新的肿瘤抑制分子－钙周期素结合蛋白（CacyBP/SIP）对细胞周期G2/M期的调控作用

项目名称： 新的肿瘤抑制分子－钙周期素结合蛋白（CacyBP/SIP）对细胞周期G2/M期的调控作用

项目编号： No.30872964

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 环境科学、安全科学

项目作者： 宁晓暄

作者单位： 中国人民解放军第四军医大学

项目金额： 31万元

中文摘要： S100蛋白是维持细胞内Ca2+稳定和转导钙信号的关键分子。CacyBP/SIP是S100蛋白的靶分子，也是泛素连接酶复合物成员之一，参与细胞的多种生理病理过程。我们已证实：CacyBP/SIP是新的抑癌基因，抑制胃癌细胞的生长、增殖，并发现CacyBP/SIP可能参与了细胞周期的调控。本研究表明：1. CacyBP/SIP均存在细胞周期依赖性的定位变化及磷酸化状态的变化，G2期时向核周及胞核中转位，而这种胞核转位不需核定位信号介导。CacyBP/SIP的结合蛋白Siah-1和Skp1也存在细胞周期依赖性定位变化，G2期在核周及胞核呈现与CacyBP/SIP的共定位。2. CacyBP/SIP存在细胞密度依赖性转位,当细胞融合时，CacyBP/SIP定位于胞膜，失去了胞核定位的特性。3.CacyBP/SIP的磷酸化是细胞周期依赖性转位所必需的，CDK1能使CacyBP/SIP磷酸化，促使G2期CacyBP/SIP的核转位。4. G2期细胞的胞核中, CacyBP/SIP可以与Siah-1和Skp1结合，可以形成泛素连接酶复合物,并具有蛋白降解活性，可以降解Mad2，进而细胞周期.

中文关键词： Cacybp/SIP;细胞周期；泛素连接酶

英文摘要： CacyBP/SIP, a target protein of S100, is involved in various physiological and pathological processes. It is found by our previous work that CacyBP/SIP suppressed growth and proliferation of gastric cancer cells. According to our study, we speculated that CacyBP/SIP played a critical role in regulation of cell cycle. In this study, we observed that CacyBP/SIP translocated from cytoplasma to nuclues and perinuclear region in cell cycle dependent manner, which phosphorylation and nuclear translocation of CacyBP/SIP occurred in G2/M phase. CDK1 (Cyclin-dependent kinases), participating in regulation for G2/M phase, could phosphorylate CacyBP/SIP, further resulting into translocation of CacyBP/SIP into nucleus in G2 phase. During G2 phase, CacyBP/SIP formed ubiquitin ligase complex by binding Siah-1 and Skp1 in nucleus, which was involved in the degradation of β65293;catenin. In addition, we found that Mad2 is a target for Siah/CacyBP/Skp1 ubiquitin ligase. CacyBP/SIP affected cell cycle process by inducing the degradation of Mad2. CacyBP/SIP can promote the expression of p53 and inhibit the expression of cyclinA and cyclin B at transcription level, contributing to cell cycle arrest.

英文关键词： Cacybp/SIP;cell cycle；ubiquitin ligase