Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cancer Cell. 2011 Oct 18;20(4):427-42. doi: 10.1016/j.ccr.2011.08.016.
Wnt/β-catenin signaling is essential for stem cell regulation and tumorigenesis, but its molecular mechanisms are not fully understood. Here, we report that FoxM1 is a downstream component of Wnt signaling and is critical for β-catenin transcriptional function in tumor cells. Wnt3a increases the level and nuclear translocation of FoxM1, which binds directly to β-catenin and enhances β-catenin nuclear localization and transcriptional activity. Genetic deletion of FoxM1 in immortalized neural stem cells abolishes β-catenin nuclear localization. FoxM1 mutations that disrupt the FoxM1-β-catenin interaction or FoxM1 nuclear import prevent β-catenin nuclear accumulation in tumor cells. FoxM1-β-catenin interaction controls Wnt target gene expression, is required for glioma formation, and represents a mechanism for canonical Wnt signaling during tumorigenesis.
Wnt/β-catenin 信号通路对于干细胞调控和肿瘤发生至关重要，但它的分子机制尚不完全清楚。在这里，我们报告 FoxM1 是 Wnt 信号通路的下游组成部分，对于肿瘤细胞中β-catenin 的转录功能至关重要。Wnt3a 增加 FoxM1 的水平和核转位，FoxM1 直接与β-catenin 结合，增强β-catenin 的核定位和转录活性。在永生化神经干细胞中遗传敲除 FoxM1 会消除β-catenin 的核定位。破坏 FoxM1-β-catenin 相互作用或 FoxM1 核输入的 FoxM1 突变可防止肿瘤细胞中β-catenin 的核积累。FoxM1-β-catenin 相互作用控制 Wnt 靶基因表达，是胶质瘤形成所必需的，代表了肿瘤发生过程中经典 Wnt 信号的一种机制。
