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Crosstalk between Wnt and Notch signaling in colonic epithelium.

结肠上皮中 Wnt 和 Notch 信号传导之间的串扰。

基本信息

批准号：
21590805
负责人：
SUZUKI Shinji
金额：
$ 3万
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 (C)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

项目摘要

Wnt and Notch pathways are known to function together to regulate proliferation and differentiation of intestinal epithelium ; however, the molecular mechanism of their functional interplay remains unclear. In this study, we aimed at investigating the signaling crosstalk between these two pathways in colonic epithelium. First, by using several human colon cancer-derived cell lines, we have demonstrated that the expression of Hath1, a bHLH transcription factor known to be involved in Notch signaling, is regulated by the proteasome-mediated protein degradation that is under the control of Wnt signaling. We also showed that this post-translational regulation of Hath1 by Wnt/Notch signals is important for cell fate determination of colonic cells. Second, in order to investigate the crosstalk between Wnt/Notch signals, we have established a novel method to isolate and culture normal colonic epithelium in vitro. By this method, colonic cells continuously grow and the Lgr5+colonic stem cells preferentially expand as a result of Wnt/Notch activation. We also showed for the first time that the cultured colonic cells are able to regenerate damaged epithelium in recipient mice when transplanted. These data would built a basis for the future study to elucidate molecular mechanism that govern the interplay of Wnt/Notch signals to regulate the regenerative properties and/or malignant transformation of colonic epithelial cells.

已知Wnt和Notch通路共同作用以调节肠上皮的增殖和分化;然而，它们功能相互作用的分子机制仍不清楚。在本研究中，我们的目的是研究这两个途径之间的信号串扰在结肠上皮细胞。首先，通过使用几种人结肠癌衍生的细胞系，我们已经证明，Hath 1的表达，已知参与Notch信号传导的bHLH转录因子，是由蛋白酶体介导的蛋白质降解的Wnt信号的控制下调节。我们还表明，这种Hath 1的Wnt/Notch信号的翻译后调节对于结肠细胞的细胞命运决定是重要的。第二，为了研究Wnt/Notch信号之间的串扰，我们建立了一种新的方法，在体外分离和培养正常结肠上皮。通过这种方法，结肠细胞连续生长，并且由于Wnt/Notch激活，Lgr 5+结肠干细胞优先扩增。我们还首次表明，培养的结肠细胞在移植时能够再生受体小鼠中受损的上皮。这些数据为进一步研究Wnt/Notch信号相互作用调控结肠上皮细胞再生特性和/或恶性转化的分子机制奠定了基础。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Epithelial regeneration by cultured colonic cells expanded from a single adult Lgr5+ stem cell

由单个成体 Lgr5 干细胞扩增的培养结肠细胞实现上皮再生

DOI：
发表时间：
2013
期刊：
影响因子：
0
作者：
中村哲也;渡辺守;高野晴子，幡野雅彦，坂本明美，高野和儀，徳久剛史，遠藤　剛;Nakamura Tetsuya
通讯作者：
Nakamura Tetsuya

GSK3 inhibitor induces the intestinal differentiation by the protein stabilization of Atoh1

GSK3 抑制剂通过 Atoh1 的蛋白质稳定作用诱导肠分化

DOI：
发表时间：
2009
期刊：
影响因子：
0
作者：
Tsuchiya K;et al.
通讯作者：
et al.

Longtudinal cell formation in the entire human small intestine is correlated with the localization of Hathl and KIM

整个人类小肠中的纵向细胞形成与 Hathl 和 KIM 的定位相关

DOI：
发表时间：
2011
期刊：
J Gastroenterol.
影响因子：
0
作者：
Iwasaki M;Tsuchiya K;Okamoto R;Zheng X;Kano Y;Okamoto E;Okada E;Araki A;Suzuki S;Sakamoto N;Kitagaki K;Akashi T;Eishi Y;Nakamura T;Watanabe__M
通讯作者：
Watanabe__M

Signaling pathway via TNF-alpha/NF-kappaB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis.

肠上皮细胞中通过 TNF-α/NF-κB 的信号通路可能直接参与结肠炎相关的癌变。