Molecular Oncology Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612-9416, USA.
Oncogene. 2011 May 12;30(19):2188-97. doi: 10.1038/onc.2010.607. Epub 2011 Jan 17.
Initiation of centrosome duplication and DNA replication is coupled, which is primarily achieved by the late G1 phase-specific activation of cyclin-dependent kinase 2 (CDK2)-cyclin E, which triggers both centrosome duplication and DNA replication. Uncoupling of these two events contributes to overduplication of centrosomes, resulting in the presence of more than two centrosomes (centrosome amplification). Centrosome amplification, which is frequently observed in cancers, contributes to tumor development through destabilizing genomes. Nucleophosmin (NPM/B23) is one of the phosphorylation targets of CDK2-cyclin E for the initiation of centrosome duplication. It has been found that NPM/B23 phosphorylated on Thr199 by CDK2-cyclin E acquires a high binding affinity to ROCK II kinase. The Thr199-phosphorylated NPM/B23 physically interacts with and super-activates the centrosomally localized ROCK II, which is a critical event for centrosomes to initiate duplication. Here, we provide direct evidence for the activation of ROCK II as a primary and sufficient downstream event of CDK2-cyclin E for the initiation of centrosome duplication and for the induction of centrosome amplification.
中心体复制的起始与 DNA 复制相偶联，这主要是通过晚期 G1 期特异性激活周期蛋白依赖性激酶 2（CDK2）-细胞周期蛋白 E 来实现的，这触发了中心体复制和 DNA 复制。这两个事件的解偶联导致中心体过度复制，导致出现两个以上的中心体（中心体扩增）。中心体扩增在癌症中经常观察到，通过破坏基因组促进肿瘤的发展。核仁磷酸蛋白（NPM/B23）是 CDK2-细胞周期蛋白 E 起始中心体复制的磷酸化靶标之一。已经发现 CDK2-细胞周期蛋白 E 磷酸化的 NPM/B23 在 Thr199 上获得与 ROCK II 激酶的高结合亲和力。Thr199 磷酸化的 NPM/B23 与定位于中心体的 ROCK II 相互作用并超激活，这是中心体开始复制的关键事件。在这里，我们提供了直接证据，证明 ROCK II 的激活是 CDK2-细胞周期蛋白 E 为中心体复制起始和中心体扩增诱导的主要和充分的下游事件。
