Identification of a Polo-like Kinase 4-Dependent Pathway for De Novo Centriole Formation
Identification of a Polo-like Kinase 4-Dependent Pathway for De Novo Centriole Formation
复制标题
DOI：
10.1016/j.cub.2011.01.072
复制
发表时间：
2011-03-08
期刊：
影响因子：
9.2
通讯作者：
Maller, James L.
中科院分区：
文献类型：
--
作者：
Eckerdt, Frank;Yamamoto, Tomomi M.;Maller, James L.
额外中心体是癌细胞中基因组不稳定的关键原因[1]。新的中心粒可以通过与母中心粒作为平台的复制产生，或者在没有预先存在的中心粒的情况下，通过从头形成[2]。Polo样激酶4（Plk 4）调节中心粒生物发生的两种模式，Plk 4失调与肿瘤发生有关[1，3]。我们发现，Plx 4，非洲爪蟾同源哺乳动物Plk 4和果蝇Sak，诱导从头中心粒形成在体内激活的卵母细胞和卵提取物中，但不是在未成熟或体外成熟的卵母细胞。Plx 4的激酶活性和polo box结构域都是从头中心粒生物发生所必需的。在“循环”卵提取物的偏光显微镜表明，从头中心粒的形成是独立的Cdk 2活性，一个主要的区别相比，模板驱动的中心体复制，是与核周期，需要cyclinA/E/Cdk 2。此外，我们表明，Mos-MAPK通路阻断Plx 4依赖的从头中心粒形成受精前，从而确保父系遗传的中心体。这些结果为研究从头中心粒形成和中心粒生物发生的生化和分子基础提供了一个新的体系。
Supernumerary centrosomes are a key cause of genomic instability in cancer cells [1]. New centrioles can be generated by duplication with a mother centriole as a platform or, in the absence of preexisting centrioles, by formation de novo [2]. Polo-like kinase 4 (Plk4) regulates both modes of centriole biogenesis, and Plk4 deregulation has been linked to tumor development [1, 3]. We show that Plx4, the Xenopus homolog of mammalian Plk4 and Drosophila Sak, induces de novo centriole formation in vivo in activated oocytes and in egg extracts, but not in immature or in vitro matured oocytes. Both kinase activity and the polo-box domain of Plx4 are required for de novo centriole biogenesis. Polarization microscopy in "cycling" egg extracts demonstrates that de novo centriole formation is independent of Cdk2 activity, a major difference compared to template-driven centrosome duplication that is linked to the nuclear cycle and requires cyclinA/E/Cdk2. Moreover, we show that the Mos-MAPK pathway blocks Plx4-dependent de novo centriole formation before fertilization, thereby ensuring paternal inheritance of the centrosome. The results define a new system for studying the biochemical and molecular basis of de novo centriole formation and centriole biogenesis in general.