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，我们揭示了通过HATH1基因调节蚂蚁和缺口信号在肠道分化中起着至关重要的作用的串扰。TOH1/HATH1对于插入式上皮细胞的分化是必不可少的，但是调节HATH1功能的是什么是未知的。因此，我们评估了ANT和Notch信号对HATH1的影响，然后，我们揭示了两个信号中HATH1的新信号传导途径。 Notch信号除了增加HES1基因表达外，还抑制了HATH1 mRNA转录。此外，除了稳定β-catenin蛋白外，ANT信号通过GSK3降解了HATH1蛋白，从而导致肠上皮细胞的分化。接下来，我们证明了这些系统的失败是否遗漏了HATH1的表达并导致结肠病。在结肠癌中，异常的蚂蚁信号导致HATH1蛋白降解，而β-catenin蛋白的稳定性倒数。在溃疡性结肠炎中。 Notch信号异常激活，导致HATH1基因抑制和杯状细胞耗竭。这些数据表明，肠道分化受Hath1表达的调节，这些HATH1表达在两个不同的点上受控，notch信号和ANT信号分别效应。此外，这些系统的失败会导致重大结肠疾病，例如癌症或炎症。因此，这些新机制可能是针对结肠疾病治疗的新靶标。