NF-kappaB only partially mediates Epstein-Barr virus latent membrane protein 1 activation of B cells.

Liljeholm, S; Hughes, Kate; Grundström, Thomas; Brodin, Peter

doi:10.1099/0022-1317-79-9-2117

Cited by 16 publications

(12 citation statements)

References 57 publications

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“…Using bio-informatics analysis, we identified three potential κB motives in the 2550 bp segment upstream from the transcription start site of the human polβ gene, but only the proximal κB-site at −211 to −199nt (κB-site3) has been shown to be an LMP1-dependent p50/c-Rel DNA binding target. In agreement with our data, a previous study showed that LMP1 expression activates the transcription from the c-Rel-responsive promoter, and that this activity can be completely inhibited by expression of a dominant inhibitory IκB mutant (45). In addition, several c-Rel target genes, such as c-myc, CD21, bcl-2, bcl-xL, involved in growth, proliferation, and survival of B cells, were also regulated by LMP1 (13).…”

Section: Discussionsupporting

confidence: 78%

Regulation of DNA Polymerase β by the LMP1 Oncoprotein of EBV through the Nuclear Factor-κB Pathway

et al. 2009

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The repair DNA polymerase β (Polβ), when overexpressed, plays a critical role in generating genetic instability via its interference with the genomic replication program. Up-regulation of Polβ has been reported in many tumor types that exhibit genetic aberrations, including EBV-related B-cell lymphomas. However, the mechanisms responsible for its overexpression have never been examined. Here, we report that both expression and activity of Polβ, in EBV-immortalized B cells, are induced by several natural genetic variants of LMP1, an oncoprotein associated with the vast majority of EBV-related tumors. Conversely, we found that the expression of Polβ decreased when LMP1 signaling was down-regulated by a dominant negative of LMP1 or an inhibitor of the nuclear factor-κB (NF-κB) pathway, the main transduction pathway activated by LMP1, strongly supporting a role of NF-κB in the LMP1-mediated Polβ regulation. Using electrophoretic mobility shift assay experiments from several EBV-immortalized B-cell nuclear extracts, we identified an LMP1-dependent p50/c-Rel heterodimer on a proximal κB binding site (−211 to −199nt) of the Polβ promoter. This result was correlated with a specific Polβ κB transcriptional activity. Taken together, our data enlighten a new mechanism responsible for Polβ overexpression in EBV-infected cells, mediated by LMP1 and dependent on NF-κB activation. [Cancer Res 2009; 69(12):5177-85]

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Section: Discussionsupporting

confidence: 78%

Regulation of DNA Polymerase β by the LMP1 Oncoprotein of EBV through the Nuclear Factor-κB Pathway

et al. 2009

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“…Initially, expression vectors derived from the plasmid pEFCX were used for the expression of LMP1 and other effector proteins in transient transfections. Recombinant genes expressed from pEFCX are driven by the promoter for the polypeptide chain elongation factor 1␣ in an NF-B-independent manner (83). LMP1 levels expressed from pEFCX-LMP1 would not therefore be expected to fluctuate in the presence of molecules that regulate activation of this transcription factor.…”

Section: Resultsmentioning

confidence: 99%

Nuclear Factor κB-Dependent Activation of the Antiapoptoticbfl-1Gene by the Epstein-Barr Virus Latent Membrane Protein 1 and Activated CD40 Receptor

D’Souza

Edelstein²,

Pegman

et al. 2004

J Virol

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Suppression of the cellular apoptotic program by the oncogenic herpesvirus Epstein-Barr virus (EBV) is. We now report that LMP1 drives bfl-1 promoter activity through interactions with components of the tumor necrosis factor receptor (TNFR)/CD40 signaling pathway. We present evidence that this process is NF-B dependent, involves the recruitment of TNFR-associated factor 2, and is mediated to a greater extent by the carboxyl-terminal activating region 2 (CTAR2) relative to the CTAR1 domain of LMP1. Activation of CD40 receptor also led to increased bfl-1 mRNA levels and an NF-B-dependent increase in bfl-1 promoter activity in Burkitt's lymphoma-derived cell lines. We have delineated a 95-bp region of the promoter that functions as an LMP1-dependent transcriptional enhancer in this cellular context. This sequence contains a novel NF-B-like binding motif that is essential for transactivation of bfl-1 by LMP1, CD40, and the NF-B subunit protein p65. These findings highlight the role of LMP1 as a mediator of EBV-host cell interactions and may indicate an important route by which it exerts its cellular growth transforming properties.

