李林研究组最新文章解析经典Wnt信号通路调控机制

　　

　国际学术期刊Journal of Molecular Cell Biology 杂志近日在线发表了中国科学院上海生命科学研究院生物化学与细胞生物学研究所李林实验室的研究论文Thymine DNA glycosylase promotes transactivation of ß-catenin/TCFs by cooperating with CBP。这项研究揭示了碱基错配修复酶TDG参与经典Wnt 信号转导通路进而促进下游基因转录的分子机制。　　 

　　Wnt信号通路是一类在多细胞真核生物中高度保守的信号通路，决定了生物体早期胚胎发育多个环节，并且Wnt信号通路异常活化与肿瘤的发生、发展也有着密切的关系。

   在该研究工作中，李林实验室的贾莹莹等人发现Wnt信号转导通路的转录因子LEF-1的一个新的相互作用蛋白TDG，并发现TDG可以正向调控Wnt信号转导通路。进一步的机制研究表明，TDG和一个已知的 ß-catenin转录激活子－乙酰化酶CBP的转录激活能力具有相互依赖性，并且TDG和CBP可以稳定彼此招募在Wnt信号通路的靶基因启动子区，促进靶基因启动子区H4乙酰化。

  另外，研究人员还发现TDG在结肠肿瘤样本中呈现高表达现象，下调TDG水平还可以在结肠癌细胞中降低Wnt靶基因表达和抑制细胞增值，提示了TDG可能在肿瘤发生中发挥一定作用。

　　此项研究获得国家科技部、国家自然科学基金委和中科院上海生科院优秀青年人才领域前沿项目的经费资助。

原文摘要：

Thymine DNA glycosylase promotes transactivation of ß-catenin/TCFs by cooperating with CBP

Thymine DNA glycosylase (TDG), an enzyme that initiates the repair of G/T and G/U mismatches, has been lately found crucial in embryonic development to maintain epigenetic stability and facilitate the active DNA demethylation. Here we report a novel role of TDG in Wnt signaling as a transcriptional coactivator of β-catenin/TCFs complex. Our data show that TDG binds to the transcriptional factor family LEF1/TCFs and potentiates β-catenin/TCFs transactivation, while TDG depletion suppresses Wnt3a-stimulated reporter activity or target gene transcription. Next, we show that CBP, a known coactivator, is also required for TDG function through forming a cooperative complex on target promoters. Moreover, there is an elevation of TDG levels in human colon cancer tissue, and knockdown of TDG inhibits proliferation of the colon cells. Overall, our results reveal that TDG, as a new coactivator, promotes β-catenin/TCFs transactivation and functionally cooperates with CBP in canonical Wnt signaling.