Department of Cellular and Molecular Medicine, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
J Cell Biol. 2011 Oct 17;195(2):231-43. doi: 10.1083/jcb.201107086. Epub 2011 Oct 10.
Centriole duplication is a tightly regulated process that must occur only once per cell cycle; otherwise, supernumerary centrioles can induce aneuploidy and tumorigenesis. Plk4 (Polo-like kinase 4) activity initiates centriole duplication and is regulated by ubiquitin-mediated proteolysis. Throughout interphase, Plk4 autophosphorylation triggers its degradation, thus preventing centriole amplification. However, Plk4 activity is required during mitosis for proper centriole duplication, but the mechanism stabilizing mitotic Plk4 is unknown. In this paper, we show that PP2A (Protein Phosphatase 2A(Twins)) counteracts Plk4 autophosphorylation, thus stabilizing Plk4 and promoting centriole duplication. Like Plk4, the protein level of PP2A's regulatory subunit, Twins (Tws), peaks during mitosis and is required for centriole duplication. However, untimely Tws expression stabilizes Plk4 inappropriately, inducing centriole amplification. Paradoxically, expression of tumor-promoting simian virus 40 small tumor antigen (ST), a reported PP2A inhibitor, promotes centrosome amplification by an unknown mechanism. We demonstrate that ST actually mimics Tws function in stabilizing Plk4 and inducing centriole amplification.
中心体复制是一个受到严格调控的过程，每个细胞周期只能进行一次；否则，多余的中心体可能导致非整倍体和肿瘤发生。Plk4（Polo 样激酶 4）的活性启动中心体复制，并受到泛素介导的蛋白水解调控。在整个间期，Plk4 的自身磷酸化触发其降解，从而防止中心体扩增。然而，Plk4 的活性在有丝分裂期间对于正确的中心体复制是必需的，但稳定有丝分裂 Plk4 的机制尚不清楚。在本文中，我们表明 PP2A（蛋白磷酸酶 2A(Twins)）拮抗 Plk4 的自身磷酸化，从而稳定 Plk4 并促进中心体复制。与 Plk4 一样，PP2A 的调节亚基 Twins（Tws）的蛋白水平在有丝分裂期间达到峰值，并且是中心体复制所必需的。然而，Tw 不恰当地表达会使 Plk4 稳定，导致中心体扩增。矛盾的是，肿瘤促进的猴病毒 40 小肿瘤抗原（ST）的表达通过未知机制促进中心体扩增。我们证明 ST 实际上模拟了 Tws 在稳定 Plk4 和诱导中心体扩增方面的功能。