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“…However it has been described that LMP1 triggers NF B and JNK/AP1 activities but clear links of the activation of both signal cascades to the known EBV-activated cellular genes are so far missing. 32,35,38,49 Our experiments presented here show that the main promoter activity for IL-10 is located within 350 bp upstream from the transcriptional start site. In this area no consensus sequences for NF B or AP1 have been identified, thus revealing no direct involvement of these transcription factors in EBV-associated regulation of IL-10.…”

Section: Discussionmentioning

confidence: 72%

“…This result supports the growing evidence that for EBV and particularely LMP1, signaling is rather complex and consists of a number of signal mediators like NF B or AP1 or complex interactions between both factors. 49 It has been reported that a mutant LMP1⌬187-351 (containing only the C-terminal activation region-2 (CTAR2) of the cytoplasmic C-terminus) is still able to activate CD54 to approximately 50% of wild-type LMP1 in B cell lines, whereas the ability to activate NF B differs and is cell line-dependent. 49 However the high number of transcription factor binding sites in addition to NF B or AP1 in the CD54 promoter or the lack of typical sites in the analysed IL-10-promoter region makes it possible that additional signal transduction pathways could be involved.…”

Section: Discussionmentioning

confidence: 99%

“…49 It has been reported that a mutant LMP1⌬187-351 (containing only the C-terminal activation region-2 (CTAR2) of the cytoplasmic C-terminus) is still able to activate CD54 to approximately 50% of wild-type LMP1 in B cell lines, whereas the ability to activate NF B differs and is cell line-dependent. 49 However the high number of transcription factor binding sites in addition to NF B or AP1 in the CD54 promoter or the lack of typical sites in the analysed IL-10-promoter region makes it possible that additional signal transduction pathways could be involved. 17,23 In addition, the mutant LMP1⌬187-351 was unable to induce IL-10 and the expression of a dominant negative I B␣ did not lead to an inhibition of LMP1 associated IL-10 expression in BL2 cells.…”

Section: Discussionmentioning

confidence: 99%

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The AT-rich region between −54 to −66 is important for the promoter activity of interleukin-10 in Epstein–Barr virus positive Burkitt’s lymphoma cells

et al. 1999

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IL-10 is an important regulatory cytokine. The recent characterization of the 5Ј-flanking region of IL-10 led to the identification of the promoter region. The infection of B cells with EBV induces IL-10 production which may contribute to EBV-induced transformation. In the present report, IL-10 promoter elements involved in the constitutive expression of IL-10 in EBV-positive lymphoma cells are described. The AT-rich region between −54/−66 from the transcriptional start site was found to be important for IL-10-promoter activity in BL36. A point mutation at position −60 (T/A) was associated with over 90% reduction of luciferase activity in the cell lines BL36 and BL74. The conversion of A/T at position −57 led to enhanced promoter activity. In addition the AT-rich region could serve as an enhancer for the ␤-globin basic promoter. In BJAB cells (EBV-negative), sequences between −205/−139 rather than the AT-rich region were involved in IL-10 promoter regulation. This underlines the importance of the AT-rich region for EBV-associated IL-10 promoter regulation. Our results further the understanding of how the IL-10 gene could be regulated in B cell lymphomas.

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NF-kappaB only partially mediates Epstein-Barr virus latent membrane protein 1 activation of B cells.

Cited by 16 publications

References 57 publications

Regulation of DNA Polymerase β by the LMP1 Oncoprotein of EBV through the Nuclear Factor-κB Pathway

Regulation of DNA Polymerase β by the LMP1 Oncoprotein of EBV through the Nuclear Factor-κB Pathway

Nuclear Factor κB-Dependent Activation of the Antiapoptoticbfl-1Gene by the Epstein-Barr Virus Latent Membrane Protein 1 and Activated CD40 Receptor

The AT-rich region between −54 to −66 is important for the promoter activity of interleukin-10 in Epstein–Barr virus positive Burkitt’s lymphoma cells

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