Cdk2 and Cdk4 Regulate the Centrosome Cycle and Are Critical Mediators of Centrosome Amplification in p53-Null Cells
Cdk2 and Cdk4 Regulate the Centrosome Cycle and Are Critical Mediators of Centrosome Amplification in p53-Null Cells
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DOI：
10.1128/mcb.00253-09
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发表时间：
2010-02-01
影响因子：
5.3
通讯作者：
Saavedra, Harold I.
中科院分区：
文献类型：
--
作者：
Adon, Arsene M.;Zeng, Xiangbin;Saavedra, Harold I.
有丝分裂的两个中心体指导纺锤体的双极性以维持整倍性。中心体扩增-获得>= 3个中心体-产生多极有丝分裂、非整倍体和染色体不稳定性以促进癌症生物发生。虽然许多证据表明Cdk 2是中心体周期的主要导体，并且它介导由各种改变的肿瘤抑制因子诱导的中心体扩增，但Cdk 4在正常或失调的中心体周期中所起的作用尚不清楚。使用基因敲除的方法，我们报告说，Cdk 2和Cdk 4的中心体周期是至关重要的，因为中心体分离和复制是过早的Cdk 2（-/-）小鼠胚胎成纤维细胞（MEFs）和Cdk 4（-/-）MEFs受到损害。此外，Cdk 4或Cdk 2的消融消除了p53无效MEFs中的中心体扩增和染色体不稳定性。Cdk 2或Cdk 4的缺失通过消除过度的中心粒复制来阻止中心体扩增。此外，过度活跃的Cdk 2和Cdk 4通过过度磷酸化Thr 199处的核磷蛋白（NPM）来解除p53缺失细胞中中心体复制周期的许可，如观察到Cdk 2、Cdk 4或Cdk 2和Cdk 4两者的消融消除了过度磷酸化所证明的。由于缺乏G（1）Cdk磷酸化位点的NPM突变体（NPMT 199 A）阻止中心体扩增的程度与Cdk 2或Cdk 4的消融相同，我们得出结论，Cdk 2/Cdk 4/NPM途径是中心体功能障碍和基因组完整性的主要监护人。
The two mitotic centrosomes direct spindle bipolarity to maintain euploidy. Centrosome amplification-the acquisition of >= 3 centrosomes-generates multipolar mitoses, aneuploidy, and chromosome instability to promote cancer biogenesis. While much evidence suggests that Cdk2 is the major conductor of the centrosome cycle and that it mediates centrosome amplification induced by various altered tumor suppressors, the role played by Cdk4 in a normal or deregulated centrosome cycle is unknown. Using a gene knockout approach, we report that Cdk2 and Cdk4 are critical to the centrosome cycle, since centrosome separation and duplication are premature in Cdk2(-/-)mouse embryonic fibroblasts (MEFs) and are compromised in Cdk4(-/-) MEFs. Additionally, ablation of Cdk4 or Cdk2 abrogates centrosome amplification and chromosome instability in p53-null MEFs. Absence of Cdk2 or Cdk4 prevents centrosome amplification by abrogating excessive centriole duplication. Furthermore, hyperactive Cdk2 and Cdk4 deregulate the licensing of the centrosome duplication cycle in p53-null cells by hyperphosphorylating nucleophosmin (NPM) at Thr199, as evidenced by observations that ablation of Cdk2, Cdk4, or both Cdk2 and Cdk4 abrogates that excessive phosphorylation. Since a mutant form of NPM lacking the G(1) Cdk phosphorylation site (NPMT199A) prevents centrosome amplification to the same extent as ablation of Cdk2 or Cdk4, we conclude that the Cdk2/Cdk4/NPM pathway is a major guardian of centrosome dysfunction and genomic integrity.