Forester Craig M, Maddox Jessica, Louis Justin V, Goris Jozef, Virshup David M
Department of Oncological Sciences and Center for Children, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19867-72. doi: 10.1073/pnas.0709879104. Epub 2007 Dec 4.
Inactivation of maturation-promoting factor [(MPF) Cdk1/Cyclin B] is a key event in the exit from mitosis. Although degradation of Cyclin B is important for MPF inactivation, recent studies indicate that Cdk1 phosphorylation and inactivation occur before Cyclin B degradation and, therefore, also may be important steps in the exit from mitosis. Cdk1 activity is controlled by the Cdc25C phosphatase, which is turned on at the G(2)/M transition to catalyze Cdk1 activation. PP2A:B56delta is a negative regulator of Cdc25C during interphase. We show here that PP2A:B56delta also regulates Cdc25C at mitosis. Failure of PP2A:B56delta to dephosphorylate Cdc25C at mitosis results in prolonged hyperphosphorylation and activation of Cdc25C, causing persistent dephosphorylation and, hence, activation of Cdk1. This constitutive activation of Cdc25C and Cdk1 leads to a delayed exit from mitosis. Consistent with Cdk1 as a major biological target of B56delta, stable knockdown and germ-line mouse KO of B56delta leads to compensatory transcriptional up-regulation of Wee1 kinase to oppose the Cdc25C activity and permit cell survival. These observations place PP2A:B56delta as a key upstream regulator of Cdk1 activity upon exit from mitosis.
成熟促进因子[（MPF）Cdk1/细胞周期蛋白B]的失活是有丝分裂退出过程中的关键事件。虽然细胞周期蛋白B的降解对MPF失活很重要，但最近的研究表明，Cdk1磷酸化和失活发生在细胞周期蛋白B降解之前，因此也可能是有丝分裂退出过程中的重要步骤。Cdk1活性受Cdc25C磷酸酶控制，该酶在G(2)/M期转换时被激活以催化Cdk1活化。PP2A:B56δ在间期是Cdc25C的负调节因子。我们在此表明，PP2A:B56δ在有丝分裂期间也调节Cdc25C。PP2A:B56δ在有丝分裂时不能使Cdc25C去磷酸化，导致Cdc25C持续过度磷酸化并活化，引起Cdk1持续去磷酸化并因此活化。Cdc25C和Cdk1的这种组成性活化导致有丝分裂退出延迟。与Cdk1作为B56δ的主要生物学靶点一致，B56δ的稳定敲低和种系小鼠敲除导致Wee1激酶的代偿性转录上调，以对抗Cdc25C活性并允许细胞存活。这些观察结果表明PP2A:B56δ是有丝分裂退出时Cdk1活性的关键上游调节因子。
