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Identification of the crosstalk between Notch signaling and Wnt signaling in the differentiation of the intestinal epithelial cells.

鉴定肠上皮细胞分化过程中 Notch 信号和 Wnt 信号之间的串扰。

基本信息

批准号：
17209027
负责人：
WATANABE Mamoru
金额：
$ 31.95万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

In this study, we revealed the crosstalk between Ant and Notch signaling in the regulation of the intestinal differentiation via Hath1 gene that plays a crucial role in intestinal differentiation.Atoh1/Hath1 is indispensable to the differentiation of the intestinal epithelial cells, however what regulates Hath1 function has unknown. So we assessed the effect of Ant and Notch signal for Hath1 and then, we revealed new signaling pathway for Hath1 in both signals. Notch signal suppresses the Hath1 mRNA transcription besides increasing HES1 gene expression. Moreover Ant signal degrades Hath1 protein via GSK3 besides stabilizing beta-catenin protein, resulting the differentiation of intestinal epithelial cells.Next we demonstrated whether the failure of these systems misses Hath1 expression and causes colon disease. In colon cancer, aberrant Ant signal caused the degradation of Hath1 protein in inverse of the stabilization of beta-catenin protein. In ulcerative colitis. Notch signal is aberrantly activated, causing Hath1 gene suppression and goblet cell depletion.All these data indicate that intestinal differentiation is regulated by Hath1 expression controlled in two distinct points on which Notch signal and Ant signal have effects respectively. Moreover, the failure of these systems causes major colon disease such as cancer or inflammation. Therefore, these new mechanisms may be new targets on the therapy for colon diseases.

在这项研究中，我们通过Hath1基因揭示了Ant和Notch信号在调节肠道分化中的相互作用。Atoh1/Hath1是肠道上皮细胞分化所必需的，但Hath1功能的调节尚不清楚。因此，我们评估了Ant和Notch信号对Hath1的影响，并揭示了Hath1在这两种信号中的新的信号通路。Notch信号除了促进HES1基因的表达外，还抑制Hath1mRNA的转录。此外，Ant信号除了稳定β-catenin蛋白外，还通过GSK3降解Hath1蛋白，导致肠上皮细胞分化。接下来，我们论证了这些系统的失败是否错过了Hath1的表达，从而导致结肠疾病。在结肠癌中，Ant信号的异常导致Hath1蛋白的降解，而β-catenin蛋白的稳定则相反。在溃疡性结肠炎中。Notch信号被异常激活，导致Hath1基因抑制和杯状细胞枯竭，这些数据表明Hath1的表达调控在两个不同的点上，Notch信号和Ant信号分别影响肠道分化。此外，这些系统的故障会导致重大的结肠疾病，如癌症或炎症。因此，这些新的作用机制可能成为结肠疾病治疗的新靶点。