TEAD4蛋白以YAP非依赖的方式抑制TGF-β信号和Smad蛋白转录调控活性的分子机制

Smad蛋白是TGF-β通路下游的信号分子和转录因子，通过调控基因转录而介导TGF-β在肝癌细胞中的各种生物学功能。TEAD家族转录因子主要结合辅激活因子YAP而诱导基因转录，也能以不依赖于YAP的方式发挥特定功能；细胞内分别存在YAP-Smad和TEAD-YAP-Smad蛋白复合物，在TGF-β信号转导中发挥有差别的功能。但是，TEAD和Smad蛋白是否能形成独立复合物及其功能仍然不清楚。我们的预实验结果显示，TEAD4蛋白能以不依赖于YAP和不结合DNA的方式减弱TGF-β信号和Smad蛋白转录活性，并抑制TGF-β诱导的肝癌细胞增殖、迁移和侵袭。本项目致力于理解TEAD4蛋白干扰Smad蛋白转录活性的作用、分子机制，及其在肝癌发展中的功能；相关结果有助于进一步理解TGF-β信号在肝癌中的调控机制，以及TEAD蛋白和Smad蛋白在基因转录调控中的相互关系。

Smad proteins act as downstream signaling molecules and transcription factors in TGF-β signaling, mediating the multiple functions of TGF-β in liver cancer by regulating gene transcription. The TEAD family transcription factors, including TEAD1-4, activate gene transcription by associating with the co-activator YAP, whereas they could also function in a YAP-independent manner in certain circumstances. It has been found that there exist the YAP-Smads complex and the TEAD-YAP-Smads complex in mammalian cells, playing distinct roles in TGF-β signaling. However, whether TEADs could form a complex with Smad proteins independently of YAP are yet to be elucidated. Our unpublished data indicated that TEAD4 protein could inhibit TGF-β signaling and Smads-mediated gene transcription in the absence of YAP and DNA binding, thereby attenuating TGF-β-induced liver cancer cell proliferation, migration and invasion. This proposal aims to understand the role and mechanism of TEAD4 protein in regulating TGF-β signaling and Smads-mediated gene transcription, and the functional consequences of this regulation in liver cancer development. The expected results would advance our understanding regarding the regulatory mechanisms of TGF-β signaling in liver cancer and the interplay between TEADs and Smads in controlling gene transcription.