Abstract
Glycogen synthase kinase 3 beta (GSK3β) is a critical protein kinase that phosphorylates numerous proteins in cells and thereby impacts multiple pathways including the β-Catenin/TCF/LEF-1 pathway. MicroRNAs (miRs) are a class of noncoding small RNAs of ∼22 nucleotides in length. Both GSK3β and miR play myriad roles in cell functions including stem cell development, apoptosis, embryogenesis and tumorigenesis. Here we show that GSK3β inhibits the expression of miR-96, miR-182 and miR-183 through the β-Catenin/TCF/LEF-1 pathway. Knockout of GSK3β in mouse embryonic fibroblast cells increases expression of miR-96, miR-182 and miR-183, coinciding with increases in the protein level and nuclear translocation of β-Catenin. In addition, overexpression of β-Catenin enhances the expression of miR-96, miR-182 and miR-183 in human gastric cancer AGS cells. GSK3β protein levels are decreased in human gastric cancer tissue compared with surrounding normal gastric tissue, coinciding with increases of β-Catenin protein, miR-96, miR-182, miR-183 and primary miR-183-96-182 cluster (pri-miR-183). Furthermore, suppression of miR-183-96-182 cluster with miRCURY LNA miR inhibitors decreases the proliferation and migration of AGS cells. Knockdown of GSK3β with siRNA increases the proliferation of AGS cells. Mechanistically, we show that β-Catenin/TCF/LEF-1 binds to the promoter of miR-183-96-182 cluster gene and thereby activates the transcription of the cluster. In summary, our findings identify a novel role for GSK3β in the regulation of miR-183-96-182 biogenesis through β-Catenin/TCF/LEF-1 pathway in gastric cancer cells.
Highlights
Glycogen synthase kinase 3 beta (GSK3b) is a serine/ threonine protein kinase whose function is required for the NF-kB–mediated anti-apoptotic response to tumor necrosis factor alpha [1]
Wnt signal inhibits GSK3b activity and increases free cytosolic b-Catenin level. b-Catenin translocates to the nucleus to act as a cofactor for the T cell factor (TCF) family of transcription factors, including TCF-1, TCF-3, TCF-4 and LEF-1. b-Catenin/TCF/ LEF-1 complex activates oncogenic target genes such as c-myc [6], c-jun [7] and cyclin D1 [8]
The Wnt signaling plays a pivotal role in tumorigenesis in various cancers including gastric cancer [37,38]
Summary
Glycogen synthase kinase 3 beta (GSK3b) is a serine/ threonine protein kinase whose function is required for the NF-kB–mediated anti-apoptotic response to tumor necrosis factor alpha [1]. GSK3b plays a critical role in numerous signaling pathways including Wnt/b-Catenin/ TCF/LEF-1 signaling pathway. GSK3b is constitutively active in cells and forms a complex with adenomatous polyposis coli (APC) and scaffold protein Axin in the absence of Wingless/Wnt signal. Phosphorylation of APC by GSK3b provides a docking site for b-Catenin binding. B-Catenin is a key component of both the cadherin cell adhesion system and the Wnt signaling pathway [2,3,4]. GSK3b phosphorylates b-Catenin leading to its degradation by ubiquitin-proteasome pathway [5]. Wnt signal inhibits GSK3b activity and increases free cytosolic b-Catenin level. B-Catenin/TCF/ LEF-1 complex activates oncogenic target genes such as c-myc [6], c-jun [7] and cyclin D1 [8] Wnt signal inhibits GSK3b activity and increases free cytosolic b-Catenin level. b-Catenin translocates to the nucleus to act as a cofactor for the T cell factor (TCF) family of transcription factors, including TCF-1, TCF-3, TCF-4 and LEF-1 (leukemia enhancer factor 1). b-Catenin/TCF/ LEF-1 complex activates oncogenic target genes such as c-myc [6], c-jun [7] and cyclin D1 [8]
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