Restriction of intestinal stem cell expansion and the regenerative response by YAP.
Restriction of intestinal stem cell expansion and the regenerative response by YAP.
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作者：
再生过程的一个显着特征是，一旦器官的结构得到恢复，它们就能够停止增殖。Wnt信号通路是哺乳动物肠道内稳态自我更新和再生的主要驱动力。平衡Wnt驱动的增殖的机制知之甚少。我们在这里证明了雅普，一种以其强大的生长诱导和致癌特性而闻名的蛋白质，具有意想不到的生长抑制功能，限制了肠道再生过程中的Wnt信号。雅普的转基因表达降低了Wnt靶基因的表达并导致肠隐窝的快速丧失。此外，雅普的缺失导致再生期间的Wnt超敏反应，导致肠干细胞（ISC）和生态位细胞的增生、扩增，以及异位隐窝和微腺瘤的形成。我们发现胞质雅普通过限制Dishevelled（DVL）的活性来限制升高的Wnt信号传导，而不依赖于APC/Axin/GSK 3 β复合物。DVL信号在ISCs的核中，并且其强制表达导致隐窝中Wnt信号的增强。雅普通过限制再生生长过程中DVL核转位来抑制Wnt信号。最后，我们提供的证据表明，雅普是沉默的一个子集的高度侵袭性和未分化的人结直肠癌（CRC）和它的表达可以限制CRC异种移植物的生长。总的来说，我们的工作描述了一种新的机制范式，增殖信号是如何在再生组织中平衡的。此外，我们的发现对雅普在人类恶性肿瘤中的靶向作用具有重要意义。
A remarkable feature of regenerative processes is their ability to halt proliferation once an organ’s structure has been restored. The Wnt signaling pathway is the major driving force for homeostatic self-renewal and regeneration in the mammalian intestine. The mechanisms that counterbalance Wnt-driven proliferation are poorly understood. We demonstrate here that YAP, a protein known for its powerful growth-inducing and oncogenic properties, has an unexpected growth-suppressive function restricting Wnt signals during intestinal regeneration. Transgenic expression of YAP reduces Wnt target gene expression and results in the rapid loss of intestinal crypts. In addition, loss of YAP results in Wnt hypersensitivity during regeneration, leading to hyperplasia, expansion of intestinal stem cells (ISCs) and niche cells, and formation of ectopic crypts and microadenomas. We find that cytoplasmic YAP restricts elevated Wnt signaling independently of the APC/Axin/GSK3β complex partly by limiting the activity of Dishevelled (DVL). DVL signals in the nucleus of ISCs and its forced expression leads to enhanced Wnt signaling in crypts. YAP dampens Wnt signals by restricting DVL nuclear translocation during regenerative growth. Finally, we provide evidence that YAP is silenced in a subset of highly aggressive and undifferentiated human colorectal carcinomas (CRC) and its expression can restrict the growth of CRC xenografts. Collectively, our work describes a novel mechanistic paradigm for how proliferative signals are counterbalanced in regenerating tissues. Additionally, our findings have important implications for the targeting of YAP in human malignancies.
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影响因子：
4.8
作者：
Konsavage, Wesley M., Jr.;Kyler, Sydney L.;Yochum, Gregory S.
通讯作者：
Yochum, Gregory S.
影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia
DOI：
10.1083/jcb.200710050
发表时间：
2008-03-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gan XQ;Wang JY;Xi Y;Wu ZL;Li YP;Li L
通讯作者：
Li L
影响因子：
5
作者：
Colnot, S;Niwa-Kawakita, M;Perret, C
通讯作者：
Perret, C
影响因子：
4.8
作者：
Madison, BB;Dunbar, L;Gumucio, DL
通讯作者：
Gumucio, DL