Function of Nucleophosmin/B23 in Centrosome Duplication

核磷蛋白/B23 在中心体复制中的功能

• 批准号: 6839433
• 负责人: KENJI FUKASAWA
• 金额: $ 26.86万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6839433
• 关键词: centrosome; cyclin dependent kinase; cyclins; enzyme activity; gene induction /repression; neoplasm /cancer genetics; neoplastic cell; phosphoproteins; phosphorylation; protein structure function; recombinant proteins; tissue /cell culture

DESCRIPTION (provided by applicant): Chromosome instability is a formidable force in the multi-step carcinogenesis by facilitating the accumulation of genetic lesions required for the acquisition of malignant phenotypes. During last several years, there is an accumulation of evidence that abnormal amplification of centrosomes due to the deregulated duplication of centrosomes is common in human tumors. A deleterious consequence of centrosome hyperamplification is featured during mitosis by the formation of aberrant spindles organized by multiple spindle poles, leading to an increased frequency of chromosome segregation errors. Thus, centrosome hyperamplification is one major factor that contributes to chromosome instability in human cancers. Centrosome duplication is triggered by cyclin-dependent kinase (CDK)2/cyclin E (and/or cyclin A) in a kinase activity-dependent manner. Because CDK2/cyclin E also drives cells to initiate DNA synthesis, the temporal activation of CDK2/cyclin E occurring in the mid-late G1 is believed to coordinate centrosome duplication and other cell cycle events, including DNA replication. We have recently found that nucleophosmin (NPM)/B23 is a key centrosomal target of CDK2 in the initiation of centrosome duplication. NPM/B23 is directly phosphorylated by CDK2/cyclin E, and dissociates from the centrosomes upon CDK2/cyclin E-mediated phosphorylation. Microinjection of anti-NPM/B23 antibody as well as expression of a dominant negative NPM/B23 inhibits centrosome duplication. These results suggest that dissociation of centrosomal NPM/B23 induced by CDK2-mediated phosphorylation is a critical event for the initiation of centrosome duplication, constituting a licensing system for centrosome duplication, ensuring the coordination of centrosome and DNA duplication as well as restricting centrosome duplication to occur once within a single cell cycle. Elucidation of the functional role of NPM/B23 in centrosome duplication, especially in association with CDK2/cyclin E (and cyclin A), at a molecular level will provide crucial information for further understanding of the regulation of centrosome duplication, which leads to the potential of designing effective cancer intervention protocols targeting centrosome duplication. Such an approach may prove effective, since centrosome duplication, like DNA replication, is restricted to proliferating cells. Moreover, blocking the centrosome duplication process results in suppression of chromosome instability as well as cell division.

描述（由申请人提供）：染色体不稳定性是一种可怕的现象 通过促进多步骤致癌作用的积累 获得恶性表型所需的遗传损伤。期间 近几年来，越来越多的证据表明异常 由于中心体复制失调而导致中心体扩增 常见于人类肿瘤。中心体的有害后果 有丝分裂过程中通过形成异常的超扩增来表征 主轴由多个主轴极组成，导致频率增加 染色体分离错误。因此，中心体过度扩增是一种 导致人类癌症染色体不稳定的主要因素。 中心体复制由细胞周期蛋白依赖性激酶 (CDK)2/细胞周期蛋白 E 触发 （和/或细胞周期蛋白A）以激酶活性依赖性方式。因为CDK2/细胞周期蛋白E 还驱动细胞启动 DNA 合成，即时间激活 CDK2/细胞周期蛋白 E 发生在 G1 中晚期，被认为协调中心体 复制和其他细胞周期事件，包括 DNA 复制。我们有 最近发现核磷蛋白（NPM）/B23是CDK2的关键中心体靶标 中心体复制的起始。 NPM/B23直接磷酸化 通过 CDK2/细胞周期蛋白 E，并通过 CDK2/细胞周期蛋白从中心体解离 E介导的磷酸化。显微注射抗 NPM/B23 抗体以及 显性失活 NPM/B23 的表达抑制中心体复制。 这些结果表明中心体 NPM/B23 的解离由 CDK2介导的磷酸化是启动的关键事件 中心体复制，构成中心体的许可系统 复制，确保中心体和 DNA 复制的协调 以及限制中心体复制在单个细胞内发生一次 循环。阐明 NPM/B23 在中心体复制中的功能作用， 尤其是在分子水平上与 CDK2/细胞周期蛋白 E（和细胞周期蛋白 A）相关 水平将为进一步理解提供重要信息 中心体复制的调节，这导致了设计的潜力 针对中心体复制的有效癌症干预方案。这样的 一种方法可能被证明是有效的，因为中心体复制，如DNA 复制，仅限于增殖细胞。此外，阻止 中心体复制过程导致染色体不稳定的抑制 以及细胞分裂。