Abl激酶介导的iASPP酪氨酸磷酸化对其活性的调控及其在Abl激酶依赖性的细胞增殖和转化中的作用

项目名称： Abl激酶介导的iASPP酪氨酸磷酸化对其活性的调控及其在Abl激酶依赖性的细胞增殖和转化中的作用

项目编号： No.31301131

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 胡颖

作者单位： 哈尔滨工业大学

项目金额： 25万元

中文摘要： iASPP为一种新发现的癌基因产物，与多种肿瘤的发生和耐药相关。诸多结合伴侣的报道提示该蛋白具有多种生物学活性，然而其活性的调控机制却尚不清楚，与不同伴侣相互作用的生物学意义也有待阐明，这严重限制了iASPP作为肿瘤靶标在临床上的应用。酪氨酸磷酸化为调控蛋白活性的重要机制之一，生物信息学数据和前期实验结果显示Abl酪氨酸激酶可磷酸化iASPP。在此基础上，本项目将：①明确Abl激酶磷酸化iASPP的规律及两种蛋白的结合机制；②探讨Abl激酶介导的酪氨酸磷酸化对iASPP活性的调控机制；③研究磷酸化的iASPP在Abl激酶依赖性的细胞增殖和转化过程中的作用。本项目研究不仅有助于全面认识iASPP的功能，明确其多种活性的调控机制；还有助于深入理解Abl激酶异常活化相关肿瘤的发病机制，从而更好地指导iASPP作为新肿瘤靶标在临床诊断和治疗中的应用，提高肿瘤的治疗效率。

中文关键词： iASPP；c-Abl；磷酸化；转录后修饰；肿瘤

英文摘要： iASPP is a novel oncogene identified recently. Enhanced iASPP protein levels have been found to be associated with oncogenesis and drug resistance in various cancers. An increasing number of iASPP binding patterns have been reported since its discovery, suggesting that iASPP has multiple functions. However, the biological importance of the interactions needs to be further clarified and how iASPP's activities are regulated in cells remains obscure. This has limited clinical application of iASPP as a therapeutic target or biological marker. Post-translational modification by phosphorylation is the main method that a cell uses to control the activities of its proteins. Our preliminary data showed that iASPP is a potential substrate of Abl tyrosine kinase, which is supported by kinase motif prediction data revealed by bioinformatic tools. Therefore, this project will further ① validate that iASPP is a substrate of Abl tyrosine kinase; ② exam the roles of Abl-mediated iASPP tyrosine phosphorylation in regulating iASPP activities; ③ investigate the roles of tyrosine phosphorylated iASPP in Abl-induced cell proliferation and transformation. These data will not only improve an overall understanding of iASPP functions and its regulatory mechanisms; but also contribute to a better understanding of molecular mechanisms und

英文关键词： iASPP；c-Abl；phophorylation；post-transcriptional modification；cancer