Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.
Mol Cell Biol. 2012 Jun;32(11):2099-109. doi: 10.1128/MCB.06316-11. Epub 2012 Mar 26.
Temporal changes in transcription programs are coupled to control of cell growth and division. We here report that Mediator, a conserved coregulator of eukaryotic transcription, is part of a regulatory pathway that controls mitotic entry in fission yeast. The Mediator subunit cyclin-dependent kinase 8 (Cdk8) phosphorylates the forkhead 2 (Fkh2) protein in a periodic manner that coincides with gene activation during mitosis. Phosphorylation prevents degradation of the Fkh2 transcription factor by the proteasome, thus ensuring cell cycle-dependent variations in Fkh2 levels. Interestingly, Cdk8-dependent phosphorylation of Fkh2 controls mitotic entry, and mitotic entry is delayed by inactivation of the Cdk8 kinase activity or mutations replacing the phosphorylated serine residues of Fkh2. In addition, mutations in Fkh2, which mimic protein phosphorylation, lead to premature mitotic entry. Therefore, Fkh2 regulates not only the onset of mitotic transcription but also the correct timing of mitotic entry via effects on the Wee1 kinase. Our findings thus establish a new pathway linking the Mediator complex to control of mitotic transcription and regulation of mitotic entry in fission yeast.
转录程序的时空调控与细胞生长和分裂的控制相关。我们在此报告，真核转录的保守共调节因子 Mediator 是控制有丝分裂酵母进入有丝分裂的调节途径的一部分。Mediator 亚基周期蛋白依赖性激酶 8（Cdk8）周期性地磷酸化叉头框 2（Fkh2）蛋白，这与有丝分裂期间基因激活相吻合。磷酸化防止了蛋白酶体对 Fkh2 转录因子的降解，从而确保了 Fkh2 水平在细胞周期中的变化。有趣的是，Cdk8 依赖性 Fkh2 磷酸化控制有丝分裂进入，而 Cdk8 激酶活性失活或取代 Fkh2 磷酸化丝氨酸残基的突变会延迟有丝分裂进入。此外，模拟蛋白质磷酸化的 Fkh2 突变会导致过早的有丝分裂进入。因此，Fkh2 通过对 Wee1 激酶的影响，不仅调节有丝分裂转录的开始，还调节有丝分裂进入的正确时间。我们的发现因此建立了一个新的途径，将 Mediator 复合物与有丝分裂转录的控制和有丝分裂酵母进入的调节联系起来。
