JNK信号通路对细胞迁移的调控机制

The JNK signal transduction pathway is highly conserved from Drosophila to human, while its dysregulation has been implicated in the development of cancer, diabetes and immune deficiency. Upon various stimuli and cellular contexts, activation of JNK signaling results in cell proliferation, cell death or cell migration, suggest the divergent functions of JNK pathway are regulated by distinct cellular factors. The roles of JNK signaling in cell proliferation and cell death have been well studied, but its role in cell migration remains elusive. We have used Drosophila as the model organism, activated the JNK signaling along the A/P compartment boundary, and observed a cell migration and EMT phenotype. We performed a pilot screen based on this phenotype, and identified 5 regulator. Based on these preliminary data, we will use this JNK-mediated cell migration model to carry out a large scale screen in order to identify additional regulators. We will characterize the molecular functions of these genes, identify their targets, determine the mechanism by which the JNK pathway perform different functions. Such studies not only help us find the modulators of the JNK pathway, elucidate their role in the development of cancers, but also provide us novel drug targets and treatments against the diseases.

以JNK 为中心的信号转导通路从果蝇到人类高度保守，其失调与癌症、糖尿病和免疫缺陷等重大疾病的发生与发展密切相关。在体内，依据不同的外源刺激或细胞背景，激活JNK通路可导致细胞增殖、凋亡或迁移等迥异的后果，提示JNK通路在细胞内不同因子的调控下，发挥不同的功能。JNK信号通路在细胞增殖和凋亡中的作用及调节机理已有较多的研究，但其对细胞迁移的调控机制尚不清楚。我们以果蝇为模式动物，在翅成虫盘的前后交界处激活JNK通路，发现细胞产生迁移和上皮间质转换表型。我们以此表型进行了小规模的预筛选，发现并鉴定了5个调控因子。本项目拟在前期工作基础上，利用JNK介导的细胞迁移模型，在全基因组范围大规模筛选和鉴定相关调控因子，研究其分子功能，阐明其作用机理，揭示JNK通路行使不同功能的调节机制，完善现有的信号转导网络，诠释癌症等相关疾病的复杂致病机制，以期为疾病的诊断和治疗提供新的方案和药物靶点。

JNK信号通路是动物发育中起重要作用的信号转导通路，在进化中高度保守，在细胞增殖、迁移及凋亡等生理过程中起重要作用，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。JNK信号通路与其它哪些信号通路发生交互作用，共同调控生理过程，目前所知甚少，其作用机制更不清楚。我们以果蝇为模式动物，在不同组织中激活JNK信号通路，可诱导细胞凋亡和迁移的发生，并产生相应表型。我们利用上述表型对果蝇基因组进行遗传筛选，发现JNK通路与经典的Wg、Hippo信号通路相互作用，共同调控细胞凋亡和细胞迁移，便参与肿瘤的发生与侵袭。此外，我们还发现了Hippo通路的两个新的调控因子-POSH和Rox8，并阐明了它们的作用机制；发现CHIP通过调控细胞自噬参与APP诱导的病理功能。通过本项目的研究，我们发现了JNK信号通路新的调控因子，确定了JNK通路与其它信号通路的相互作用和机制。本项目的研究不仅有助于我们了解发育中不同信号通路间的相互作用，完善调控发育的信号转导网络，也为癌症等疾病的防治提供了新的药物靶点和治疗方案。