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Fig. 7. A model to illustrate the cell cycle-dependent regulation of FOXM1c function. (A) Location of the PGS331P and PGS704P ERK1/2 phosphorylation sites (shown in red circles). The 331 motif within exon Va (yellow) is close to the DNA binding domain (DBD, red) and a putative NLS (sequence of the NLS is provided in Fig. S2 of the supplementary material). The 704 motif is in close proximity to the Cdk phosphorylation sites (green circles) identified within the transactivating domain (TAD, violet). (B) During late S phase, the Raf/MEK/MAPK pathway phosphorylates FOXM1 and stimulates its nuclear translocation and transactivating activity. Active cyclin-Cdk2 (Cyclin E/A-Cdk2) phosphorylates FOXM1 at the Cdk1/2 phosphorylation sites within the TAD. This promotes recruitment of p300/CBP and transcription of FOXM1 target genes like cyclin B1 and Cdc25B. Cdk1 becomes activated by binding of cyclin B1 and dephosphorylation by Cdc25B. Active cyclin B1-Cdk1 phosphorylates FOXM1 and further promotes transcription of cyclin B1 and Cdc25B. This positive-feedback loop produces a burst of cyclin B1-Cdk1 activity to drive the cell into mitosis.





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