RhoB在细胞活性氧应激调控反应中的作用及机制的研究

活性氧（ROS）与肿瘤的发生发展密切相关。我们前期工作发现细胞中ROS水平的升高促进细胞自噬的过程伴随着RhoB蛋白水平的上调，敲除RhoB则会明显抑制ROS刺激引起的细胞自噬和细胞死亡，说明RhoB在细胞ROS应激调控反应中起着重要的作用。进一步的研究发现ROS刺激会通过调控RhoB的去棕榈酰化使得RhoB从细胞质膜解离下来进入细胞质并且被SUMO化修饰，进而将TSC复合物转运至溶酶体以抑制mTORC1的活性，启动细胞自噬。同时，我们的肿瘤样本分析和生物信息学分析结果表明RhoB在多种肿瘤中的表达下调，并且存在会影响其SUMO化修饰的突变。在本课题中，我们将进一步阐明RhoB在ROS诱导的细胞自噬中的作用和分子机制，并从动物模型和临床水平研究RhoB调控ROS应激反应在肿瘤发生发展过程中的作用，这对我们深入理解肿瘤发病机理并探索特异的肿瘤治疗方法将具有重要的理论和临床指导意义。

Reactive oxygen species (ROS) play critical roles in tumorigenesis. Our preliminary study found that ROS stress up-regulated RhoB levels during its promotion of autophagy. Knockout of RhoB remarkably inhibited the autophagy and cell death induced by ROS stress, suggesting that RhoB plays an important role in the regulation of ROS stress. Further mechanism study found that de-palmitoylation of RhoB is required for its dissociation from plasma membrane and being sumoylated in cytosol. Sumoylated RhoB transfers TSC complex to lysosomes to inhibit mTORC1 activity, thereby initiates autophagy. In addition, we found that RhoB is down-regulated in many types of cancers and there exists a mutation that interrupts RhoB sumoylation. In this proposal, we will further elucidate the underlying mechanism of RhoB in the regulation of ROS stress, and the role of RhoB-mediated ROS stress response in tumorigenesis via cellular, animal, and clinical studies, which will provide us new insights into tumor development and potential strategy for cancer therapy.