Wnt信号通路中β-catenin及其细胞核内共激活因子复合物的结构生物学研究

项目名称： Wnt信号通路中β-catenin及其细胞核内共激活因子复合物的结构生物学研究

项目编号： No.31500610

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 孙伟

作者单位： 中国科学院生物物理研究所

项目金额： 20万元

中文摘要： Wnt/β-catenin信号通路的过度激活会导致许多癌症的发生。β-catenin是该通路上的中心效应分子，它的表达上调是这些癌症发生的驱动因素。在细胞核内，多种共激活因子与β-catenin相互作用，共同激活下游肿瘤促进因子如cyclin-D和c-Myc的转录，其中M1型叉头框蛋白（FoxM1）和PCNA相关因子（PAF）就是其中两个。FoxM1促进β-catenin在细胞核内的定位，并可以促进Wnt应激基因的表达，在人类的多种肿瘤（比如神经胶质瘤）中都有过表达。PAF则在结直肠癌和肠干细胞中特异表达。因为β-catenin-FoxM1和β-catenin-PAF复合体的形成是Wnt/β-catenin下游的重要事件，对肿瘤的发生及恶化起重要作用，我们计划对它们开展结构生物学研究，以便阐释相关癌症的发生机理，并为人类癌症治疗提供新的思路。

中文关键词： 蛋白质；相互作用；晶体筛选；结构解析；分子置换

英文摘要： Hyperactivation of the canonical Wnt/β-catenin signaling pathway can cause many types of cancers. β-catenin is the central effector of this signaling pathway, and its upregulation is a driving factor for these cancers. In the nucleus, many coactivators interact with β-catenin, activating transcription of downstream tumor-promoting factors such as cyclin-D and c-Myc. Forhead box protein M1 type (FoxM1) and PCNA-associated factor (PAF) are two β-catenin-specific transcriptional coactivators. FoxM1 promotes β-catenin nuclear localization and induces expression of Wnt responsive genes, and is overexpressed in many cancer types, including glioma. As to PAF, it is specifically expressed in colon cancer and intestine stem cells. Because formations of β-catenin-FoxM1 and β-catenin-PAF complex are critical events downstream of Wnt/β-catenin signaling pathway, which play vital roles in tumorigenesis and metastasis of many cancers, we embark on investigating the interactions between β-catenin and FoxM1/PAF employing structural biological methods. We aim to elucidate the molecular mechanism of tumorigenicity and try to provide novel insights into the therapy of human cancers.

英文关键词： protein;interaction;crystal screen;structure determination;molecular replacement