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	Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2
	Shihao Zhang ; Zhang SH(张世浩) ; Qinghua Chen ; Chen QH(陈青花) ; Qingxu Liu ; Liu QX(刘清许) ; Li Yuxi ; Li YX(李玉席) ; Xiufeng Sun ; Sun XF(孙秀峰) ; Lixin Hong ; Suyuan Ji ; Chengyan Liu ; Jing Geng ; Weiji Zhang ; Zhonglei Lu ; ZhenYu Yin ; Yuanyuan Zeng ; Kwang-Huei Lin ; Qiao Wu ; Qiyuan Li ; Keiko Nakayama ; Keiich I.Nakayama ; Xianming Deng ; Randy L.Johnson ; Liang Zhu ; Daming Gao ; Lanfen Chen ; Chen LF(陈兰芬) ; Dawang Zhou ; Zhou DW(周大旺)
	2017-05
英文摘要	大多数真核生物的体细胞是二倍体，即仅含有两组染色体，分别遗传自父本和母本。而一些特定组织如心脏、肝脏等就含有多倍体细胞，特别是肝脏组织含有较高比例的四、八倍体等多倍体细胞。肝脏是人体的重要解毒器官，同时酒精、肝炎病毒等毒性物质或毒性代谢物容易诱发肝细胞的基因突变，多倍体被认为有利于提供代偿性的正常基因来维持肝脏稳态。然而肝脏受损后，多倍体细胞将会受胁迫进行增殖，再生修复受损的肝组织。因此研究机体调控多倍体细胞产生及多倍体细胞进行细胞分裂的调控机理对于理解肝癌的发病机理和肝癌的治疗至关重要。Hippo信号通路在调节组织成体干细胞的分化和增殖，调控器官再生与尺寸大小中具有重要作用。深入研究发现, Hippo信号通路下游效应分子YAP通过AKT-SKP2信号促进二倍体细胞向多倍体转化及多倍体细胞的生长增殖。本项研究阐明了Hippo缺失及YAP激活促进多倍体细胞产生及增殖作为肝癌发生发展中的一个重要机制，为肝癌诊疗提供了新的策略。 周大旺，博士，厦门大学生命科学学院教授、副院长、国家杰出青年基金获得者。; 【Abstract】Polyploidy can lead to aneuploidy and tumorigenesis. Here, we report that the Hippo pathway effector Yap promotes the diploid-polyploid conversion and polyploid cell growth through the Akt-Skp2 axis. Yap strongly induces the acetyltransferase p300-mediated acetylation of the E3 ligase Skp2 via Akt signaling. Acetylated Skp2 is exclusively localized to the cytosol, which causes hyper-accumulation of the cyclin-dependent kinase inhibitor p27, leading to mitotic arrest and subsequently cell polyploidy. In addition, the pro-apoptotic factors FoxO1/3 are overly degraded by acetylated Skp2, resulting in polyploid cell division, genomic instability, and oncogenesis. importantly, the depletion or inactivation of Akt or Skp2 abrogated Hippo signal deficiency-induced liver tumorigenesis, indicating their epistatic interaction. Thus, we conclude that Hippo-Yap signaling suppresses cell polyploidy and oncogenesis through Skp2.; 该研究工作获得了国家自然科学基金委、国家重点基础研究发展计划(973)项目、青年千人计划和中央高校基本科研基金的资助。 The Yap (S127A) transgenic mice were kindly provided by Dr. Fernando Camargo from Harvard Medical School, Boston, MA. D.Z. and L.C. were supported by the National Natural Science Foundation of China (31625010,U1505224, and J1310027 to D.Z.; 81422018, U1405225, and 81372617 to L.C.; 81472229 to L.H.), the National Basic Research Program (973) of China (2015CB910502 to L.C.), the Fundamental Research Funds for the Central Universities of China-Xiamen University (20720140551 to L.C. and 2013121034 and 20720140537 to D.Z.).
语种	中文
出版者	Elsevier Inc
内容类型	其他
源URL	[http://dspace.xmu.edu.cn/handle/2288/127732]
专题	生命科学－已发表论文
推荐引用方式 GB/T 7714	Shihao Zhang,Zhang SH,Qinghua Chen,et al. Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2. 2017-05-01.

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