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  • Title: Inhibition of GSK-3beta mediates expression of MMP-9 through ERK1/2 activation and translocation of NF-kappaB in rat primary astrocyte.
    Author: Kim SD, Yang SI, Kim HC, Shin CY, Ko KH.
    Journal: Brain Res; 2007 Dec; 1186():12-20. PubMed ID: 17996850.
    Abstract:
    Glycogen synthase kinase (GSK)-3beta and extracellular signal-regulated kinase (ERK) regulate several cellular signaling pathways in common, including embryonic development, cell differentiation and apoptosis. In this study, we investigated whether GSK-3beta inhibition is involved in ERK activation, which affects the activation of NF-kappaB and induction of MMP-9 in cultured rat primary astrocytes. Here, we found that GSK-3beta inhibition using GSK-3beta inhibitor TDZD-8 increased the phosphorylation of GSK-3beta at Ser9 site as well as the phosphorylation of ERK1/2 and Akt at Ser473 site. In this condition, GSK-3beta inhibition increased MMP-9 but not MMP-2 activity in a concentration-dependent manner. In RT-PCR analysis, MMP-9 mRNA level was increased by GSK-3beta inhibition in a concentration-dependent manner. MMP-9 promoter reporter activity was similarly increased by GSK-3beta inhibition. Pretreatment of U-0126 (MEK1/2 inhibitor) completely abolished the GSK-3beta inhibition-induced phosphorylation of ERK1/2. U-0126 prevented GSK-3beta inhibition-mediated induction of MMP-9 reporter activity as well as the MMP-9 gene expression. The transcriptional activity of NF-kappaB was significantly increased by GSK-3beta inhibition, which was determined by nuclear translocation of NF-kappaB. Inhibition of ERK1/2 activity by U-0126 also completely blocked the nuclear translocation of NF-kappaB. Transfection of dominant negative plasmid (S9A) of GSK-3beta significantly decreased phosphorylation of ERK, MMP-9 expression and nuclear translocation of NF-kappaB by GSK-3beta inhibition as compared to wild type GSK-3beta. These data suggest that GSK-3beta inhibition mediates ERK1/2 activation followed by NF-kappaB activation, which directly regulates the induction of MMP-9 in rat primary astrocytes.
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