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J. Biol. Chem., Vol. 283, Issue 30, 20770-20778, July 25, 2008

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FoxM1 Regulates Transcription of JNK1 to Promote the G₁/S Transition and Tumor Cell Invasiveness^*

I-Ching Wang¹², Yi-Ju Chen², Douglas E. Hughes, Timothy Ackerson, Michael L. Major, Vladimir V. Kalinichenko, Robert H. Costa, Pradip Raychaudhuri, Angela L. Tyner, and Lester F. Lau³

From the Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60607 and the Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039

The Forkhead box M1 (FoxM1) protein is a proliferation-specific transcription factor that plays a key role in controlling both the G₁/S and G₂/M transitions through the cell cycle and is essential for the development of various cancers. We show here that FoxM1 directly activates the transcription of the c-Jun N-terminal kinase (JNK1) gene in U2OS osteosarcoma cells. Expression of JNK1, which regulates the expression of genes important for the G₁/S transition, rescues the G₁/S but not the G₂/M cell cycle block in FoxM1-deficient cells. Knockdown of either FoxM1 or JNK1 inhibits tumor cell migration, invasion, and anchorage-independent growth. However, expression of JNK1 in FoxM1-depleted cells does not rescue these defects, indicating that JNK1 is a necessary but insufficient downstream mediator of FoxM1 in these processes. Consistent with this interpretation, FoxM1 regulates the expression of the matrix metalloproteinases MMP-2 and MMP-9, which play a role in tumor cell invasion, through JNK1-independent and -dependent mechanisms in U2OS cells, respectively. Taken together, these findings identify JNK1 as a critical transcriptional target of FoxM1 that contributes to FoxM1-regulated cell cycle progression, tumor cell migration, invasiveness, and anchorage-independent growth.

Received for publication, December 4, 2007 , and in revised form, June 2, 2008.

^* This work was supported by National Institutes of Health Grants AG21842, DK54687, CA124488 (to R. H. C.), CA46565 and HL081390 (to L. F. L.), CA100035, and CA124488 (to P. R.), and DK44525 and DK68503 (to A. L. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This report is dedicated to the memory of Dr. Robert H. Costa, who unfortunately passed away after a heroic fight with cancer.

¹ Current address: Neonatology Division, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039.

² Both authors contributed equally to this work.

³ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Genetics (MC/669), University of Illinois at Chicago, 900 S. Ashland Ave, Chicago, IL 60607-7170. Tel.: 312-996-6978; Fax: 312-996-7034; E-mail: LFLau{at}uic.edu.

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