权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

在本研究中，我们揭示了Ant和Notch信号之间通过Hath1基因调控肠分化的串扰，Hath1基因在肠分化中起着至关重要的作用。Atoh1/Hath1对于肠上皮细胞的分化是不可缺少的，但Hath1功能的调节机制尚不清楚。因此，我们评估了 Ant 和 Notch 信号对 Hath1 的影响，然后，我们揭示了这两个信号中 Hath1 的新信号通路。 Notch 信号除了增加 HES1 基因表达外，还抑制 Hath1 mRNA 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。接下来我们证明这些系统的故障是否会错过Hath1表达并导致结肠疾病。在结肠癌中，异常的 Ant 信号导致 Hath1 蛋白的降解，与 β-catenin 蛋白的稳定性相反。于溃疡性结肠炎。 Notch信号被异常激活，导致Hath1基因抑制和杯状细胞耗竭。所有这些数据表明，肠分化是由Hath1表达调节的，这两个不同的点分别受Notch信号和Ant信号的影响。此外，这些系统的故障会导致严重的结肠疾病，例如癌症或炎症。因此，这些新机制可能成为治疗结肠疾病的新靶点。