YAP/TAZ转录激活域的鉴定与功能研究及其小分子抑制剂筛选系统的探索

YAP/TAZ是Hippo信号通路下游核心转录激活因子，其异常调节与肿瘤发生与发展密切相关，成为癌症治疗的重要靶点，但临床尚无有效的治疗药物，因而更深入理解其功能和开发抑制剂是核心问题之一。当前对YAP/TAZ的C端转录激活结构域(291-504)功能和作用机制缺乏深入了解。我们前期研究将YAP C端分为Coiled coil，sIDR，sTAD 三段，发现Coiled coil结构域和sIDR介导了YAP相分离，sTAD(450-504)发挥核心转录激活功能。突变sTAD明显抑制肿瘤的生长，并完全干扰YAP招募MED1的能力。本课题将继续研究sTAD在肿瘤中的功能及其分子机制，深入探究sTAD与MED1及其他转录调节因子的互作方式，并探索针对sTAD 转录激活功能的小分子抑制剂筛选。本项目的完成将明确YAP/TAZ的C端结构和功能，并鉴定出小分子抑制剂，为癌症提供新的靶向治疗方案。

YAP/TAZ is the transcriptional activator of the Hippo signaling pathway. Its irregulation always lead to tumor progression, which has become a critical target for cancer therapy. As poor know of the function and specific mechanism of the C-terminal transcription activation domain of YAP/TAZ, our previous study showed that the coiled coil domain and sIDR mediate the phase separation of YAP, and sTAD (450-504) is responsible for the transcriptional activation, when the C-terminus was divided into three segments: Coiled coil, sIDR and sTAD. We found that sTAD mutation significantly suppressed the tumor growth in vitro and in vivo, and completely interfered with YAP recruiting MED1. We will further study the functions and mechanisms of sTAD in tumorigenesis and progression, explore the interactions between sTAD and other transcription regulators such as MED1, and screen the inhibitors targeting sTAD transcriptional activity. The completion of this project will help to understand the transcription activation domain TAD in further, and provide new strategies for YAP-targeted clinical cancer therapy in the future.