Cyclin D1/Cdk4 increases the transcriptional activity of FOXM1c without phosphorylating FOXM1c.
Anders et al. (2011) [11] reported that cyclinD1/Cdk4 and cyclinD3/Cdk6 enhance the transcriptional activity of FOXM1c by phosphorylating its TAD. They defined 12 Cdk consensus sites as essential for the activation of FOXM1c by cyclinD1/Cdk4 and cyclinD3/Cdk6 and stated that the 12 Cdk-sites are positioned within the TAD of FOXM1c. In contrast, this study demonstrates that all potential cyclin/Cdk phosphorylation sites S/T-P of FOXM1c are located outside its TAD so that the TAD of FOXM1c contains no potential cyclin/Cdk site, which excludes a phosphorylation of the FOXM1c-TAD by cyclinD1/Cdk4 and cyclinD3/Cdk6. This study shows that the activation of FOXM1c by cyclinD1/Cdk4 is lost without removal of any cyclin/Cdk site and gained without addition of any cyclin/Cdk site because it depends on a FOXM1c domain with no potential cyclin/Cdk site, namely on the interaction domain for the tumor suppressor RB, which binds to and represses FOXM1c. CyclinD1/Cdk4 activates FOXM1c because cyclinD1/Cdk4 releases FOXM1c from its repression by RB through removal of RB from FOXM1c. For this purpose, cyclinD1/Cdk4 phosphorylates only RB, but not FOXM1c, so that cyclinD1/Cdk4 increases the transcriptional activity of FOXM1c without phosphorylating FOXM1c and activates FOXM1c independently of cyclin/Cdk phosphorylation sites in FOXM1c. In summary, this study changes the model of Anders et al. (2011) [11] completely because it disproves their central conclusion that cyclinD1/Cdk4 and cyclinD3/Cdk6 enhance the transcriptional activity of FOXM1c by phosphorylating its TAD at the 12 Cdk-sites.
['Wierstra|Inken|I|']
D002460:Cell Line D019938:Cyclin D1 D051358:Cyclin-Dependent Kinase 4 D000072278:Forkhead Box Protein M1 D051858:Forkhead Transcription Factors D006801:Humans D010766:Phosphorylation D017434:Protein Structure, Tertiary D016160:Retinoblastoma Protein D014158:Transcription, Genetic
Cdk4 Transcription CyclinD1 RB Cell cycle FOXM1