Laoukili Jamila, Alvarez-Fernandez Monica, Stahl Marie, Medema René H
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.
Cell Cycle. 2008 Sep 1;7(17):2720-6. doi: 10.4161/cc.7.17.6580. Epub 2008 Sep 10.
The Forkhead transcription factor FoxM1 is required for the timely expression of many mitotic regulators, such as Cyclin B, Plk1, Aurora B and Cdc25B.(1-3) For this, FoxM1 is specifically activated in G(2) phase through Cyclin A/cdk2-dependent phosphorylation.(4-6) However, it is currently unclear how FoxM1 activity is removed as cells complete mitosis, and need to shut down expression of the mitotic regulators that are transcriptional targets of FoxM1. Here, we demonstrate that FoxM1 is actively degraded during exit from mitosis by the APC/C. We find that FoxM1 degradation requires Cdh1, a known co-factor for APC/C that is responsible for degradation of many mitotic regulators from anaphase until early G(1). FoxM1 binds to Cdh1, and FoxM1 degradation involves both D- and KEN-boxes present in the N-terminal part of FoxM1. Based on these data we propose that Cdh1-dependent degradation of FoxM1 is required to shut down transcriptional activation of mitotic regulators during exit from mitosis.
叉头转录因子FoxM1是许多有丝分裂调节因子（如细胞周期蛋白B、Plk1、Aurora B和Cdc25B）及时表达所必需的。（1 - 3）为此，FoxM1在G2期通过细胞周期蛋白A/cdk2依赖性磷酸化被特异性激活。（4 - 6）然而，目前尚不清楚随着细胞完成有丝分裂，FoxM1的活性是如何被消除的，并且细胞需要关闭作为FoxM1转录靶标的有丝分裂调节因子的表达。在这里，我们证明FoxM1在有丝分裂退出过程中被APC/C主动降解。我们发现FoxM1的降解需要Cdh1，Cdh1是APC/C的一个已知辅助因子，负责从后期到G1早期许多有丝分裂调节因子的降解。FoxM1与Cdh1结合，并且FoxM1的降解涉及FoxM1 N端部分存在 的D盒和KEN盒。基于这些数据，我们提出有丝分裂退出过程中需要Cdh1依赖性降解FoxM1来关闭有丝分裂调节因子的转录激活。
