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- W2334220092 abstract "The Wnt signaling pathway has been found to be disregulated in many carcinomas of gastrointestinal system. GSK-3β and CK1α act as molecular switch that dictates both on and off states of Wnt/beta-catenin signaling by regulating cellular levels of the Wnt effector molecule β-catenin. In the absence of the Wnt signal β-catenin is initially phosphorylated by CK1α at S45, followed by GSK-3β at S41, T37 and S33 which marks it for proteosomal degradation. Although GSK-3β is one of the key regulators of the Wnt signaling pathway, the ability for direct, non-invasive & real-time measurement of its kinase activity has been unavailable. Here we describe a chimeric, gain of function, split luciferase based novel reporter for monitoring of dual kinase (GSK-3β and CK1α) activity. The N-terminal β-catenin peptide (aa 29-48) harboring phosphorylation sites for GSK-3β and CK1α was synthesized and used to construct bioluminescence β-catenin reporter (BCR). This reporter when expressed in SW620 colon carcinoma cells and treated with LiCl and small molecular inhibitors SB415286 (GSK-3β) and CKI-7 (CK1α), lead to a dose and time dependent increase in the bioluminescence which was validated by western blotting. Cell lines stably expressing mutant reporters exhibited attenuated response to LiCl & SB415286 (S37A mutant) and to CKI-7 (S45A mutant) confirming specificity of the reporter. To quantify the Wnt dependent change in the activity of the reporters, stable cell lines were generated in HEK293 background which has an intact Wnt signaling pathway. The WT reporter cell line showed over two fold induction with Wnt conditioned media while S37A mutant reporter cell line did not show a significant change in reporter activity corroborating the specificity of the reporters. In mice bearing tumors expressing the wild-type reporter, treatment with LiCl resulted an initial increase in the bioluminescence activity at 4 h which peaked at 7 h. Subsequent imaging revealed oscillations of the bioluminescence activity with a frequency of 14 h and an amplitude that decreased with time. Our reporters provide a powerful, novel tool for sensitive, real time, dynamic, non-invasive monitoring of GSK-3β and CK1α kinase activities in-vitro and in-vivo and have the potential in executing novel therapeutic regimens targeting GSK-3β/CK1α. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5222." @default.
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- W2334220092 date "2010-04-15" @default.
- W2334220092 modified "2023-09-27" @default.
- W2334220092 title "Abstract 5222: Molecular imaging of GSK-3β and CK1α kinase activities in response to Wnt signaling" @default.
- W2334220092 doi "https://doi.org/10.1158/1538-7445.am10-5222" @default.
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