Function of Nucleophosmin/B23 in Centrosome Duplication

描述(申请人提供)：染色体不稳定是一种可怕的疾病 在多步致癌过程中的促进作用 获得恶性表型所需的遗传损伤。在.期间 在过去的几年里，有越来越多的证据表明 中心体的非调控复制导致中心体的扩增 在人类肿瘤中很常见。中心体的有害后果 在有丝分裂过程中，由于异常的形成而表现为过度放大。 由多个主轴极组织的主轴，导致频率增加 染色体分离错误。因此，中心体过度放大是一种 人类癌症中导致染色体不稳定的主要因素。 细胞周期蛋白依赖性激酶(CDK)2/细胞周期蛋白E触发中心体复制 (和/或细胞周期蛋白A)以一种依赖于激酶活性的方式。因为CDK2/Cyclin E 也驱动细胞启动DNA合成，瞬时激活 发生在G1中晚期的CDK2/Cyclin E被认为是协调中心体的 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的一个关键的中心体靶点 在中心体复制的启动中。NPM/B23直接磷酸化 通过CDK2/Cyclin E，并在CDK2/Cyclin上与中心体解离 E介导的磷酸化。微量注射抗NPM/B23抗体以及 显性负性NPM/B23的表达抑制中心体复制。 这些结果表明，核心体NPM/B23的解离可被 CDK2介导的磷酸化是启动细胞周期调控的关键事件 中心体复制，构成中心体许可制度 复制，确保中心体和DNA复制的协调 以及将中心体复制限制为在单个细胞内发生一次 周而复始。阐明NPM/B23在中心体复制中的功能作用， 特别是与CDK2/Cyclin E(和Cyclin A)结合时，在一个分子上 级别将为进一步理解 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。是这样的 一种方法可能被证明是有效的，因为中心体复制，如DNA 复制，仅限于增殖的细胞。此外，阻止 中心体复制过程导致染色体不稳定性的抑制 以及细胞分裂。

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.