PDF(Pubmed)
Abstract：
Centrosome amplification is a hallmark of cancer and PLK4 is one of the responsible factors for cancer associated centrosome amplification. Increased PLK4 levels was also shown to contribute to generation of cells with centriole amplification in mammalian tissues as olfactory neuron progenitor cells. PLK4 overexpression generates centriole rosette (CR) structures which harbor more than two centrioles each. Long term PLK4 overexpression results with centrosome amplification, but the maturation of amplified centrioles in CRs and linking of PLK4 induced amplified centrosomes has not yet been investigated in detail. Here, we show evidence for generation of large clustered centrosomes which have more than 2 centriole rosettes and define these structures as centriole rosette clusters (CRCs) in cells that have high PLK4 levels for 2 consecutive cell cycles. In addition, we show that PLK4 induced CRs follow normal centrosomal maturation processes and generate CRC structures that are inter-connected with canonical centrosomal linker proteins as C-Nap1, Rootletin and Cep68 in the second cell cycle after PLK4 induction. Increased PLK4 levels in cells with C-Nap1 and Rootletin knock-out resulted with distanced CRs and CRCs in interphase, while Nek2 knock-out inhibited separation of CRCs in prometaphase, providing functional evidence for the binding of CRC structures with centrosomal linker proteins. Taken together, these results suggest a cell cycle dependent model for PLK4 induced centrosome amplification which occurs in 2 consecutive cell cycles: (i) CR state in the first cell cycle, and (ii) CRC state in the second cell cycle.
摘要：
中心体扩增是癌症的标志,并且PLK4是癌症相关中心体扩增的负责因素之一。还显示增加的PLK4水平有助于在哺乳动物组织中产生具有中心粒扩增的细胞作为嗅觉神经元祖细胞。PLK4过表达产生中心粒玫瑰花结(CR)结构,其每个具有多于两个中心粒。长期PLK4过表达结果与中心体扩增，但是尚未详细研究CRs中扩增中心粒的成熟和PLK4诱导的扩增中心体的连接。这里,我们显示了产生具有2个以上中心粒玫瑰花结的大型簇状中心体的证据,并将这些结构定义为在2个连续细胞周期中具有高PLK4水平的细胞中的中心粒玫瑰花结簇(CRC).此外,我们显示PLK4诱导的CRs遵循正常的中心体成熟过程，并在PLK4诱导后的第二个细胞周期中产生与规范的中心体连接蛋白C-Nap1，Rootletin和Cep68相互连接的CRC结构。C-Nap1和Rootletin敲除导致细胞中PLK4水平增加，而Nek2敲除抑制前中期CRC的分离，提供CRC结构与中心体连接蛋白结合的功能证据。一起来看,这些结果表明了PLK4诱导的中心体扩增的细胞周期依赖性模型，该模型发生在2个连续的细胞周期中：（i）第一个细胞周期中的CR状态，和(ii)第二细胞周期中的CRC状态。
