Taylor Michael D, Zhang Xiaoyun, Liu Ling, Hui Chi-Chung, Mainprize Todd G, Scherer Stephen W, Wainwright Brandon, Hogg David, Rutka James T
The Division of Neurosurgery, The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
Oncogene. 2004 Jun 3;23(26):4577-83. doi: 10.1038/sj.onc.1207605.
Germline mutations of APC in patients with Turcot syndrome (colon cancer and medulloblastoma), was well as somatic mutations of APC, beta-catenin, and Axin in sporadic medulloblastomas (MBs) have shown the importance of WNT signaling in the pathogenesis of MB. A subset of children with MB have germline mutations of SUFU, a known inhibitor of Hedgehog signal transduction. A recent report suggested that murine Sufu can bind beta-catenin, export it from the nucleus, and thereby repress beta-catenin/T-cell factor (Tcf)-mediated transcription. We show that an MB-derived mutant of SUFU has lost the ability to decrease nuclear levels of beta-catenin, and cannot inhibit beta-catenin/Tcf-mediated transcription as compared to wild type SUFU. Our results suggest that loss of function of SUFU results in overactivity of both the Sonic Hedgehog, and the WNT signaling pathways, leading to excessive proliferation and failure to differentiate resulting in MB.
在Turcot综合征（结肠癌和髓母细胞瘤）患者中，APC的种系突变以及散发性髓母细胞瘤（MBs）中APC、β-连环蛋白和Axin的体细胞突变均表明WNT信号在MB发病机制中的重要性。一部分患有MB的儿童具有SUFU的种系突变，SUFU是一种已知的Hedgehog信号转导抑制剂。最近的一份报告表明，小鼠Sufu可以结合β-连环蛋白，将其从细胞核中输出，从而抑制β-连环蛋白/T细胞因子（Tcf）介导的转录。我们发现，一个源自MB的SUFU突变体失去了降低β-连环蛋白核水平的能力，与野生型SUFU相比，不能抑制β-连环蛋白/Tcf介导的转录。我们的结果表明，SUFU功能丧失导致Sonic Hedgehog和WNT信号通路均过度活跃，导致过度增殖和分化失败，从而引发MB。
