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Restriction of intestinal stem cell expansion and the regenerative response by YAP

机译:YAP对肠道干细胞扩增的限制和再生反应

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摘要

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 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 hyperpla-sia, expansion of intestinal stem cells and niche cells, and formation of ectopic crypts and microadenomas. We find that cytoplasmic YAP 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 that YAP 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 of YAP in human malignancies.
机译:再生过程的显着特征是一旦恢复器官的结构,它们便具有阻止增殖的能力。 Wnt信号通路是哺乳动物肠道中自我平衡和自我更新的主要驱动力。但是,人们对平衡Wnt驱动的增殖的机制了解甚少。在这里,我们在小鼠和人类中证明,yes相关蛋白1(YAP;也称为YAP1)-一种以其强大的诱导生长和致癌特性而闻名的蛋白-具有意想不到的生长抑制功能,在肠道再生过程中限制了Wnt信号。 YAP的转基因表达降低了Wnt靶基因的表达,并导致肠隐窝快速丢失。此外,YAP的丧失会导致再生过程中Wnt超敏反应,从而导致增生,肠干细胞和小生境细胞的扩增以及异位隐窝和微腺瘤的形成。我们发现,胞质YAP部分地通过限制蓬乱(DVL)的活性来限制升高的Wnt信号传导,而独立于AXIN-APC-GSK-3β复合物。 DVL在肠道干细胞的细胞核中发出信号,其强制表达导致隐窝中Wnt信号增强。 YAP通过限制再生生长期间DVL核易位来抑制Wnt信号。最后,我们提供的证据表明,在高度侵袭性和未分化的人类结直肠癌的子集中,YAP被沉默,并且其表达可限制结直肠癌异种移植物的生长。总的来说,我们的工作描述了一种新颖的机制范例,说明在再生组织中如何平衡增殖信号。此外,我们的发现对以人类恶性肿瘤中的YAP为靶标具有重要意义。

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  • 来源
    《Nature》 |2013年第7430期|106-110|共5页
  • 作者单位

    Stem Cell Program and Department of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA,Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA;

    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02215, USA;

    Stem Cell Program and Department of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA;

    Stem Cell Program and Department of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA;

    Stem Cell Program and Department of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA;

    Departmentof Medicine, Hematology Division, Stanford University, Stanford, California 94305, USA;

    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02215, USA,Channing Laboratory, Departmentof Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;

    Departments of Medicine and Biomedical Engineering,The University of North Carolina at Chapel Hill, Chapel Hill,North Carolina 27599, USA;

    Department of Gastroenterology and Hepatology, Erasmus MC, 3000 CA Rotterdam, The Netherlands;

    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02215, USA,Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;

    Departmentof Medicine, Hematology Division, Stanford University, Stanford, California 94305, USA;

    Stem Cell Program and Department of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA,Departmentof Medicine, Hematology Division, Stanford University, Stanford, California 94305, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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