SUMO特异性蛋白酶SENP1介导的Sp1去SUMO化修饰异常在Nano-Co诱导细胞恶性转化中的作用

项目名称： SUMO特异性蛋白酶SENP1介导的Sp1去SUMO化修饰异常在Nano-Co诱导细胞恶性转化中的作用

项目编号： No.81473009

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 万榕

作者单位： 福建医科大学

项目金额： 60万元

中文摘要： 研究表明：Nano-Co可刺激细胞产生过多的ROS,诱导细胞恶性转化和动物肿瘤形成,但其潜在致癌机制尚未阐明。本项目前期研究发现：Nano-Co诱导细胞恶性转化中高表达的SENP1促进Sp1表达上调，免疫共沉淀显示二者存在相互作用。因此，我们提出SENP1介导的Sp1去SUMO化修饰异常可能在Nano-Co诱导细胞恶性转化中具有重要作用的假说。拟利用低剂量Nano-Co诱导人支气管上皮细胞恶性转化的模型，研究SENP1介导的Sp1去SUMO化修饰作用，观察SENP1表达失调对Sp1转录活性、蛋白稳定性、下游靶基因转录活化及对转化细胞生长和凋亡的影响，探讨Nano-Co诱导的氧化应激对SENP1介导的Sp1去SUMO化修饰的调节作用。研究结果将揭示SENP1介导的Sp1去SUMO化修饰异常在细胞恶性转化中的重要作用，阐明Nano-Co的潜在致癌作用。这将有助于了解纳米材料基因毒性和致癌性。

中文关键词： 金属钴纳米颗粒；SENP1；Sp1；细胞转化；活性氧

英文摘要： With the growth of nanotechnology, a large number of nanomaterials will be developed and produced as new formulations with diverse surface properties. Therefore,the population exposure to nanoparticles is growing, and the potential health impact, especially potential carcinogenic effects of these new products cannot be ignored. Here we chose Nano-Co as a model of metal nanoparticles to investigate its carcinogenesis and the potential underlying mechanisms. Previous studies suggest that some metal nanoparticles may have genotoxic and carcinogenic effects, however, the mechanism is still unclear. Our and other previous studies showed that exposure to Nano-Co caused oxidative stress, which may further result in cell malignant transformation and tumor formation in rat. Our preliminary data demonstrated that SP1 was up-regulated through Nano-Co-induced SENP1 overexpression in Nano-Co-transformed cells, which was further confirmed by co-immunoprecipitation. Therefore, we hypothesize that SENP1-mediated Sp1 desumoylation may play an important role in Nano-Co induced cell malignant transformation. To test our hypothesis, we will first investigate whether SENP1 will mediate desumoylation of Sp1 in Nano-Co-transformed human bronchial epithelial BEAS-2B cells by determining the transactivation activity and protein stability of Sp1, the transcriptional activities of downstream genes, and the proliferation, colony formation, cell cycle progression and apoptosis in Nano-Co-transformed cells. Then we will investigate the effects of oxidative stress induced by Nano-Co on the SENP1- mediated Sp1 desumoylation.We expect that our results will reveal the role of SENP1 in Sp1 desumoylation in Nano-Co-induced malignant transformation, and elucidate the potential molecular mechanisms involved in Nano-Co-induced carcinogenesis. Successful completion of this project will lead to a better understanding of the mechanisms by which metal nanoparticles induce carcinogenesis.

英文关键词： Nano-Co;SUMO specific protease 1(SENP1);Specific protein 1(Sp1);cell transformation;ROS