cells [21] or MEFs [27]. However, TRAF6 is required for signals through LMP1 in MEFs and epithelial cells [20,27]. In a TRAF6 deficient B cell line, JNK activation through LMP1 is abrogated, though NFkB1 and NFkB2 activation is still observed (LLS & GAB, unpublished).…”

Section: Lmp1mentioning

confidence: 99%

Roles of TRAF molecules in B lymphocyte function

Xie

Kraus

Stunz

et al. 2008

Cytokine & Growth Factor Reviews

View full text Add to dashboard Cite

Tumor necrosis factor receptor associated factors (TRAFs) play a variety of interesting and important roles in the regulation of B lymphocyte function. They act both as cytoplasmic regulatory molecules, and as signal transducers for receptors involved in both innate and adaptive humoral immune responses. In this brief review, we highlight the current state of knowledge of the diverse roles of TRAF molecules in the functions of B lymphocytes. CD40CD40 is the most well-studied member of the TNFR superfamily expressed by B lymphocytes, so its interactions with TRAF molecules have also been intensively investigated. B cell CD40 is important in the induction of B cell survival and expansion, immunoglobulin (Ig) production and isotype switching, upregulation of surface molecules involved in B cell antigen presentation, differentiation to B memory cells, and the production of various cytokines (reviewed in [1]. The TRAF molecules have been shown to contribute to each of these functions (reviewed in [2].In 1994, TRAF3 became the first cytoplasmic molecule demonstrated to associate with CD40 (reviewed in [2]). However, for many years, its roles in CD40 signaling were largely unknown, and are still not completely understood. TRAF3 -/-mice die shortly after birth, but adoptive transfer of fetal liver cells from these mice suggested that their B cells were capable of reconstituting the humoral response [3], implying that TRAF3 is not required to promote CD40-mediated antibody responses. This conclusion was supported by experiments in B cell lines demonstrating that inducible overexpression of TRAF3 inhibits both CD40 responses [4], and cooperation between CD40 and the BCR [5]. Subsequently, B cell lines made completely TRAF3-deficient via gene targeting by homologous recombination show no defects in CD40 signaling overall, and display enhanced CD40-mediated c-jun kinase (JNK) activation and IgM production [6]. Recently, mice made conditionally deficient in TRAF3 only in CD19+ B cells show no deficiencies in CD40 signaling in vitro and have enhanced antibody responses [7]. TRAF2 was initially demonstrated to bind CD40 by exogenous overexpression studies in adenocarcinoma cell lines, in which it promotes JNK activation and the activity of NF-κB reporter genes (reviewed in [2]. Because TRAF2 -/-mice have an early lethal phenotype [8],Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers

show abstract

Evaluation of TRAF6 in a large multiancestral lupus cohort

Namjou

Choi

Harley

et al. 2012

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. TRAF6 is a candidate gene for SLE, which has a major role in several signaling pathways that are important for immunity and organ development. Methods Fifteen single-nucleotide polymorphisms (SNPs), across TRAF6 were evaluated in 7,490 SLE and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated. Results Evidence of associations in multiple SNPs was detected. The best overall p values were obtained for SNPs rs5030437 and rs4755453 (p=7.85×10−5 and p=4.73×10−5, respectively) without significant heterogeneity among populations (p=0.67 and p=0.50 in Q-statistic). In addition, rs540386 previously reported to be associated with RA was found to be in LD with these two SNPs (r2= 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis p=9.15×10−4, OR=0.89, 95%CI=0.83–0.95). Thrombocytopenia improved the overall results in different populations (meta-analysis p=1.99×10−6, OR=0.57, 95%CI=0.45–0.72, for rs5030470). Finally evidence of family based association in 34 African-American pedigrees with the presence of thrombocytopenia were detected in one available SNP rs5030437 with Z score magnitude of 2.28 (p=0.02) under a dominant model. Conclusion Our data indicate the presence of association of TRAF6 with SLE in agreement with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.

show abstract

TRAF6 is a critical mediator of signal transduction by the viral oncogene latent membrane protein 1

Cited by 113 publications

References 70 publications

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

Roles of TRAF molecules in B lymphocyte function

Evaluation of TRAF6 in a large multiancestral lupus cohort

Contact Info

Product

Resources

About