双功能基因APE1氧化修饰调控VEGF表达及其机制的研究

项目名称： 双功能基因APE1氧化修饰调控VEGF表达及其机制的研究

项目编号： No.30801368

项目类型： 青年科学基金项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 仲召阳

作者单位： 中国人民解放军第三军医大学

项目金额： 20万元

中文摘要： 我们前期首先证实双功能基因APE1对VEGF具有调控作用。APE1不仅以氧化还原活性（redox）调控HIF-1α65292;而且还以DNA修复活性参与VEGF启动子区单链断裂（SSB）形成，增强HIF-1α19982;VEGF启动子结合，但这一结合启动过程需要SSB暴露。而APE1酶切后为什么不能完成SSB碱基切除修复（BER），反使SSB暴露，其机制尚不清楚。肿瘤在低氧环境下APE1双功能可同时发挥作用，故此我们提出发挥redox而处于氧化态的APE1可干扰其募集下游的修复酶阻滞正常BER途径，从而导致SSB的暴露。本项目应用免疫共沉淀、特异性抑制剂等方法研究APE1自身氧化修饰对BER途径的影响，以及APE1双功能在VEGF调控中的偶联协同效应。该研究不仅第一次揭示APE1两个相对独立功能域可能具有偶联协同作用，而且可进一步阐明Ape1对 VEGF的调控机制和核心作用，为肿瘤抗血管生成治疗提供新的思路。

中文关键词： VEGF；APE1/Ref-1；氧化还原修饰；DNA损伤修复；转录调控

英文摘要： Our previous researches have proved that bifunctional gene APE1 can control VEGF. APE1 regulates HIF-1αhrough redox activity, participates in the formation of VEGF promoter region Single Strand Breakage (SSB) through its DNA repair activity and boosts the combination of HIF-1αnd VEGF promoter, while the start process of combination requires the exposure of SSB. The mechanism has not been confirmed yet why SSB base- excision repair (BER) can not be done, but leads to SSB exposure after APE1 enzyme digestion. When tumor is in hypoxia environment, APE1 exerts bifunction simualtaneously. Therefore, we figured out that oxidated APE1 with redox activity can prevent the down- stream repair enzyme collected from blocking regular BER track and hence leads to the exposure of SSB. This project aims to study the effect of APE1 oxidation on BER tracks and the coupling reaction of APE1 bifunction in regulating VEGF by using immune response and specific depressor. This research not only for the first time uncovered that two comparatively independent functions of APE1 possibly have coupling reaction. Furthermore, it further illustrated the regulation mechanism and core function of APE1 to VEGF, which brings new thoughts on tumor anti-angiogenesis therapy.

英文关键词： VEGF;APE1/Ref-1;redox; DNA injure and repair; transcriptional control