Activation of the wnt signaling pathway: A molecular mechanism for lithium action
Activation of the wnt signaling pathway: A molecular mechanism for lithium action
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DOI：
10.1006/dbio.1997.8552
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发表时间：
1997-05-01
影响因子：
2.7
通讯作者：
Klein, PS
中科院分区：
文献类型：
--
作者：
Hedgepeth, CM;Conrad, LJ;Klein, PS
糖原合成酶激酶-3 β（GSK-3 β/zeste-white-3/shaggy）是wnt信号通路的负调控因子，在无脊椎动物和脊椎动物的发育中起核心作用; GSK-3 β的功能丧失和显性负突变导致果蝇和爪蟾中wnt通路的激活。我们现在提供的证据表明，锂激活体内wnt信号通路的下游成分，导致β-连环蛋白的积累。我们的数据表明，wnt通路的这种激活是锂抑制GSK-3 β的结果。使用一种新的测定卵母细胞中的GSK-3 β，我们表明，锂抑制GSK-3 β从不同的物种，如Dictyosteelium discoideum和非洲爪蟾，提供了一个生化机制，锂对这些生物体的发展的行动。锂处理还导致非洲爪蟾胚胎中AP-1-荧光素酶报告基因的激活，这与先前的GSK-3 β抑制c-jun活性的观察结果一致。肌醇抑制了GSK-3 β显性负性形式的wnt途径的激活，类似于先前描述的肌醇与锂共注射的效果。肌醇抑制显性负性GSK-3 β和锂的机制仍不确定。(C)北京：科学出版社.
Glycogen synthase kinase-3 beta (GSK-3 beta/zeste-white-3/shaggy) is a negative regulator of the wnt signaling pathway which plays a central role in the development of invertebrates and vertebrates; loss of function and dominant negative mutations in GSK-3 beta lead to activation of the wnt pathway in Drosophila and Xenopus. We now provide evidence that lithium activates downstream components of the wnt signaling pathway in vivo, leading to accumulation of beta-catenin protein. Our data indicate that this activation of the wnt pathway is a consequence of inhibition of GSK-3 beta by lithium. Using a novel assay for GSK-3 beta in oocytes, we show that lithium inhibits GSK-3 beta from species as diverse as Dictyostelium discoideum and Xenopus laevis, providing a biochemical mechanism for the action of lithium on the development of these organisms. Lithium treatment also leads to activation of an AP-l-luciferase reporter in Xenopus embryos, consistent with previous observations that GSK-3 beta inhibits c-jun activity. Activation of the wnt pathway with a dominant negative form of GSK-3 beta is inhibited by myo-inositol, similar to the previously described effect of coinjecting myo-inositol with lithium. The mechanism by which myo-inositol inhibits both dominant negative GSK-3 beta and lithium remains uncertain. (C) 1997 Academic Press.