Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase.
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.
Wang
I-Ching
IC
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, 60607-7170, USA.
Chen
Yi-Ju
YJ
Hughes
Douglas
D
Petrovic
Vladimir
V
Major
Michael L
ML
Park
Hyung Jung
HJ
Tan
Yongjun
Y
Ackerson
Timothy
T
Costa
Robert H
RH
D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001324:Autoantigens / Q000032:analysis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002467:Cell Nucleus / Q000737:chemistry; D000076247:Centromere Protein A; D051936:Centromere Protein B / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D015536:Down-Regulation; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005796:Genes / Q000235:genetics; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008938:Mitosis / Q000235:genetics*; D009154:Mutation; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases / Q000235:genetics
D001324:Autoantigens; C000619700:CENPA protein, human; C497926:CENPB protein, human; D018797:Cell Cycle Proteins; C000619701:Cenpa protein, mouse; D000076247:Centromere Protein A; D051936:Centromere Protein B; D002868:Chromosomal Proteins, Non-Histone; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D044843:SKP Cullin F-Box Protein Ligases; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases