Wnt-3A/β-catenin signaling induces transcription from the LEF-1 promoter
Wnt-3A/β-catenin signaling induces transcription from the LEF-1 promoter
复制标题
DOI：
10.1074/jbc.m107977200
复制
发表时间：
2002-09-06
影响因子：
4.8
通讯作者：
Engelhardt, JF
中科院分区：
文献类型：
--
作者：
Filali, M;Cheng, NL;Engelhardt, JF
分泌型分子的Wnt家族成员已被确定为决定细胞命运和形态发生信号传导的关键因素。长期以来人们已经认识到，Wnt通过调节细胞内游离的β-连环蛋白（Tcf/LEF - 1转录因子的辅因子）水平，经由Tcf/LEF - 1级联反应诱导形态发生信号传导。在本研究中，我们已经证明Wnt - 3A也能够直接诱导LEF - 1启动子的转录。这种诱导依赖于糖原合成酶激酶3β失活、细胞内游离β-连环蛋白增加以及LEF - 1启动子中一个110bp的短Wnt反应元件（W - RE）。该WRE的线性缺失和内部缺失导致LEF - 1启动子的组成性活性显著增加以及对Wnt - 3A的反应性丧失。单独来看，110bp的WRE赋予异源SV40启动子不依赖环境的对Wnt - 3A或β-连环蛋白（S37A）的反应性。对表达LEF - 1、β-连环蛋白、GSK - 3β以及β-连环蛋白/LEF - 1融合蛋白的显性激活和显性失活形式的研究表明，Wnt - 3A通过依赖β-连环蛋白但不依赖LEF - 1的过程激活LEF - 1启动子。Wnt - 3A的表达还诱导了因子与WRE结合的多种变化，这表明调节机制可能涉及多蛋白复合物的调节。总之，这些结果为Wnt对LEF - 1启动子的转录调控提供了证据，并增进了对Wnt/β-连环蛋白信号传导在LEF - 1依赖性发育过程调控中的机制理解。
Members of the Wnt family of secreted molecules have been established as key factors in determining cell fate and morphogenic signaling. It has long been recognized that Wnt induces morphogenic signaling through the Tcf/LEF-1 cascade by regulating free intracellular levels of beta-catenin, a co-factor for Tcf/LEF-1 transcription factors. In the present study, we have demonstrated that Wnt-3A can also directly induce transcription from the LEF-1 promoter. This induction was dependent on glycogen synthase kinase 3beta inactivation, a rise in free intracellular beta-catenin, and a short 110-bp Wnt-responsive element (W-RE) in the LEF-1 promoter. Linear and internal deletion of this WRE led to a dramatic increase in constitutive LEF-1 promoter activity and loss of Wnt-3A responsiveness. In isolation, the 110-bp WRE conferred context-independent Wnt-3A or beta-catenin(S37A) responsiveness to a heterologous SV40 promoter. Studies expressing dominant active and negative forms of LEF-1, beta-catenin, GSK-3beta, and beta-catenin/LEF-1 fusions suggest that Wnt-3A activates the LEF-1 promoter through a beta-catenin-dependent and LEF-1-independent process. Wnt-3A expression also induced multiple changes in the binding of factors to the WRE and suggests that regulatory mechanisms may involve modulation of a multiprotein complex. In summary, these results provide evidence for transcriptional regulation of the LEF-1 promoter by Wnt and enhance the mechanistic understanding of Wnt/beta-catenin signaling in the regulation of LEF-1-dependent developmental processes.