摘要
由超氧离子、过氧化氢和羟自由基组成的活性氧(ROS)是细胞代谢的副产品。活性氧水平对细胞生死有着复杂的影响,由此对肿瘤、糖尿病、神经退行性病变等氧化应激相关疾病的发生和进程带来复杂的影响,其中机制则尚不清楚。本研究组近十多年来致力于阐明活性氧水平的高低如何影响细胞的生物学活动和生死命运,即活性氧在细胞增殖、分化和凋亡中的信号调控作用,特别聚焦于活性氧调控的蛋白质翻译后修饰如氧化修饰、类泛素修饰(SUMO)化修饰等在细胞信号转导中的作用及其与肿瘤发生发展和治疗的关系。本研究组主要的发现有:①肿瘤细胞对三氧化二砷、顺铂和柔红霉素等促凋亡药物的易感性与细胞固有活性氧水平正相关,用大黄素等化合物或强制表达Nox质粒等手段提高活性氧水平,造成重度氧化应激,可以增强白血病和实体瘤细胞对药物促凋亡的易感性,其作用机制涉及升高的活性氧抑制肿瘤细胞中原有的RhoA、HIF-1、NF-κB等抗凋亡促存活信号通路,并激活Caspase-9等促凋亡因子;②肿瘤细胞中的轻度氧化应激通过诱导SENP3影响蛋白质SUMO化修饰和基因表达格局,促进肿瘤发生发展。SENP3是SUMO蛋白酶,我们首次证明该分子是氧化还原感应蛋白,自身在活性氧诱导下快速累积,调控一系列核蛋白底物(如p300、PML和p53等)的SUMO化,介导肿瘤细胞适应氧化应激环境并强化其增殖、存活和血管生成等表型。该方向下的研究共发表国际杂志论文26篇,获得国家自然科学基金项目12项。研究成果获2011年教育部自然科学二等奖。
Reactive oxygen species （ROS） mainly comprised of super oxide, hydrogen peroxide and hydroxyl free radicals, are the side products of cell metabolism. The level of ROS brings complex impacts on cell fate, leading to complex impacts on the occurrence and progression of the oxidative stress-related human diseases such as cancer, diabetes, and neurodegeneration, but the underlying mechanism remain to be clarified. Our research group aimed in elucidating the mechanisms how different levels of ROS affect the biological events and the fate of cells, i.e. the regulatory role of ROS in signaling determining cell proliferation, differentiation and apoptosis. We specifically focus on the signaling role of ROS-regulated post-translational modifications of proteins, e.g. oxidation, ubiqnitination and SUMOylation, and their links to formation, progression and remedy of cancers. Our major findings are： ①The sensitivity of cancer cells to arsenic trioxide, eisplatin and doxorubicin and other apoptosis-inducing drugs is positively correlated to the inherent cellular level of ROS. The increase of ROS level by using emodin and some other compounds, or enforced expression of Nox to cause severe oxidative stress can sensitize the apoptotie susceptibility of leukemic eells and solid tumor cells. The underlying mechanisms involve in an inhibition of RhoA, HIF-1, NF-κB and other pro-survival signaling pathways, and simultaneously an activation of easpase 9 by ROS. ②The mild oxidative stress existed in cancer cells promotes cancer genesis and progression, which may be via an induction of SENP3 to regulate the profiles of protein SUMOylation and gene expression. We ascertained for the first time that SUMO protease SENP3 is a redox sensing protein. Being induced by ROS, it is rapidly accumulated and thus regulates the sUMOylation status of a number of substrates in the nucleus, such as p300, PML and p53, leading to an adaptation of cancer ceils to stressful environment and the more malignant phenotypes including survival, proli
出处
《上海交通大学学报（医学版）》
CAS
CSCD
北大核心
2012年第9期1122-1127,共6页
Journal of Shanghai Jiao tong University:Medical Science
基金
国家自然科学基金面上项目(30971437)
国家自然科学基金重大研究计划项目(91013012)
国家自然科学基金重点项目(21230037)
国家重点基础研究发展计划("九七三"计划)(2013CB910902)
关键词
活性氧
氧化应激
氧化修饰
类泛素修饰
肿瘤
reactive oxygen species
oxidative stress
oxidative modification
small ubiquitin-like modifiers
cancer
