FIG. 8.

Model for Cdk-cyclin-mediated stimulation of FoxM1B-dependent transcription. FoxM1B transcriptional activity is restricted to proliferating cells through interaction with and phosphorylation by the Cdk-cyclin complexes. Activated Cdk2-cyclin E or A or Cdk1-cyclin B complexes phosphorylate FoxM1B Thr 596, which is required for the recruitment of CBP for FoxM1B transcriptional activation. FoxM1B transcriptional activity requires binding of Cdk1-cyclin B or Cdk2-cyclin E/A complexes through the FoxM1B LXL motif, which mediates efficient phosphorylation of the FoxM1B Cdk site at position 596. Furthermore, FoxM1B interacts with RB at the G₁ phase of the cell cycle, and RB thus may negatively regulate FoxM1B transcriptional activity. We have previously demonstrated that FoxM1B is essential for transcription of the Cdc25B phosphatase gene (59), which is required for dephosphorylation and activation of Cdk1 protein (7, 41, 62). Taken together, these data establish a positive regulatory loop between FoxM1B, Cdc25B, and Cdk1.