项目名称: ILKAP催化核仁磷蛋白NPM去磷酸化调控骨肉瘤恶性生物学行为的机制研究
项目编号: No.81201556
项目类型: 青年科学基金项目
立项/批准年度: 2013
项目学科: 肿瘤学1
项目作者: 周旺
作者单位: 中国人民解放军第二军医大学
项目金额: 23万元
中文摘要: 骨肉瘤是一种常见的原发恶性骨肿瘤,具有恶性度高,侵袭力强且易转移的特点,目前尚缺乏明确的分子治疗靶点。近年来研究显示,核仁磷蛋白(NPM)的磷酸化状态与多种肿瘤的增殖与转移密切相关。本课题组在前期研究中发现,一种核仁定位的蛋白磷酸酶ILKAP可以催化NPM的去磷酸化,并抑制骨肉瘤细胞的增殖。同时发现骨肉瘤中ILKAP存在广泛的失活突变;这提示ILKAP可能通过调节NPM的磷酸化影响骨肉瘤的发生、增殖与转移。本项目拟通过探讨ILKAP催化NPM的磷酸化位点,以确定其催化NPM后对应的肿瘤相关信号通路,并利用骨肉瘤模型细胞系检测过量表达或敲除ILKAP后NPM的磷酸化状态,观察骨肉瘤细胞增殖、侵袭、粘附能力的变化。再利用动物模型检测过量表达或敲除ILKAP对骨肉瘤成瘤与转移的影响。阐明ILKAP调控NPM的去磷酸化机制及对骨肉瘤恶性生物学行为的影响,为骨肉瘤的治疗提供新的分子靶点和治疗途径。
中文关键词: 整合素激酶相关磷酸酶;核仁磷蛋白;骨肉瘤;;
英文摘要: Osteosarcoma is the most common primary malignant bone tumor,with high malignance, fast growing, early metastasis and strong invasion, about 80% of patients had been found the transfer of lung or other parts at diagnosis in clinical work and no definite molecular target point for the cure of osteosarcoma. Nucleophosmin(NPM)is a phosphorus-rich protein localized in nucleolus and closely related with tumors. The over-phosphorylation of NPM causes tumor generation and proliferation especially in human osteosarcoma. The dysregulation of NPM phosphorylation is the main cause of the over-phosphorylation of NPM and the generation and proliferation of osteosarcoma. To discover the mechanism of the dysregulation of NPM is the way to resolve the molecular target point for the cure of osteosarcoma. We found ILKAP is the only known phosphatase localized in the nucleolus and directly catalysis of NPM. We also found ILKAP inactivated mutants widely exist in human osteosarcoma. Those resules suggest that ILKAP maybe regulate the generation, proliferation and metastatic potential in osteosarcoma through dephosphorylation of NPM. We plan to explore the specific sites about ILKAP catalytic of NPM, in order to clarify the mechanism about the dephosphorylation of NPM. We plan to detect the change of NPM phosphorylation and the abil
英文关键词: ILKAP;MPN;osteosarcoma;;