nature20130103-7

来自哈佛大学干细胞研究中心的Fernando D. Camargo等人发表文章证明在小鼠和人中yes相关蛋白YAP,一种已知的诱导生长的并具有原癌性质的蛋白,还具有一种令人意外的生长抑制功能。

-2013年1月3日《自然》


中文翻译


【题目】YAP限制肠内干细胞扩增和再生反应的

【译文】再生过程的一个明显特征是一旦器官结构完成修复则停止增殖。Wnt信号通路是哺乳动物肠道稳态的自我更新及再生的主要驱动力。 然而与之相抗衡的机制还不明确。本研究证明在小鼠和人中yes相关蛋白1(YAP1),一种已知的诱导生长的并具有原癌性质的蛋白,还具有一种令人意外的生长抑制功能,YAP1可以在肠道再生的过程中抑制Wnt信号。转基因表达YAP基因降低Wnt信号的靶基因表达,并且导致肠隐窝迅速消失。 另外,敲除YAP可导致肠再生过程中Wnt信号的过敏症,引起肠细胞增生,肠干细胞及生境细胞的增殖,形成异位隐窝和微腺瘤。我们发现,限制细胞质中表达YAP可增强Wnt信号,这种作用不依赖于AXIN–APC–GSK-3β复合物,而一部分原因是由于限制了散乱蛋白(DVL)的活性。DVL信号表达与肠干细胞中,它的过表达会增强隐窝中Wnt信号。在再生过程中,YAP降低Wnt信号的作用是通过限制DVL的核转位来实现的。 最后,文章中证明,在一系列高度侵蚀性且高度未分化的人类大肠癌肿瘤中,YAP表达受抑制。而且在这些肿瘤中表达YAP可限制这些肿瘤的异体移植生长。总之,本研究提供了再生组织中增殖信号被抵抗的一个新的机制模式。同时我们的发现也为人类恶性肿瘤中YAP的靶向中提供重要应用价值

英文原稿


[Title]: Restriction of intestinal stem cell expansion and the regenerative response by YAP

[Authors]:Evan R. Barry,1, 2, 3 Teppei Morikawa,4 Brian L. Butler,1, 2 Kriti Shrestha,1 Rosemarie de laRosa,1 Kelley S. Yan,5 Charles S. Fuchs,4, 6 Scott T. Magness,7 Ron Smits,8 Shuji Ogino,4, 9 Calvin J. Kuo5 & Fernando D. Camargo1, 2, 3

[Abstract]A remarkable feature of regenerative processes is their ability to halt proliferation once an organ’s structure has been restored. The Wnt signalling pathway is the major driving force for homeostatic self-renewal and regeneration in the mammalian intestine. However, the mechanisms that counterbalance Wnt-driven proliferation are poorly understood. Here we demonstrate in mice and humans that yes-associated protein 1 (YAP; also known as YAP1)—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 ofYAP reduces Wnt target gene expression and results in the rapid loss of intestinal crypts. In addition, loss ofYAP results in Wnt hypersensitivity during regeneration, leading to hyperplasia, expansion of intestinal stem cells and niche cells, and formation of ectopic crypts and microadenomas. We find that cytoplasmicYAP restricts elevated Wnt signalling independently of the AXIN–APC–GSK-3β complex partly by limiting the activity of dishevelled (DVL). DVL signals in the nucleus of intestinal stem cells, and its forced expression leads to enhanced Wnt signalling in crypts.YAP dampens Wnt signals by restricting DVL nuclear translocation during regenerative growth. Finally, we provide evidence thatYAP is silenced in a subset of highly aggressive and undifferentiated human colorectal carcinomas, and that its expression can restrict the growth of colorectal carcinoma 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 ofYAP in human malignancies.

原文地址

http://www.nature.com/nature/journal/v493/n7430/full/nature11693.html

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