Cyclin-Dependent Kinase 8 Regulates Mitotic Commitment in Fission Yeast

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 co-incides with gene activation during mitosis. Phosphorylation prevents degradation of the Fkh2 transcription factor by the pro-teasome, thus ensuring cell cycle-dependent variations in Fkh2 levels. Interestingly, Cdk8-dependent phosphorylation of Fkh2 controls mitotic entry, andmitotic entry is delayed by inactivation of the Cdk8 kinase activity or mutations replacing the phos-phorylated 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 theWee1 kinase. Our findings thus establish a new pathway linking theMediator complex to control of mitotic transcription and regulation of mitotic entry in fission yeast. Signaling pathways can control the activation of gene expres-sion programs and thereby regulate cell fate determination. In embryonic stem cells, certain gene expression programs allow the cells to self-renew whereas other programs trigger differentiation into specific cell types as a response to developmental signaling (58). Elucidation of how temporal changes in transcription pro