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: 7011191
• 负责人: KENJI FUKASAWA
• 金额: $ 26.21万
• 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 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7011191
• 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）：染色体不稳定性是强大的 通过促进多步癌发生的力 获得恶性表型所需的遗传病变。期间 最近几年，有大量证据表明异常 由于中心体的放松调节，对中心体的扩增 在人类肿瘤中很常见。中心体的有害后果 通过形成异常，在有丝分裂过程中特征过度扩增 由多个主轴杆组织的主轴，导致频率增加 染色体隔离错误。因此，中心体高增加是一个 导致人类癌症染色体不稳定性的主要因素。 中心体重复是由细胞周期蛋白依赖性激酶（CDK）2/细胞周期蛋白E触发的 （和/或细胞周期蛋白A）以激酶活性依赖性方式。因为CDK2/Cyclin e 还驱动细胞启动DNA合成，即时间激活 CDK2/Cyclin E发生在中期G1中 重复和其他细胞周期事件，包括DNA复制。我们有 最近发现核磷脂（NPM）/B23是CDK2的关键中心靶标 在开始中心体重复的过程中。 NPM/B23直接磷酸化 通过CDK2/细胞周期蛋白E，并在CDK2/Cyclin上与中心体分离 电子介导的磷酸化。抗NPM/B23抗体的显微注射以及 显性负NPM/B23的表达抑制了中心体重复。 这些结果表明，由中心体NPM/B23解离 CDK2介导的磷酸化是开始的关键事件 中心体重复，构成中心体的许可系统 重复，确保中心体和DNA重复的协调为 以及限制中心体重复一次，一次在一个单元格内发生 循环。阐明NPM/B23在中心体重复中的功能作用， 特别是与CDK2/细胞周期蛋白E（和细胞周期蛋白A）相关，在分子上 级别将提供关键信息，以进一步了解 中心体重复的调节，这导致了设计的潜力 有效的癌症干预方案针对中心体重复。这样的 方法可能有效，因为中心体重复，例如DNA 复制，仅限于增殖细胞。而且，阻止 中心体重复过程导致抑制染色体不稳定性 以及细胞分裂。