Snail与FoxO在果蝇中的相互作用及调控细胞凋亡的机制研究

JNK/FoxO signaling is involved in the regulation of a wide range of physiological activities, including apoptosis, proliferation，differentiation and migration, while its deregulation has been implicated in many diseases including developmental defects and cancers. Snail is shown to be essential for the formation of the mesoderm in embryonic development, and also play central roles in epithelial-mesenchymal transition (EMT) and tumorigenesis. However, little is known about whether Snail and JNK signaling interact with each other to regulate certain physiological processes in development and disease, not to mention the mechanism. We have used Drosophila as a model organism, and showed previously that activated JNK signaling in the eye induced cell death and produced a small eye phenotype. Using this phenotype, we have performed a genetic screen and found that Snail modulates JNK-mediated apoptosis via interacting with FoxO. Based on the previous data, we will further investigate the interactions between Snail and FoxO, elucidate the underlying mechanisms. This study not only help us to understand the interactions between different signal pathways and cell factors in development, improve the current signal pathway network, but also provide novel therapeutic strategies and drug targets for the prevention and cure of diseases like cancer.

JNK/FoxO信号通路参与并调控了一系列重要的生理活动，包括细胞凋亡、增殖、分化、迁移等，其失调与发育缺陷和肿瘤等多种重大疾病的发生与发展密切相关。Snail调控了胚胎发育过程的中胚层形成，并在上皮间质转化以及肿瘤发生过程中扮演着重要角色。Snail与JNK通路在发育或疾病中是否发生交互作用，共同调控哪些生理过程，目前所知甚少。我们以果蝇为模式动物，在其眼中激活JNK信号可诱导细胞凋亡并产生小眼表型。利用此表型，我们对果蝇基因组进行遗传筛选，发现Snail作用于转录因子FoxO调控JNK信号介导的细胞凋亡，并且可与FoxO相互结合，促进其核定位。本项目拟在前期研究基础上，深入研究Snail与FoxO的相互作用及调控细胞凋亡的分子机制。这项研究有助于我们进一步了解发育过程中不同信号通路与细胞因子的相互作用，构建和完善调控细胞凋亡的信号转导网络，为癌症等疾病的防治提供新的药物靶点和治疗方案。

程序性细胞死亡（也称细胞凋亡）在动物体的生长发育和组织稳态调节中起关键作用。有关细胞生死存亡的信号通路调控网络研究一直是现代生物学的中心论题。该过程的失调与人类多种疾病相关，包括发育缺陷、免疫疾病、神经退行性疾病以及肿瘤等。JNK信号通路从果蝇到人类高度保守，尽管其在细胞凋亡中的功能已经被广泛研究且非常明确，但其下游的调控因子及作用机制仍然未知。为了发现更多的调控因子，我们利用GMR>Egr诱导的小眼表型在果蝇基因组范围内进行遗传筛选，发现锌指结构转录因子-Snail参与其中，是Egr诱导/JNK介导的细胞凋亡的全新调节剂，并阐明了作用机制。主要结果如下：1）发育过程中，Snail以非组织特异性的方式参与了Egr异位表达触发的细胞凋亡；2）Snail作用于Bsk下游调节细胞凋亡；3）snail对于内源JNK信号介导的细胞死亡是必需的；4）Snail在眼睛和翅膀发育过程中调控了FoxO诱导的细胞死亡；5）JNK信号可激活dFoxO依赖的snail转录；6）Snail在体内诱导puc活化；7）dFoxO对GMR>Snail诱导的细胞凋亡是必要的；8）Snail在S2细胞中招募dFoxO进入细胞核；9）Snail与dFoxO的结合是通过Snail的C末端和dFoxO的aa155-225区域相互作用实现的。至此，我们的研究不但揭示了Snail调节JNK介导细胞凋亡的新功能及分子机制，进一步完善了细胞死亡的信号转导网络，更为相关疾病的预防、治疗和寻找可能的药物靶点提供了新的思路。