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  • Title: Oncogenic K-ras stimulates Wnt signaling in colon cancer through inhibition of GSK-3beta.
    Author: Li J, Mizukami Y, Zhang X, Jo WS, Chung DC.
    Journal: Gastroenterology; 2005 Jun; 128(7):1907-18. PubMed ID: 15940626.
    Abstract:
    BACKGROUND & AIMS: Two key genetic events underlying the development of colon cancer are activation of the K-ras and Wnt signaling pathways. We have previously shown that these 2 pathways can cooperate to regulate vascular endothelial growth factor (VEGF) gene expression. The goal of this study was to define the molecular basis for this interaction. METHODS: The effects of K-ras(Val12) on VEGF and T-cell factor 4 (TCF-4) promoter activity, nuclear levels of beta-catenin and beta-catenin/TCF-4 complexes, glycogen synthase kinase 3beta (GSK-3beta) phosphorylation, and GSK-3beta kinase activity were measured. LY294002 and PD98059 were used to define the role of specific ras effector pathways. RESULTS: Oncogenic K-ras up-regulated the activity of the VEGF promoter, and selective mutagenesis of TCF-4 binding sites significantly blocked this induction. K-ras(Val12) also induced the activity of a heterologous TCF-4 reporter construct in Caco-2 and HeLa cells. LY294002 and dominant negative phosphatidylinositol 3-kinase nearly completely blocked this induction. K-ras(Val12) increased the stability of beta-catenin, the levels of nuclear beta-catenin, and the formation of nuclear beta-catenin/TCF-4 complexes, and these effects were also blocked by LY294002. Finally, K-ras(Val12) inhibited the kinase activity of total cellular GSK-3beta and GSK-3beta complexed with Axin. This effect was not mediated through phosphorylation at serine 9 but did depend on phosphatidylinositol 3-kinase. CONCLUSIONS: Our results suggest a unique cooperative interaction between 2 critical oncogenic pathways in colorectal tumorigenesis and highlight the pivotal role of GSK-3beta.
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