Mechanism of GABP, a Novel Component of the Hippo Pathway, in Growth and Antioxidant Defense

Hippo信号通路是一条在进化上高度保守的激酶级联的信号转导通路，它能够负调控转录共激活因子YAP及其同源物TAZ。Hippo信号通路中任意成员的缺失均能造成YAP的激活并导致细胞增殖的增加，细胞凋亡的减少，器官变大以及肿瘤的发生。YAP是一个原癌基因，在许多人类癌症疾病中，YAP的蛋白水平及其细胞核定位都是增加的。研究表明，YAP的蛋白水平是其行使其原癌基因功能的一个非常重要的方面。尽管已经有许多文章探讨了YAP磷酸化修饰，降解及其细胞核定位调控的具体机制，但关于YAP基因的表达是如何被调控的仍有待阐明。 在研究中我们发现了Ets转录因子家族成员GABP能够和YAP基因的启动子结合并激活Y...The Hippo pathway is an evolutionarily conserved protein kinase cascade that negatively regulates the transcriptional coactivator Yes-associated protein (YAP) and its paralog, TAZ. The loss of any component of this pathway results in a YAP-dependent increase in proliferation, resistance to apoptosis, massive organ overgrowth and tumorigenesis. YAP is a candidate oncogene in humans because YAP prot...学位：理学博士院系专业：生命科学学院_生物化学与分子生物学学号：2162011015396

The Ets Transcription Factor GABP Is a Component of the Hippo Pathway Essential for Growth and Antioxidant Defense

这是周大旺教授继2009年首次发现了Hippo信号通路在哺乳动物中控制器官大小及肿瘤发生具有重要作用后的又一重大研究成果，该研究系统阐述了 YAP基因在转录调控水平上的的调控机理，进一步完善了人们对Hippo信号通路的认识，也为由YAP调控异常所引发的癌症提供了一个潜在的治疗靶点。 该论文的第一作者为博士生吴黉坦和硕士生肖玉波和张世浩, 通讯作者是周大旺教授和陈兰芬副教授，该工作是与厦门市中医院、中山医院和医学高等专科学校等单位合作完成的。周大旺教授是中央首批“青年千人计划”入选者并获得国家首批“优秀青年科学基金”资助。The transcriptional coactivator Yes-associated protein (YAP) plays an important role in organ-size control and tumorigenesis. However, how Yap gene expression is regulated remains unknown. This study shows that the Ets family member GABP binds to the Yap promoter and activates YAP transcription. The depletion of GABP downregulates YAP, resulting in a G1/S cell-cycle block and increased cell death, both of which are substantially rescued by reconstituting YAP. GABP can be inactivated by oxidative mechanisms, and acetaminophen-induced glutathione depletion inhibits GABP transcriptional activity and depletes YAP. In contrast, activating YAP by deleting Mst1/Mst2 strongly protects against acetaminophen-induced liver injury. Similar to its effects on YAP, Hippo signaling inhibits GABP transcriptional activity through several mechanisms. In human liver cancers, enhanced YAP expression is correlated with increased nuclear expression of GABP. Therefore, we conclude that GABP is an activator of Yap gene expression and a potential therapeutic target for cancers driven by YAP