Epstein-Barr Virus Latent Membrane Protein 1 Induces Cellular MicroRNA miR-146a, a Modulator of Lymphocyte Signaling Pathways

Cameron, Jennifer E.; Yin, Qinyan; Fewell, Claire; Lacey, Michelle; McBride, Jane; Wang, Xia; Lin, Zhen; Schaefer, Brian C.; Flemington, Erik K.

doi:10.1128/jvi.02136-07

Cited by 270 publications

(268 citation statements)

References 42 publications

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“…miR-29a/b/c and miR-146a are among those miRs that are highly induced by LMP1. Previous findings that LMP1 induces miR-146a are consistent with our results (Motsch et al, 2007;Cameron et al, 2008). Supplementary Figure 1 shows the heat map of the miR profile.…”

Section: Mir Profiling Of U2932 Dlbcls Transfected With Lmp1supporting

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: Mir Profiling Of U2932 Dlbcls Transfected With Lmp1supporting

confidence: 91%

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

et al. 2009

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“…8H). Previously, miR-146a was shown to be induced by endotoxin (lipopolysaccharide) through two consensus NF-B binding sites in the promoter region (9). This region is highly homologous between human and mouse, suggesting an evolutionarily conserved regulatory mechanism for controlling miR-146a expression.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

Mei

Bachoo²,

Zhang³

2011

Molecular and Cellular Biology

159

131

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Dysregulated epidermal growth factor receptor (EGFR) signaling through either genomic amplification or dominant-active mutation (EGFR vIII ), in combination with the dual inactivation of INK4A/ARF and PTEN, is a leading cause of gliomagenesis. Our global expression analysis for microRNAs revealed that EGFR activation induces miR-146a expression, which is further potentiated by inactivation of PTEN. Unexpectedly, overexpression of miR-146a attenuates the proliferation, migration, and tumorigenic potential of Ink4a/Arf ؊/؊ Pten ؊/؊ Egfr vIII murine astrocytes. Its ectopic expression also inhibits the glioma development of a human glioblastoma cell line in an orthotopic xenograft model. Such an inhibitory function of miR-146a on gliomas is largely through downregulation of Notch1, which plays a key role in neural stem cell maintenance and is a direct target of miR-146a. Accordingly, miR-146a modulates neural stem cell proliferation and differentiation and reduces the formation and migration of glioma stem-like cells. Conversely, knockdown of miR-146a by microRNA sponge upregulates Notch1 and promotes tumorigenesis of malignant astrocytes. These findings indicate that, in response to oncogenic cues, miR-146a is induced as a negative-feedback mechanism to restrict tumor growth by repressing Notch1. Our results provide novel insights into the signaling pathways that link neural stem cells to gliomagenesis and may lead to new strategies for treating brain tumors.Gliomas are the most frequently observed brain tumors, with glioblastoma multiforme (GBM) being the most common and aggressive form in adults (35). Despite major therapeutic improvements made by combining neurosurgery, chemotherapy, and radiotherapy, the prognosis and survival rate for patients with GBM is still extremely poor (7). The deadly nature of GBM originates from explosive growth and invasive behavior, which are fueled by dysregulation of multiple signaling pathways. Epidermal growth factor receptor (EGFR) activation, in cooperation with loss of tumor suppressor functions, such as mutations in Ink4a/Arf and Pten genes, constitutes a lesion signature for GBM (4). Such dysregulated genetic pathways are sufficient to transform neural stem cells (NSCs) or astrocytes into cancer stem-like cells. This gives rise to highgrade malignant gliomas with a pathological phenotype resembling human GBM (5, 59). However, the downstream events underlying these genetic dysregulations in gliomagenic cells have not been fully elucidated.MicroRNAs are 20-to 22-nucleotide noncoding RNA molecules that have emerged as key players in controlling NSC self-renewal and differentiation (11,57). Aberrant expression of miRNAs, such as miR-21, miR-124, and miR-137, is linked to glioma formation (49). miR-199b-5p and miR-34a impair cancer stem-like cells through the negative regulation of several components of the Notch pathway in brain tumors (18,21). The Notch pathway is an evolutionarily conserved signaling pathway that plays an important role in neurogenesis (3, 10, 23). Upon bindi...

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“…1), which suggests that there is no differential processing of precursor miRNAs into mature miRNAs with age. Recent reports demonstrated the NF-jB-dependent induction of miR-146a expression by TLR signaling (Taganov et al, 2006;Cameron et al, 2008;Lukiw et al, 2008). Although details about the mechanisms of immunosenescence have yet to be elucidated, many studies have been conducted in aged humans to establish a clear correlation between an increase in the constitutive activation of NF-jB and chronic inflammation (Helenius et al, 1996;Spencer et al, 1997;Kim et al, 2002;Sarkar & Fisher, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Two NF-jB-binding sites, site I and II, are crucial for LPS-induced miR-146a expression (Taganov et al, 2006;Cameron et al, 2008;Lukiw et al, 2008) (Fig. 4A).…”

Section: Mir-146a Is Highly Expressed In the Macrophages Of Aged Micementioning

confidence: 99%

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

Jiang¹,

Xiang²,

Wang

et al. 2011

Aging Cell

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SummaryAge-associated immune dysfunction, characterized by increased systemic levels of cytokines, manifests as an increased susceptibility to infections. Thus, understanding these negative regulators of the immune response has paved the way to delineating signaling pathways that impact immune senescence. In the present study, we found that miR-146a, which negatively regulated the expression of IL-1b and IL-6, was highly expressed in aged mice. However, there was a lack of response to the stimulation of lipopolysaccharide (LPS) and proinflammatory cytokines in macrophages of aged mice. As a result, the negative feedback regulation loop with miR-146a involving down-regulation of inflammation factors was interrupted in aged mice. Aberrant NF-jB binding to the miR-146a promoter was demonstrated to be associated with the abnormal expression of miR-146a in aged mice. The DNA methyltransferase inhibitor (5-aza-2-deoxycytidine) and the histone deacetylase inhibitor [trichostatin A (TSA)] both significantly up-regulated miR-146a transcriptional activation by altering the DNA-binding activity of NF-jB in macrophages isolated from aged mice, which suggests that DNA methylation and histone acetylation are involved in the suppression of age-dependent miR-146a expression. Additionally, high levels of histone deacetylase (HDACs) expressions contributed to the inhibition of miR-146a expression in LPS-stimulated macrophages from aged mice in vitro. While the suppression of HDACs activities by TSA could improve LPS-induced inflammatory responses owing to up-regulation of miR-146a expression in macrophages from aged mice. These data indicate that the dysregulated expression of miR-146a results in the age-associated dysfunction of macrophages, and miR-146a may be a good target for the treatment of age-related inflammatory diseases.

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Epstein-Barr Virus Latent Membrane Protein 1 Induces Cellular MicroRNA miR-146a, a Modulator of Lymphocyte Signaling Pathways

Cited by 270 publications

References 42 publications

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

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

MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

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