基于小分子探针的细胞命运决定的分子机制研究

项目名称： 基于小分子探针的细胞命运决定的分子机制研究

项目编号： No.91413121

项目类型： 重大研究计划

立项/批准年度： 2015

项目学科： 遗传学与生物信息学、细胞生物学

项目作者： 俞强

作者单位： 中国科学院上海药物研究所

项目金额： 50万元

中文摘要： JAK/STAT信号通路是介导细胞因子信号转导的关键通路，在细胞生长、分化、迁移、凋亡中起着重要的调节作用，和各种免疫系统疾病及肿瘤等有着密切的关系。该项目的前期工作发现了一个增强STAT1信号通路活性的化合物蟛蜞菊内酯，并发现其靶蛋白为STAT1信号通路中的一个负调控蛋白：酪氨酸磷酸酶TCPTP。蟛蜞菊内酯通过抑制 TCPTP的活性，从而抑制STAT1的去磷酸化来实现增强STAT1信号通路的作用。我们同时也发现TCPTP受细胞密度、粘附和细胞骨架的调节，揭示了一个潜在的细胞骨架蛋白调控JAK/STAT信号通路的新机制。该项目将继续以小分子化合物Wedelolactone为探针，解析其靶点蛋白TCPTP所介导的JAK/STAT通路负调控信号，阐明其负调控机制，全面认识JAK/STAT信号通路的正负双向调控功能和机制，并探索蟛蜞菊内酯成为治疗肿瘤和炎症等疾病药物的可能性。

中文关键词： TCPTP；蛋白骨架；细胞凋亡；负调控；STAT1

英文摘要： The JAK/STAT signaling pathway is the key pathway for cytokine signal transduction. It plays important regulatory roles in cell proliferation, differentiation, migration, and apoptosis, as well as in immune system diseases and cancer. Our earlier work has identified a natural compound wedelolactone that enhances the STAT1 activity and the protein target of wedelolactone, the protein tyrosine phosphatase TCPTP. Wedelolactone increases the activity STAT1 signaling by inhibiting TCPTP and the dephosphorylation of STAT1. Our work also found that TCPTP was regulated cell density, adhesion, and cytoskeleton, indicating a potential new mechanism by which the cytoskeleton proteins regulate JAK/STAT signaling. The proposed project will continue to use wedelolactone as a probe to understand the negative signals and regulations of the JAK/STAT signaling pathway, to reveal the relationships between the JAK/STAT, TCPTP, and cytoskeleton proteins, and to explore the potential to develop wedelolactone into an anti-inflammation and anti-cancer drug.

英文关键词： STAT1；negative regulation；TCPTP；actin；apoptosis