Mailand Niels, Podtelejnikov Alexandre V, Groth Anja, Mann Matthias, Bartek Jiri, Lukas Jiri
Danish Cancer Society, Institute of Cancer Biology, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark
EMBO J. 2002 Nov 1;21(21):5911-20. doi: 10.1093/emboj/cdf567.
DNA replication in higher eukaryotes requires activation of a Cdk2 kinase by Cdc25A, a labile phosphatase subject to further destabilization upon genotoxic stress. We describe a distinct, markedly stable form of Cdc25A, which plays a previously unrecognized role in mitosis. Mitotic stabilization of Cdc25A reflects its phosphorylation on Ser17 and Ser115 by cyclin B-Cdk1, modifications required to uncouple Cdc25A from its ubiquitin-proteasome-mediated turnover. Cdc25A binds and activates cyclin B-Cdk1, accelerates cell division when overexpressed, and its downregulation by RNA interference (RNAi) delays mitotic entry. DNA damage-induced G(2) arrest, in contrast, is accompanied by proteasome-dependent destruction of Cdc25A, and ectopic Cdc25A abrogates the G(2) checkpoint. Thus, phosphorylation-mediated switches among three differentially stable forms ensure distinct thresholds, and thereby distinct roles for Cdc25A in multiple cell cycle transitions and checkpoints.
高等真核生物中的DNA复制需要Cdc25A激活Cdk2激酶，Cdc25A是一种不稳定的磷酸酶，在遗传毒性应激下会进一步不稳定。我们描述了一种独特的、明显稳定的Cdc25A形式，它在有丝分裂中发挥了以前未被认识到的作用。Cdc25A在有丝分裂中的稳定反映了其被细胞周期蛋白B-Cdk1在Ser17和Ser115位点磷酸化，这些修饰是使Cdc25A与其泛素-蛋白酶体介导的周转解偶联所必需的。Cdc25A结合并激活细胞周期蛋白B-Cdk1，过表达时加速细胞分裂，通过RNA干扰（RNAi）下调它会延迟有丝分裂的进入。相反，DNA损伤诱导的G2期阻滞伴随着蛋白酶体依赖性的Cdc25A破坏，异位表达的Cdc25A会消除G2期检查点。因此，磷酸化介导的三种不同稳定形式之间的转换确保了不同的阈值，从而使Cdc25A在多个细胞周期转换和检查点中发挥不同的作用。
