FOXM1c is activated by cyclin E/Cdk2, cyclin A/Cdk2, and cyclin A/Cdk1, but repressed by GSK-3alpha.
Two different inhibitory domains, N-terminus and central domain, keep FOXM1c almost inactive despite its strong transactivation domain. Here, we demonstrate that cyclin E/Cdk2, cyclin A/Cdk2, and cyclin A/Cdk1 activate FOXM1c. Cyclin E/Cdk2 does not target its transactivation domain or its DNA-binding domain. Instead, its activating effect strictly depends on the presence of either the central domain or the N-terminus of FOXM1c and thus is completely lost if both inhibitory domains are deleted. Cyclin E/Cdk2 activates FOXM1c by releasing its transactivation domain from the repression by these two inhibitory domains. However, it does not directly increase the transactivation potential of the TAD. The DNA-binding is not affected by cyclin E/Cdk2, neither directly nor indirectly. These two activating effects of cyclin E/Cdk2 via central domain and N-terminus are additive. Cyclin A/Cdk2 and cyclin A/Cdk1 show similar characteristics. GSK-3alpha, another proliferation-associated kinase, represses FOXM1c.
Wierstra
Inken
I
Institute of Molecular Biology, Medical School Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. iwiwiwi@web.de
Alves
Jürgen
J
D019925:Cyclin A / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D015533:Transcriptional Activation
D019925:Cyclin A; D019927:Cyclin E; D004268:DNA-Binding Proteins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D051357:Cyclin-Dependent Kinase 2; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha