The Forkhead box m1 (Foxm1) gene is critical for G(1)/S transition and essential 
for mitotic progression. However, the transcriptional mechanisms downstream of 
FoxM1 that control these cell cycle events remain to be determined. Here, we 
show that both early-passage Foxm1(-)(/)(-) mouse embryonic fibroblasts (MEFs) 
and human osteosarcoma U2OS cells depleted of FoxM1 protein by small interfering 
RNA fail to grow in culture due to a mitotic block and accumulate nuclear levels 
of cyclin-dependent kinase inhibitor (CDKI) proteins p21(Cip1) and p27(Kip1). 
Using quantitative chromatin immunoprecipitation and expression assays, we show 
that FoxM1 is essential for transcription of the mitotic regulatory genes 
Cdc25B, Aurora B kinase, survivin, centromere protein A (CENPA), and CENPB. We 
also identify the mechanism by which FoxM1 deficiency causes elevated nuclear 
levels of the CDKI proteins p21(Cip1) and p27(Kip1). We provide evidence that 
FoxM1 is essential for transcription of Skp2 and Cks1, which are specificity 
subunits of the Skp1-Cullin 1-F-box (SCF) ubiquitin ligase complex that targets 
these CDKI proteins for degradation during the G(1)/S transition. Moreover, 
early-passage Foxm1(-)(/)(-) MEFs display premature senescence as evidenced by 
high expression of the senescence-associated beta-galactosidase, p19(ARF), and 
p16(INK4A) proteins. Taken together, these results demonstrate that FoxM1 
regulates transcription of cell cycle genes critical for progression into 
S-phase and mitosis.