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Stambolic, V., Ruel, L. &Woodgett, J.R. Lithium inhibits glycogen synthase kinase-3 activity and mimics Wingless signaling in intact cells. Curr. Biol. 6, 1664-1668

Ontario Cancer Institute, Toronto, Canada.
Current Biology (Impact Factor: 9.57). 01/1997; 6(12):1664-8. DOI: 10.1016/S0960-9822(02)70790-2
Source: PubMed

ABSTRACT

Exposing eukaryotic cells to lithium ions (Li+) during development has marked effects on cell fate and organization. The phenotypic consequences of Li+ treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption, respectively, of a highly conserved protein serine/threonine kinase, glycogen synthase kinase-3 (GSK-3). In Drosophila, the GSK-3 homologue is encoded by zw3sgg, a segment-polarity gene involved in embryogenesis that acts downstream of wg. In higher eukaryotes, GSK-3 has been implicated in signal transduction pathways downstream of phosphoinositide 3-kinase and mitogen-activated protein kinases.
We investigated the effect of Li+ on the activity of the GSK-3 family. At physiological doses, Li+ inhibits the activity of human GSK-3 beta and Drosophila Zw3Sgg, but has no effect on other protein kinases. The effect of Li+ on GSK-3 is reversible in vitro. Treatment of cells with Li+ inhibits GSK-3-dependent phosphorylation of the microtubule-associated protein Tau. Li+ treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo/beta-catenin, demonstrating that Li+ can mimic Wingless signalling in intact cells, consistent with its inhibition of GSK-3.
Li+ acts as a specific inhibitor of the GSK-3 family of protein kinases in vitro and in intact cells, and mimics Wingless signalling. This reveals a possible molecular mechanism of Li+ action on development and differentiation.

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    • "Another intriguing therapeutic possibility in TP53-mutated SHH tumors is lithium. Lithium is an inhibitor of GSK3b, a negative regulator of the WNT pathway, and as such can mimic canonical WNT activation (Stambolic et al. 1996). Thus, one potential therapeutic option is the restoration of radiosensitivity of TP53-mutated medulloblastoma through the administration of lithium (Zhukova et al. 2014 ). "
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    • "Valproic acid (VPA) and lithium chloride (LiCl) are two mood-stabilizing drugs used to treat patients with bipolar disorder (Kazantsev and Thompson 2008; Li et al. 2012). It has been reported that the major pharmacological actions of VPA are to inhibit histone deacetylase (HDAC) and glycogen synthase kinase-3 (GSK-3) activities (Phiel et al. 2001; Werstuck et al. 2004), while LiCl is the inhibitor of GSK-3 (Stambolic et al. 1996; Zhang et al. 2003). Recent studies also demonstrate that VPA or LiCl treatment increases the expression of brain-derived neurotrophic factor (BDNF) (Yasuda et al. 2007). "

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    • "The theoretical basis for this combinatory approach would be the fact that LiCl can act both as an autophagy inducer or inhibitor, depending on the dose used (Stambolic et al., 1996; Sarkar et al., 2005). At higher dosages LiCl is actually able to inhibit GSK3, which suppresses autophagy via phosphorylation of mTOR (Stambolic et al., 1996; Chiu and Chuang, 2010); thus, a combinatory therapy with another mTOR-dependent autophagy inducer could counteract this effect. The main goal of this work was to test the potential of this combinatory treatment in MJD. "
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