Wnt/beta-catenin信号在细胞周期不同阶段调控靶基因表达的机制和功能研究

Wnt/beta-catenin signaling controls cell proliferation, differentiation and survival and plays important roles during embryonic development and tissue homeostasis. Moreover, Wnt signaling is heavily implicated with tumorigenesis. Therefore understading the mechanism and regulation of Wnt signaling is of great interests. It is generally believed that the Wnt/beta-catenin signaling largely functions via controlling target gene expression. Our results indicated that the beta-catenin/TCF transcriptional complex was enriched in G2 phase during the cell cycle and specific target genes were activated which are involved in cell cycle progression and cell surviving. We plan to investigate the mechanism that the cell cycle controls Wnt signaling. We also want to identify cell cycle specific Wnt target genes and to uncover their cellular functions. Epigenetic factors, like histone modification enzymes and readers are involved in gene transcription. We plan to further verify if any of them is cell cycle specific. With this project, we hope to clarify the mutual regulation between the cell cycle and Wnt signaling and to strength our understanding on how Wnt signaling fulfills its cellular functions.

Wnt/beta-catenin信号调控细胞增殖、分化、存活等，在胚胎发育以及成体组织动态平衡调控中发挥重要作用，该信号通路的异常激活与多种肿瘤密切相关。因此， 解析其信号转导和调控的机制具有重要意义。 Wnt/beta-catenin信号主要通过调控靶基因的表达发挥功能，我们的前期研究结果显示，负责激活靶基因的beta-catenin/TCF转录复合体的形成受细胞周期调控，在细胞G2期富集并调控特定靶基因的表达，影响细胞周期进程和细胞存活。我们希望能解析细胞周期调控Wnt信号转导的机制，鉴定Wnt信号在G1和G2期调控的特异靶基因以及它们的细胞生物学功能。我们还希望能在表观遗传调控的层面分析组蛋白修饰和识别因子沿细胞周期影响Wnt信号靶基因转录调控的机制。我们的研究有望全面阐明Wnt信号与细胞周期的相互调控关系，加深人们对Wnt信号发挥细胞功能的分子机制的理解。

Wnt/beta-catenin信号调控细胞增殖、分化、存活等，在胚胎发育以及成体组织动态平衡调控中发挥重要作用。Wnt信号通路的异常激活与多种肿瘤密切相关。因此，解析其信号转导和调控机制具有重要意义。我们研究发现，Wnt信号中负责激活靶基因表达的beta-catenin/TCF转录复合体的形成受细胞周期调控，在细胞周期G1期受到相对更强的降解调控，而在细胞周期G2期相对富集。富集的beta-catenin/TCF复合体通过调控特定靶基因的表达，影响细胞周期进程和细胞存活。另外，我们还鉴定并分析了beta-catenin上游Dvl2蛋白的一个磷酸酶PPP5C及其功能。