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  • Title: Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway.
    Author: Nakayama M, Hisatsune J, Yamasaki E, Isomoto H, Kurazono H, Hatakeyama M, Azuma T, Yamaoka Y, Yahiro K, Moss J, Hirayama T.
    Journal: J Biol Chem; 2009 Jan 16; 284(3):1612-9. PubMed ID: 18996844.
    Abstract:
    Helicobacter pylori VacA toxin contributes to the pathogenesis and severity of gastric injury. We found that incubation of AZ-521 cells with VacA resulted in phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3beta (GSK3beta) through a PI3K-dependent pathway. Following phosphorylation and inhibition of GSK3beta,beta-catenin was released from a GSK3beta/beta-catenin complex, with subsequent nuclear translocation. Methyl-beta-cyclodextrin (MCD) and phosphatidylinositol-specific phospholipase C (PI-PLC), but not 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) and bafilomycin A1, inhibited VacA-induced phosphorylation of Akt, indicating that it does not require VacA internalization and is independent of vacuolation. VacA treatment of AZ-521 cells transfected with TOPtkLuciferase reporter plasmid or control FOPtkLucifease reporter plasmid resulted in activation of TOPtkLuciferase, but not FOPtkLucifease. In addition, VacA transactivated the beta-catenin-dependent cyclin D1 promoter in a luciferase reporter assay. Infection of AZ-521 cells by a vacA mutant strain of H. pylori failed to induce phosphorylation of Akt and GSK3beta, or release of beta-catenin from a GSK3beta/beta-catenin complex. Taken together, these results support the conclusion that VacA activates the PI3K/Akt signaling pathway, resulting in phosphorylation and inhibition of GSK3beta, and subsequent translocation ofbeta-catenin to the nucleus, consistent with effects of VacA on beta-catenin-regulated transcriptional activity. These data introduce the possibility that Wnt-dependent signaling might play a role in the pathogenesis of H. pylori infection, including the development of gastric cancer.
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