Control of mitotic exit by PP2A regulation of Cdc25C and Cdk1
Control of mitotic exit by PP2A regulation of Cdc25C and Cdk1
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DOI：
10.1073/pnas.0709879104
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发表时间：
2007-12-11
影响因子：
11.1
通讯作者：
Virshup, David M.
中科院分区：
文献类型：
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作者：
Forester, Craig M.;Maddox, Jessica;Virshup, David M.
成熟促进因子（MPF） Cdk1/Cyclin B的失活是有丝分裂退出的关键事件。尽管Cyclin B的降解对于MPF失活很重要，但最近的研究表明，Cdk1磷酸化和失活发生在Cyclin B降解之前，因此，也可能是有丝分裂退出的重要步骤。Cdk1活性由Cdc25C磷酸酶控制，该酶在G(2)/M转化时开启以催化Cdk1激活。PP2A:B56 δ是间期Cdc25C的负调节因子。我们在这里显示PP2A:B56 δ也在有丝分裂时调节Cdc25C。MA:113566在有丝分裂时不能使Cdc25C去磷酸化，导致Cdc25C长时间的过度磷酸化和激活，从而引起持续的去磷酸化，从而激活Cdk1。Cdc25C和Cdk1的这种组成性激活导致有丝分裂的延迟退出。与Cdk1作为B56 delta的主要生物学靶点一致，B56 delta的稳定敲低和种系小鼠KO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:B56 delta是有丝分裂退出后Cdk1活性的关键上游调节因子。
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:B56 delta is a negative regulator of Cdc25C during interphase. We show here that PP2A:B56 delta also regulates Cdc25C at mitosis. Failure of MA:113566 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 B56 delta, stable knockdown and germ-line mouse KO of B56 delta leads to compensatory transcriptional up-regulation of Wee1 kinase to oppose the Cdc25C activity and permit cell survival. These observations place PP2A:B56 delta as a key upstream regulator of Cdk1 activity upon exit from mitosis.