title: Cyclin D1/Cdk4 increases the transcriptional activity of FOXM1c without phosphorylating FOXM1c.
abstract: 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.
authors: Institute of Molecular Biology, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. iwiwiwi@web.de
authors: Inken
authors: I
authors: Wierstra
mesh_terms: D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D016160:Retinoblastoma Protein / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D016160:Retinoblastoma Protein; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4
keywords: Cdk4; Cell cycle; CyclinD1; FOXM1; RB; Transcription