MicroRNA-22 and microRNA-140 suppress NF-κB activity by regulating the expression of NF-κB coactivators

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 08/2011; 411(4):826-31. DOI: 10.1016/j.bbrc.2011.07.048
Source: PubMed


Nuclear factor κB (NF-κB) is a transcription factor that regulates a set of genes that are critical to many biological phenomena, including liver tumorigenesis. To identify microRNAs (miRNAs) that regulate NF-κB activity in the liver, we screened 60 miRNAs expressed in hepatocytes for their ability to modulate NF-κB activity. We found that miRNA-22 and miRNA-140-3p significantly suppressed NF-κB activity by regulating the expression of nuclear receptor coactivator 1 (NCOA1) and nuclear receptor-interacting protein 1 (NRIP1), both of which are NF-κB coactivators. Our results provide new information about the roles of miRNAs in the regulation of NF-κB activity.

8 Reads
  • Source
    • "Although both miR-140-5p and -3p are transcribed from the same precursor transcript pre-miR-140, they have different seed sequences and are, therefore, predicted to target different genes. While miR-140-5p was shown to target several genes involved in OA, miR-140-3p has been reported to target dynamin 1, which plays a role in the central nervous system [16] and the nuclear factor kappa B (NF-κB) co-activator nuclear receptor-interacting protein 1 [17]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs (miRNAs) down-regulate their target genes. The intronic miR-140, present in the WW domain containing E3 ubiquitin protein ligase 2 (WWP2) gene, decreases the expression of genes that play detrimental roles in osteoarthritis (OA). As the expression level of miR-140 is significantly decreased in human OA chondrocytes, we investigated its regulation in those cells. Gene expression in human chondrocytes was determined by quantitative polymerase chain reaction (qPCR) and gene silencing was done in OA chondrocytes by transient transfection with specific small interfering RNAs (siRNAs). Binding sites of the miR-140 regulatory sequence (rsmiR-140) were identified by mutagenesis and chromatin immunoprecipitation (ChIP) in OA chondrocytes. The effects of translocation on OA chondrocytes were determined by immunocytochemistry and qPCR. In contrast to miR-140, the expression of WWP2 was similar in both normal and OA cells, suggesting that miR-140 has an additional level of regulation. rsmiR-140 showed activity and predicted binding sites for nuclear matrix transcription factor 4 (NMP4), myc-associated zinc (MAZ), nuclear factor of activated T-cells (NFAT), and mothers against decapentaplegic homolog 3 (SMAD3). Silencing NFAT3 (P <=0.01) and SMAD3 (P <=0.05) differentially regulated miR-140 independently of WWP2. Silencing NFAT5 decreased both miR-140 and WWP2 (P <=0.003 and P <=0.05, respectively). NFAT3 activation increased and transforming growth factor-beta (TGF-beta) decreased rsmiR-140 activity. Mutagenesis of rsmiR-140 and ChIP assays identified binding sites at which NFAT3 (activator) and SMAD3 (repressor) directly regulated miR-140. TGF-beta interfered with NFAT3 translocation, and subsequently with miR-140 expression. This is the first study to provide evidence of a regulatory mechanism of miR-140 independent of WWP2, and new and differential roles for NFAT3 and SMAD3 in the OA process in the regulation of miR-140 transcription. Such knowledge could advance therapeutic strategies targeting OA.
    Arthritis research & therapy 11/2013; 15(6):R197. DOI:10.1186/ar4387 · 3.75 Impact Factor
  • Source
    • "Because upregulation of MICA expression was observed in Dicer-knockdown cells18, we hypothesized that MICA expression levels may be at least partly regulated by miRNAs. We initially tested miRNAs that might affect MICA expression using reporter constructs into which MICA 3′-untranslated region (3′UTR) sequences were cloned and by transiently overexpressing 76 mature synthetic microRNAs, which were selected on the basis of their hepatic expression level, as in our previous studies1920. Among the microRNAs examined, several may target MICA 3′UTR (Supplementary Figure 1). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatocellular carcinoma (HCC) is a threat to public health worldwide. We previously identified the association of a single nucleotide polymorphism (SNP) at the promoter region of the MHC class I polypeptide-related sequence A (MICA) gene with the risk of hepatitis-virus-related HCC. Because this SNP affects MICA expression levels, regulating MICA expression levels may be important in the prevention of HCC. We herein show that the microRNA (miR) 25-93-106b cluster can modulate MICA levels in HCC cells. Overexpression of the miR 25-93-106b cluster significantly suppressed MICA expression. Conversely, silencing of this miR cluster enhanced MICA expression in cells that express substantial amounts of MICA. The changes in MICA expression levels by the miR25-93-106b cluster were biologically significant in an NKG2D-binding assay and an in vivo cell-killing model. These data suggest that the modulation of MICA expression levels by miRNAs may be a useful method to regulate HCCs during hepatitis viral infection.
    Scientific Reports 09/2013; 3:2739. DOI:10.1038/srep02739 · 5.58 Impact Factor
  • Source
    • "Plasmids expressing miR122 and miR185 precursors and the corresponding firefly luciferase-based reporters have been described previously835. Plasmids expressing miRNA-103 precursors and the corresponding luciferase reporter were newly constructed according to protocols reported previously8. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polyphenols are representative bioactive substances with diverse biological effects. Here, we show that apigenin, a flavonoid, has suppressive effects on microRNA (miRNA) function. The effects were mediated by impaired maturation of a subset of miRNAs, probably through inhibition of the phosphorylation of TRBP, a component of miRNA-generating complexes via impaired mitogen-activated protein kinase (MAPK) Erk activation. While glucose intolerance was observed in miRNA103 (miR103)-overexpressing transgenic mice, administration of apigenin improved this pathogenic status likely through suppression of matured miR103 expression levels. These results suggest that apigenin may have favorable effects on the pathogenic status induced by overexpression of miRNA103, whose maturation is mediated by phosphorylated TRBP.
    Scientific Reports 08/2013; 3:2553. DOI:10.1038/srep02553 · 5.58 Impact Factor
Show more

Similar Publications