去乙酰化酶Sirtuins 3调控突变型p53阻抑肺癌机制的研究

项目名称： 去乙酰化酶Sirtuins 3调控突变型p53阻抑肺癌机制的研究

项目编号： No.81501982

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 刘亚男

作者单位： 吉林大学

项目金额： 16万元

中文摘要： 突变型 p53（mtp53）作为肿瘤诊断治疗靶标一直受到关注。以mtp53的降解为切入点， 已经发现泛素化、乙酰化、磷酸化及甲基化等翻译后修饰参与了mtp53稳定性的维持，被认为是调控mtp53功能的机制之一。临床研究已经发现肿瘤去乙酰化酶Sirt3与mtp53的表达呈负相关，提示泛素化与乙酰化的交互作用可能是mtp53精细调控机制。因此，我们推测Sirt3影响mtp53的去乙酰化及乙酰化平衡调控其泛素化，决定了肺癌细胞mtp53的稳定性。我们利用mtp53的肺癌细胞构建过表达Sirt3肺癌细胞系，观察Sirt3通过p53泛素化连接酶MDM2影响mtp53稳定性及其他途径调控mtp53转录功能的可能；建立人肺癌裸鼠荷瘤模型，进一步确认体外实验结果，从体内外角度探讨改变mtp53活性影响化疗药物敏感性的机制。为以mtp53为靶点的肺癌治疗及新肿瘤标志物的筛选提供一个新的线索。

中文关键词： 肺肿瘤；沉默信息调节因子；突变型p53；乙酰化；泛素化

英文摘要： Mutant p53 (mtp53) has been pay close attention as a therapeutic target for tumor diagnosis. Mtp53 degradation as a starting point, post-translational modification have been found involved in maintaining stability of mtp53,like ubiquitination, acetylation, phosphorylation and methylation, considered to be one of the mechanisms in regulating mtp53 functions. Clinical studies have found that the negative correlation of deacetylase Sirt3 and mtp53 in tumor,suggesting that the cross talk of ubiquitination and acetylation may be fine-tuned mechanism regulating mtp53. Therefore, we hypothesized that Sirt3 impact balance of deacetylation and acetylation and ubiquitination regulating mtp53, that may determines the stability of mtp53 on lung cancer cells. We use mtp53 lung cancer cells overexpressing Sirt3 to build cell lines, observe Sirt3 may affect ligase MDM2 then affect mtp53 stability and other channels regulating transcriptional function on mtp53; established nude mice model, further confirmed the results in vitro, explore the mechanism of chemosensitivity by mtp53 activity changing. It provide a new clue by targeting mtp53 in lung cancer and new tumor markers.

英文关键词： lung cancer;Sirt 3;mt p53;Acetylation;Ubiquitination