Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance

被引:385
作者
Zhou, Dawang [1 ,2 ,3 ,4 ]
Zhang, Yongyou [5 ,6 ]
Wu, Hongtan [1 ,2 ,3 ,4 ]
Barry, Evan [8 ,9 ,10 ]
Yin, Yi [1 ,2 ,3 ]
Lawrence, Earl [7 ]
Dawson, Dawn [6 ,7 ]
Willis, Joseph E. [6 ,7 ]
Markowitz, Sanford D. [5 ,7 ]
Camargo, Fernando D. [8 ,9 ,10 ]
Avruch, Joseph [1 ,2 ,3 ]
机构
[1] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA
[3] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA
[4] Xiamen Univ, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian, Peoples R China
[5] Case Western Reserve Univ, Dept Med, Cleveland, OH 44016 USA
[6] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44016 USA
[7] Case Med Ctr, Ctr Comprehens Canc, Cleveland, OH 44016 USA
[8] Childrens Hosp, Stem Cell Program, Cambridge, MA 02142 USA
[9] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA
[10] Harvard Stem Cell Inst, Cambridge, MA 02138 USA
基金
美国国家卫生研究院;
关键词
HIPPO SIGNALING PATHWAY; GROWTH-CONTROL; SIZE-CONTROL; COLORECTAL-CANCER; SELF-RENEWAL; BETA-CATENIN; ORGAN SIZE; NOTCH; WNT; DIFFERENTIATION;
D O I
10.1073/pnas.1110428108
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Ablation of the kinases Mst1 and Mst2, orthologs of the Drosophila antiproliferative kinase Hippo, from mouse intestinal epithelium caused marked expansion of an undifferentiated stem cell compartment and loss of secretory cells throughout the small and large intestine. Although median survival of mice lacking intestinal Mst1/Mst2 is 13 wk, adenomas of the distal colon are common by this age. Diminished phosphorylation, enhanced abundance, and nuclear localization of the transcriptional coactivator Yes-associated protein 1 (Yap1) is evident in Mst1/Mst2-deficient intestinal epithelium, as is strong activation of beta-catenin and Notch signaling. Although biallelic deletion of Yap1 from intestinal epithelium has little effect on intestinal development, inactivation of a single Yap1 allele reduces Yap1 polypeptide abundance to nearly wild-type levels and, despite the continued Yap hypophosphorylation and preferential nuclear localization, normalizes epithelial structure. Thus, supraphysiologic Yap polypeptide levels are necessary to drive intestinal stem cell proliferation. Yap is overexpressed in 68 of 71 human colon cancers and in at least 30 of 36 colon cancer-derived cell lines. In colon-derived cell lines where Yap is overabundant, its depletion strongly reduces beta-catenin and Notch signaling and inhibits proliferation and survival. These findings demonstrate that Mst1 and Mst2 actively suppress Yap1 abundance and action in normal intestinal epithelium, an antiproliferative function that frequently is overcome in colon cancer through Yap1 polypeptide overabundance. The dispensability of Yap1 in normal intestinal homeostasis and its potent proliferative and prosurvival actions when overexpressed in colon cancer make it an attractive therapeutic target.
引用
收藏
页码:E1312 / E1320
页数:9
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