蛋白激酶Akt与转录因子Oct4 相互调节的机理研究

项目名称： 蛋白激酶Akt与转录因子Oct4 相互调节的机理研究

项目编号： No.31271465

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 王英杰

作者单位： 浙江大学

项目金额： 90万元

中文摘要： 蛋白激酶Akt和转录因子Oct4分别在促进肿瘤细胞生存和维持胚胎干细胞"干性"中处于中枢地位。 同时，Akt在胚胎干细胞中和Oct4在肿瘤细胞中也发挥重要作用，即两者均是"兼职"于胚胎干细胞和肿瘤细胞中的关键蛋白。 但是迄今尚未报道这两种蛋白之间是否存在结构和功能上的互作。申请人的前期工作表明，在胚胎癌细胞这一肿瘤干细胞模型中，Akt可以直接磷酸化Oct4，而磷酸化的Oct4又可以上调Akt基因的转录，形成了Oct4-Akt正反馈回路系统。 本项目拟在该工作基础上，运用基因组学和蛋白质组学等手段，解析出胚胎癌细胞和胚胎干细胞中较为完整的Oct4-Akt互作系统，深入比较该互作系统在两种细胞中的异同，阐明Oct4-Akt正反馈回路系统形成的机制及其在胚胎干细胞癌变中的作用。本项目的研究结果将为揭示胚胎干细胞癌变和肿瘤干细胞形成机理提供新线索，并为针对肿瘤干细胞的治疗提供新靶标和新策略。

中文关键词： Oct4；Akt；磷酸化；转录调控；肿瘤干细胞

英文摘要： It is well established that Akt and Oct4 plays a central role in cancer cell survival and embryonic stem cell self-renewal,respectively. Emerging evidence showed that Akt and Oct4 also has essential functions in embryonic stem cells and cancer cells, respectively, implicating their dual roles in those cells. However，so far it is unknown if there is any structrual or functional interactions between these two important proteins. Work from the applicant's lab has shown that in embryonal carcinoma cells which serve as a model for cancer stem cells,Akt can directly phosphorylate Oct4, and Akt-phosphorylated Oct4 can in turn up-regulate the transcription of AKT1 gene, thereby forming an Oct4-Akt positive feedback loop. Building upon these results we made this proposal in which we are going to desipher the complete Oct4-Akt interaction system and compare this system in embryonic stem cells and embryonal carcinoma cells by genomic and proteomic approches, and to unravel the mechanism by which the Oct4-Akt postive feedback loop is formed and to assess its role in tumorigenesis of embryonic stem cells. It is expected that the results from this project may provide novel clues for revealing the mechanism of cancer stem cell formation, as well as new therapeutic strategy for targeting cancer stem cells.

英文关键词： Oct4；Akt；phosphorylation；transcriptional regulation；cancer stem cell