p53-driven apoptosis limits centrosome amplification and genomic instability downstream of NPM1 phosphorylation
p53-driven apoptosis limits centrosome amplification and genomic instability downstream of NPM1 phosphorylation
复制标题
DOI：
10.1038/ncb1735
复制
发表时间：
2008-06-01
影响因子：
21.3
通讯作者：
Mittnacht, Sibylle
中科院分区：
文献类型：
--
作者：
Cuomo, Maria Emanuela;Knebel, Axel;Mittnacht, Sibylle
染色体的丢失或获得与大量实体癌有关，从而提供基因组可塑性，从而适应癌细胞(1，2)。中心体过度复制或胞质分裂失败引起的数字中心体异常是非整倍体的公认原因(3，4)。在高等真核细胞中，中心体在每个细胞周期中只复制一次，以确保形成一个两极有丝分裂纺锤体，该纺锤体协调姐妹染色单体到各自的子细胞的平衡分布(5)。在这里，我们描述了允许异常中心体复制，导致有丝分裂错误和细胞周期蛋白依赖激酶(CDK)持续活性的不正确染色体分离的事件。我们已经确定NPM1是由Kaposi肉瘤疱疹病毒(KSHV)D型周期蛋白激活的CDK6的底物，并表明p53驱动的细胞凋亡发生在NPM1磷酸化的下游，作为一种检查点机制，防止具有多余中心体的细胞积累。我们的发现提供了证据，证明KSHV感染细胞中的异常染色体分离是NPM1磷酸化的直接结果，并预测基因组不稳定是KSHV潜伏感染的必然结果。
Chromosome loss or gain is associated with a large number of solid cancers, providing genomic plasticity and thus adaptability to cancer cells(1,2). Numerical centrosome abnormalities arising from centrosome over-duplication or failed cytokinesis are a recognized cause of aneuploidy(3,4). In higher eukaryotic cells, the centrosome duplicates only once per cell cycle to ensure the formation of a bipolar mitotic spindle that orchestrates the balanced distribution of the sister chromatids to the respective daughter cells(5). Here we delineate the events that allow abnormal centrosome duplication, resulting in mitotic errors and incorrect chromosome segregation in cells with sustained cyclin-dependent kinase (CDK) activity. We have identified NPM1 as a substrate for CDK6 activated by the Kaposi's sarcoma herpesvirus (KSHV) D-type cyclin and shown that p53-driven apoptosis occurs downstream of NPM1 phosphorylation as a checkpoint mechanism that prevents accumulation of cells with supernumerary centrosomes. Our findings provide evidence that abnormal chromosome segregation in KSHV-infected cells is a direct consequence of NPM1 phosphorylation and predict that genomic instability is an inevitable consequence of latent KSHV infection.