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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Department of Biochemistry and Molecular Genetics and 2 Toxicology Research Laboratory, Department of Pharmacology, College of Medicine, University of Illinois at Chicago; 3 Charles River Laboratories, Pathology Associates; and 4 Department of Medicine, University of Chicago, Chicago, Illinois
Requests for reprints: Robert H. Costa, Department of Biochemistry and Molecular Genetics (M/C 669), College of Medicine, University of Illinois at Chicago, 900 South Ashland Avenue, MBRB Room 2220, Chicago, IL 60607-7170. Phone: 312-996-0474; Fax: 312-355-4010; E-mail: robcosta{at}uic.edu or Alexander Lyubimov, Toxicology Research Laboratory, Department of Pharmacology (M/C 868), University of Illinois at Chicago, 1940 W. Taylor St., Room 312, Chicago, IL 60612. Phone: 312-996-2123; Fax: 312-996-7755; E-mail: lyubimov{at}uic.edu.
The proliferation-specific Forkhead Box M1 (FoxM1 or FoxM1b) transcription factor is overexpressed in a number of aggressive human carcinomas. Mouse hepatocytes deficient in FoxM1 fail to proliferate and are highly resistant to developing carcinogen-induced liver tumors. We previously developed a transgenic (TG) mouse line in which the ubiquitous Rosa26 promoter was used to drive expression of the human FoxM1b cDNA transgene in all mouse cell types. To investigate the role of FoxM1b in prostate cancer progression, we bred Rosa26-FoxM1b mice with both TRAMP and LADY TG mouse models of prostate cancer. We show that increased expression of FoxM1b accelerated development, proliferation, and growth of prostatic tumors in both TRAMP and LADY double TG mice. Furthermore, development of prostate carcinomas in TRAMP/Rosa26-FoxM1b double TG mice required high levels of FoxM1 protein to overcome sustained expression of the alternative reading frame tumor suppressor, a potent inhibitor of FoxM1 transcriptional activity. Depletion of FoxM1 levels in prostate cancer cell lines PC-3, LNCaP, or DU-145 by small interfering RNA transfection caused significant reduction in proliferation and anchorage-independent growth on soft agar. This phenotype was associated with increased nuclear levels of the cyclin-dependent kinase inhibitor protein p27Kip1 and diminished expression of S-phase promoting cyclin A2 and M-phase promoting cyclin B1 proteins. Finally, we show that elevated levels of FoxM1 protein correlate with high proliferation rates in human prostate adenocarcinomas. Our results suggest that the FoxM1 transcription factor regulates development and proliferation of prostate tumors, and that FoxM1 is a novel target for prostate cancer treatment. Cancer Res 2006; 66(3): 1712-20
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 H. J. Park, R. H. Costa, L. F. Lau, A. L. Tyner, and P. Raychaudhuri Anaphase-Promoting Complex/Cyclosome-Cdh1-Mediated Proteolysis of the Forkhead Box M1 Transcription Factor Is Critical for Regulated Entry into S Phase Mol. Cell. Biol., September 1, 2008; 28(17): 5162 - 5171. [Abstract] [Full Text] [PDF]
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 I-C. Wang, Y.-J. Chen, D. E. Hughes, T. Ackerson, M. L. Major, V. V. Kalinichenko, R. H. Costa, P. Raychaudhuri, A. L. Tyner, and L. F. Lau FoxM1 Regulates Transcription of JNK1 to Promote the G1/S Transition and Tumor Cell Invasiveness J. Biol. Chem., July 25, 2008; 283(30): 20770 - 20778. [Abstract] [Full Text] [PDF]
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S. K. M. Li, D. K. Smith, W. Y. Leung, A. M. S. Cheung, E. W. F. Lam, G. P. Dimri, and K.-M. Yao FoxM1c Counteracts Oxidative Stress-induced Senescence and Stimulates Bmi-1 Expression J. Biol. Chem., June 13, 2008; 283(24): 16545 - 16553. [Abstract] [Full Text] [PDF]
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U. Schuller, Q. Zhao, S. A. Godinho, V. M. Heine, R. H. Medema, D. Pellman, and D. H. Rowitch Forkhead Transcription Factor FoxM1 Regulates Mitotic Entry and Prevents Spindle Defects in Cerebellar Granule Neuron Precursors Mol. Cell. Biol., December 1, 2007; 27(23): 8259 - 8270. [Abstract] [Full Text] [PDF]
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K. K. Deeb, A. M. Michalowska, C.-y. Yoon, S. M. Krummey, M. J. Hoenerhoff, C. Kavanaugh, M.-c. Li, F. J. Demayo, I. Linnoila, C.-x. Deng, et al. Identification of an Integrated SV40 T/t-Antigen Cancer Signature in Aggressive Human Breast, Prostate, and Lung Carcinomas with Poor Prognosis Cancer Res., September 1, 2007; 67(17): 8065 - 8080. [Abstract] [Full Text] [PDF]
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Z. Wang, S. Banerjee, D. Kong, Y. Li, and F. H. Sarkar Down-regulation of Forkhead Box M1 Transcription Factor Leads to the Inhibition of Invasion and Angiogenesis of Pancreatic Cancer Cells Cancer Res., September 1, 2007; 67(17): 8293 - 8300. [Abstract] [Full Text] [PDF]
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Y. Tan, P. Raychaudhuri, and R. H. Costa Chk2 Mediates Stabilization of the FoxM1 Transcription Factor To Stimulate Expression of DNA Repair Genes Mol. Cell. Biol., February 1, 2007; 27(3): 1007 - 1016. [Abstract] [Full Text] [PDF]
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S. K. Radhakrishnan, U. G. Bhat, D. E. Hughes, I-C. Wang, R. H. Costa, and A. L. Gartel Identification of a Chemical Inhibitor of the Oncogenic Transcription Factor Forkhead Box M1 Cancer Res., October 1, 2006; 66(19): 9731 - 9735. [Abstract] [Full Text] [PDF]
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