Antagonistic effects ofc-myc and Epstein-Barr virus latent genes on the phenotype of human B cells

Pajic, Alexander; Staege, Martin S.; Dudziak, Diana; Schuhmacher, Marino; Spitkovsky, Dimitri D.; Eißner, Günther; Brielmeier, Markus; Polack, Axel; Bornkamm, Georg W.

doi:10.1002/ijc.1404

Cited by 50 publications

(61 citation statements)

References 26 publications

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“…A similar negative effect of LMP1 on c-myc in U2932 LMP1 expressors was observed by us (data not shown). Overall, these data are consistent with the previously described incompatibility between the latency III-driven transcription program and c-myc-driven growth program (Pajic et al, 2001), and suggest that such an incompatibility might be due to differential and opposite regulation of the same miRs by c-myc and LMP1. Although further studies will be required to investigate how LMP1 downregulates c-myc and consequently alters miR expression, we would like to propose a scenario of oncogene cooperation in which suppression of miR-29b by c-myc (Chang et al, 2008) and the consequent positive regulation of TCL1 might be of critical significance in the pathogenesis of B-cell lymphomas with high c-myc and TCL1 expression.…”

Section: Discussionsupporting

confidence: 91%

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

et al. 2009

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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.

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Section: Discussionsupporting

confidence: 91%

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

et al. 2009

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“…In the cell system from which the P4936 cell line is derived, c-Myc overexpression has earlier been shown to c-Myc and the germinal center program in BL H Scheller et al induce some markers that are also found on GC cells but are negatively affected by EBV latent genes (Polack et al, 1996;Pajic et al, 2001). We, therefore, assessed whether c-Myc overexpression is also capable of inducing expression of the centroblast marker CD77.…”

Section: Resultsmentioning

confidence: 95%

“…Although earlier studies showed high c-Myc expression in the GC, more recent data revealed that c-Myc expression and activity in GC B cells are rather uncharacteristically low (MartinezValdez et al, 1996;Shaffer et al, 2001;Klein et al, 2003). In vitro models of BL pathogenesis have shown, though, that c-Myc overexpression in B cells may induce some features that are also found in GC B cells (Polack et al, 1996;Pajic et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

c-Myc overexpression promotes a germinal center-like program in Burkitt's lymphoma

et al. 2009

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The germinal center (GC) reaction has a pivotal function in human B-cell lymphomagenesis. Genetic aberrations occurring during somatic hypermutation and class switch recombination deregulate key factors controlling B-cell physiology and proliferation. Several human lymphoma entities are characterized by a constitutive GC phenotype and ongoing somatic hypermutation, but the molecular basis for this phenomenon is only partly understood. We have investigated the reasons for a constitutive GC-like program in Burkitt's lymphoma cells. Here, overexpression of c-Myc leads to a centroblast phenotype, promotes high constitutive expression of the key GC factors Bcl-6, E2A and activation-induced cytidine deaminase and contributes to proliferation and somatic hypermutation. Our findings elucidate how the activity of a pivotal transcription factor may freeze B-cell lymphoma cells in a constitutive GC-like state that is even maintained at an extrafollicular location.

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“…15 Activation of EBNA2 causes a change of the viral transcription program, followed by a shift from the group I to the group III BL phenotype, which renders the cells TGF-␤-resistant.…”

Section: Tgf-␤ Can Readily Induce Junb and Id3 Expression In Myc-and mentioning

confidence: 99%

“…The P493-6 cell line can, however, reactivate the lymphoblastoid, group III phenotype of the parental LCL upon addition of estrogen to the cell culture medium. 15 Thus, in contrast to previous results, the P493-6 cell line offers the unique option of studying epigenetic changes when proliferation is driven either by EBNA2 or by Myc on the isogenetic background of a single cell line.…”

mentioning

confidence: 93%

Epstein‐Barr virus antagonizes the antiproliferative activity of transforming growth factor‐β but does not abolish its signaling

Horndasch

Raschke

Bommer

et al. 2002

Intl Journal of Cancer

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TGF-␤ induces apoptosis and inhibits the proliferation of EBV-negative B-lymphoma cell lines. In contrast, EBV-immortalized B cells are resistant to both the proapoptotic and the antiproliferative activities of TGF-␤. We have generated a lymphoblastoid cell line, in which we can switch on and off the EBV-specific transcriptional program driven by EBNA2. When these cells express the EBNA2-driven phenotype, they are resistant to TGF-␤-mediated growth arrest. We used this cell line to readdress the question of how EBV can overcome the antiproliferative TGF-␤ activity. We show here that EBVdriven cells remain TGF-␤-responsive since TGF-␤ target genes are readily induced. Thus, EBV can overcome TGF-␤-mediated growth arrest without interfering with the core machinery of the TGF-␤ signaling pathway, which links ligand binding to the induction of TGF-␤ target genes.

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Antagonistic effects ofc-myc and Epstein-Barr virus latent genes on the phenotype of human B cells

Abstract: Epstein-Barr virus (EBV) immortalized cells and

Cited by 50 publications

References 26 publications

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

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

c-Myc overexpression promotes a germinal center-like program in Burkitt's lymphoma

Epstein‐Barr virus antagonizes the antiproliferative activity of transforming growth factor‐β but does not abolish its signaling

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