Cdk1 is sufficient to drive the mammalian cell cycle
Cdk1 is sufficient to drive the mammalian cell cycle
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DOI：
10.1038/nature06046
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发表时间：
2007-08-16
期刊：
影响因子：
64.8
通讯作者：
Barbacid, Mariano
中科院分区：
文献类型：
--
作者：
Santamaria, David;Barriere, Cedric;Barbacid, Mariano
单细胞生物如酵母需要一个单一的细胞周期蛋白依赖性激酶Cdk 1来驱动细胞分裂（1）。相比之下，哺乳动物细胞被认为需要至少四种不同的细胞周期蛋白依赖性激酶Cdk 2、Cdk 3、Cdk 4和Cdk 6的顺序激活，以驱动细胞通过间期，以及Cdk 1通过有丝分裂（2）。最近的遗传学证据表明，小鼠在缺乏单个间期Cdk的情况下存活，这一模型受到了挑战（3-8）。此外，大多数小鼠细胞类型在不存在两个或甚至三个间期Cdk的情况下增殖（8-10）。在Cdk的一些活化亚基（例如D型和E型细胞周期蛋白）的消融上也获得了类似的结果（11-14）.在这里，我们表明，小鼠胚胎缺乏所有间期Cdks（Cdk 2，Cdk 3，Cdk 4和Cdk 6）进行器官发生和发展到妊娠中期。在这些胚胎中，Cdk 1与所有细胞周期蛋白结合，导致视网膜母细胞瘤蛋白pRb磷酸化和E2 F转录因子调控的基因表达。来自这些胚胎的小鼠胚胎成纤维细胞在体外增殖，尽管由于Rb蛋白的无效失活而具有延长的细胞周期。然而，他们在不断的旅行中变得不朽。我们还报告说，胚胎未能发展到桑椹胚和囊胚阶段的Cdk 1的情况下。这些结果表明，Cdk 1是唯一必需的细胞周期Cdk。此外，他们表明，在没有间期Cdks的情况下，Cdk 1可以执行驱动细胞分裂所需的所有事件。
Unicellular organisms such as yeasts require a single cyclin-dependent kinase, Cdk1, to drive cell division(1). In contrast, mammalian cells are thought to require the sequential activation of at least four different cyclin- dependent kinases, Cdk2, Cdk3, Cdk4 and Cdk6, to drive cells through interphase, as well as Cdk1 to proceed through mitosis(2). This model has been challenged by recent genetic evidence that mice survive in the absence of individual interphase Cdks(3-8). Moreover, most mouse cell types proliferate in the absence of two or even three interphase Cdks(8-10). Similar results have been obtained on ablation of some of the activating subunits of Cdks, such as the D- type and E- type cyclins(11-14). Here we show that mouse embryos lacking all interphase Cdks ( Cdk2, Cdk3, Cdk4 and Cdk6) undergo organogenesis and develop to midgestation. In these embryos, Cdk1 binds to all cyclins, resulting in the phosphorylation of the retinoblastoma protein pRb and the expression of genes that are regulated by E2F transcription factors. Mouse embryonic fibroblasts derived from these embryos proliferate in vitro, albeit with an extended cell cycle due to inefficient inactivation of Rb proteins. However, they become immortal on continuous passage. We also report that embryos fail to develop to the morula and blastocyst stages in the absence of Cdk1. These results indicate that Cdk1 is the only essential cell cycle Cdk. Moreover, they show that in the absence of interphase Cdks, Cdk1 can execute all the events that are required to drive cell division.