Open AccessForkhead Box M1 Regulates the Transcriptional Network of Genes Essential for Mitotic Progression and Genes Encoding the SCF (Skp2-Cks1) Ubiquitin Ligase
Author(s) -
IChing Wang,
YiJu Chen,
Douglas E. Hughes,
Vladimír Petrovič,
Michael L. Major,
Hyung Jung Park,
Yongjun Tan,
Timothy Ackerson,
Robert H. Costa
Publication year - 2005
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.25.24.10875-10894.2005
Subject(s) - biology , ubiquitin ligase , plk1 , cell division control protein 4 , skp2 , microbiology and biotechnology , foxm1 , chromatin immunoprecipitation , mitosis , cell cycle , cancer research , gene expression , gene , genetics , ubiquitin , promoter
The Forkhead box m1 (Foxm1 ) gene is critical for G1 /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-passageFoxm1 − / − 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 p21Cip1 and p27Kip1 . 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 p21Cip1 and p27Kip1 . 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 G1 /S transition. Moreover, early-passageFoxm1 − / − MEFs display premature senescence as evidenced by high expression of the senescence-associated β-galactosidase, p19ARF , and p16INK4A proteins. Taken together, these results demonstrate that FoxM1 regulates transcription of cell cycle genes critical for progression into S-phase and mitosis.