Hippo-YAP 通路调控端粒酶活性的分子机制及其生物学功能

Telomerase is a RNA dependent reverse transcriptase for telomeric DNA synthesis. Telomerase is reactivated during tumorigenesis and plays a pivotal role in the pathology of aging and cancer by maintaining genome integrity, controlling cell proliferation and regulating tissue homeostasis. The mechanisms involved in telomerase regulation are critical for our understanding the mechanistic function of telomerase in aging and cancer. The recent discovered Hippo pathway plays a key role in organ size control, tumorigenesis and tissue homeostasis. Evidence suggests that telomerase and hippo pathway may have some functional relationship. Organ size control is dependent on cell proliferation potential, which is required telomerase activity to maintain telomeres. It has been reported that telomerase is up-regulated during liver regeneration, and the organ size control is regulated by the Hippo pathway. In a genome-wide Chip-Seq analysis, it was found that YAP1 and TEAD, down-stream effectors of Hippo pathway, bound to hTERT promoter. This suggests that hTERT is a target of Hippo pathway. Indeed, our preliminary data indicate that YAP1 and its active mutant YAP 5SA can activate the hTERT promoter and increase hTERT mRNA and protein expression. This project aims to understand the mechanism of telomerase regulation by the Hippo-YAP pathway, and significance of the interplay between telomerase and Hippo pathway.

端粒酶是一种能够延长端粒的逆转录酶。端粒酶在癌变过程中被激活，维持端粒的长度和细胞分裂潜能，与衰老相关疾病及肿瘤发生发展密切相关。Hippo信号通路在器官大小调控、癌症发生及组织再生等的功能上发挥重要作用。Hippo通路和端粒酶在肿瘤发生发展中具有功能上的相关性。器官大小取决于细胞增殖潜能，而细胞增殖潜能在很大程度上依赖于端粒酶活性。在肝再生过程中，端粒酶催化亚基TERT表达显著升高。全基因组水平CHIP-Seq显示，Hippo通路下游效应分子YAP1和TEAD能够结合在hTERT启动子的同一位点。预示hTERT很可能是Hippo-YAP通路的靶基因。前期工作发现，瞬时转染YAP1以及YAP1持续激活型突变体能过激活hTERT启动子报告基因、以及hTERT mRNA和蛋白的表达。本项目拟研究Hippo信号通路调控端粒酶的分子机制，探讨Hippo通路和端粒酶相互作用的生物学意义。

端粒酶是一种具有延长端粒功能的逆转录酶，可以维持基因组完整性和细胞增殖潜能，并与衰老、衰老相关疾病和肿瘤的发生发展密切相关。研究端粒酶在不同生理病理条件下的调控机制，对于深入了解端粒酶在衰老及肿瘤等相关疾病中的作用机制具有重要科学意义。本项目围绕Hippo信号通路调控端粒酶催化亚基hTERT的分子机制和生物学作用展开：（1）我们在细胞中过表达或敲低Hippo通路下游的效应分子YAP1，hTERT的基因表达相应地升高或降低，表明YAP1可以调控 hTERT的基因表达；（2）我们在肿瘤细胞系中通过血清刺激、JASP及LPA处理激活内源性的YAP1，hTERT的基因表达上调，说明在生理条件下YAP1对hTERT的表达具有调控作用；（3）在机制方面，我们的结果显示，YAP1可以通过与转录因子TEAD的相互作用结合到hTERT基因的启动子上并促进其转录；（4）在生物学功能方面，研究表明YAP1的持续激活可以提高细胞的端粒酶活性并延长端粒；（5）在生物学意义方面，我们发现在肝癌组织中hTERT的表达与YAP1的激活具有正相关，提示在肿瘤的发生发展过程中YAP1的激活可能有助于端粒酶的重新激活。在本项目的执行过程中，发表SCI论文3篇，培养硕士研究生3名。