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Molecular and Cellular Biology, December 2005, p. 10875-10894, Vol. 25, No. 24
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.24.10875-10894.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Forkhead Box M1 Regulates the Transcriptional Network of Genes Essential for Mitotic Progression and Genes Encoding the SCF (Skp2-Cks1) Ubiquitin Ligase

I-Ching Wang, Yi-Ju Chen,{dagger} Douglas Hughes,{dagger} Vladimir Petrovic,{dagger} Michael L. Major, Hyung Jung Park, Yongjun Tan, Timothy Ackerson, and Robert H. Costa*

Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, Chicago, Illinois 60607

Received 20 June 2005/ Returned for modification 18 August 2005/ Accepted 26 September 2005

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-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 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-passage Foxm1–/– MEFs display premature senescence as evidenced by high expression of the senescence-associated ß-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.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois at Chicago, College of Medicine, 900 S. Ashland Ave., MBRB Rm. 2220, Chicago, IL 60607-7170. Phone: (312) 996-0474. Fax: (312) 355-4010. E-mail: Robcosta{at}uic.edu.

{dagger} Y.-J.C., D.H., and V.P. contributed equally to the work.

Molecular and Cellular Biology, December 2005, p. 10875-10894, Vol. 25, No. 24
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.24.10875-10894.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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