Biomedical Research Institute, School of Medicine, College of Medicine, Dentistry and Nursing, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK.
EMBO J. 2010 Jul 21;29(14):2407-20. doi: 10.1038/emboj.2010.112. Epub 2010 Jun 4.
The balance between cell cycle progression and apoptosis is important for both surveillance against genomic defects and responses to drugs that arrest the cell cycle. In this report, we show that the level of the human anti-apoptotic protein Mcl-1 is regulated during the cell cycle and peaks at mitosis. Mcl-1 is phosphorylated at two sites in mitosis, Ser64 and Thr92. Phosphorylation of Thr92 by cyclin-dependent kinase 1 (CDK1)-cyclin B1 initiates degradation of Mcl-1 in cells arrested in mitosis by microtubule poisons. Mcl-1 destruction during mitotic arrest requires proteasome activity and is dependent on Cdc20/Fizzy, which mediates recognition of mitotic substrates by the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. Stabilisation of Mcl-1 during mitotic arrest by mutation of either Thr92 or a D-box destruction motif inhibits the induction of apoptosis by microtubule poisons. Thus, phosphorylation of Mcl-1 by CDK1-cyclin B1 and its APC/C(Cdc20)-mediated destruction initiates apoptosis if a cell fails to resolve mitosis. Regulation of apoptosis, therefore, is linked intrinsically to progression through mitosis and is governed by a temporal mechanism that distinguishes between normal mitosis and prolonged mitotic arrest.
细胞周期进程与细胞凋亡之间的平衡对于防止基因组缺陷和对阻止细胞周期的药物的反应都很重要。在本报告中，我们表明，人抗凋亡蛋白 Mcl-1 的水平在细胞周期中受到调节，并在有丝分裂时达到峰值。Mcl-1 在有丝分裂中 Ser64 和 Thr92 两个位点被磷酸化。由周期蛋白依赖性激酶 1（CDK1）-周期蛋白 B1 磷酸化 Thr92 启动微管毒物诱导的有丝分裂停滞细胞中 Mcl-1 的降解。Mcl-1 在有丝分裂停滞期间的破坏需要蛋白酶体活性，并且依赖于 Cdc20/Fizzy，它介导着有丝分裂底物被后期促进复合物/环体（APC/C）E3 泛素连接酶识别。通过 Thr92 或 D 盒破坏基序的突变稳定 Mcl-1 在有丝分裂停滞期间，抑制微管毒物诱导的细胞凋亡。因此，如果细胞未能解决有丝分裂，CDK1-周期蛋白 B1 对 Mcl-1 的磷酸化及其 APC/C（Cdc20）介导的破坏会引发细胞凋亡。因此，细胞凋亡的调节与有丝分裂进程内在相关，并且受到一个时间机制的控制，该机制可以区分正常有丝分裂和延长的有丝分裂停滞。
