癌症抑制因子ARID4A蛋白家族的结构与功能研究

ARID4A和ARID4B是同源的细胞周期调控蛋白和癌症抑制因子，与RB和mSin3A等蛋白形成了基因表达调控和表观遗传调控的复合物，参与白血病等癌症抑制、普拉德威利等遗传疾病以及雄性生殖过程的相关调控。研究指出，ARID4A和ARID4B在功能上既有重叠和互补，又有协同效应。目前人们还不清楚它们发挥功能的结构基础和相互作用机制。我们在ARID4A染色质结合结构域的研究上已取得一定进展。本项目中我们将使用NMR等手段深入研究ARID4A的基因抑制活性结构域和ARID4B各结构域的结构和功能，以及它们的相互作用网络，揭示它们在功能上的异同性和协同效应的结构机制。同时，还将以秀丽隐杆线虫的ARID4A家族蛋白ARID-1为对象，进行结构域的在体功能研究和基因调控通路研究。研究成果将使我们深入理解ARID4A家族蛋白的结构与功能的分子机制，为其癌症生物学的研究和潜在的药物研究提供新的线索和靶点。

ARID4A and ARID4B are homologous cell cycle controlling proteins and cancer suppressors. Together with RB and mSin3A, they form a complex containing both gene regulation and epigenetic regulation functions, which is involved in suppressing cancers like leukemia, and regulating the male reproductive process as well as the epigenetics of several genetic diseases including Prader-Willi's syndrome. It has been demonstrated that ARID4A and ARID4B have functional similarities and differences, and they also exhibit a co-operative functional effect. However, the structual basis of their function and the mechanism of their interactions is currently very poorly understood. We have previously carried out structural investigations of several ARID4A domains involved in chromatin binding. In this project, we will use NMR and other techniques to study the structures and functions of ARID4A and ARID4B domains, and also the interaction networks of ARID4A and ARID4B to reveal the structural mechanism of their functional similarities, differences, and co-operative effects. Simultaneously, we will investigate the in vivo functions of different domains and the gene regulation pathway of the ARID4A homologue protein, ARID-1, in C. elegans. This study will provide insight into the relationship between structure and function for the ARID4A protein family, and will lay a foundation for exploration of novel molecular therapeutic targets for ARID4A/4B-related cancers.