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Molecular and Cellular Biology, November 2002, p. 7842-7852, Vol. 22, No. 22
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.22.7842-7852.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Cell Cycle Inhibition by FoxO Forkhead Transcription Factors Involves Downregulation of Cyclin D

Marc Schmidt,1 Sylvia Fernandez de Mattos,2 Armando van der Horst,3 Rob Klompmaker,1 Geert J. P. L Kops,3,{dagger} Eric W.-F. Lam,2 Boudewijn M. T. Burgering,3 and René H. Medema1*

Division of Molecular Biology, Netherlands Cancer Institute, 1066 CX Amsterdam,1 Department of Physiological Chemistry and Center for Biomedical Genetics, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands,3 CRC Labs and Section of Cancer Cell Biology, Imperial College School of Medicine at Hammersmith Hospital, London W12 0NN, United Kingdom2

Received 2 April 2002/ Returned for modification 9 May 2002/ Accepted 21 August 2002

The FoxO forkhead transcription factors FoxO4 (AFX), FoxO3a (FKHR.L1), and FoxO1a (FKHR) represent important physiological targets of phosphatidylinositol-3 kinase (PI3K)/protein kinase B (PKB) signaling. Overexpression or conditional activation of FoxO factors is able to antagonize many responses to constitutive PI3K/PKB activation including its effect on cellular proliferation. It was previously shown that the FoxO-induced cell cycle arrest is partially mediated by enhanced transcription and protein expression of the cyclin-dependent kinase inhibitor p27kip1 (R. H. Medema, G. J. Kops, J. L. Bos, and B. M. Burgering, Nature 404:782-787, 2000). Here we have identified a p27kip1-independent mechanism that plays an important role in the antiproliferative effect of FoxO factors. Forced expression or conditional activation of FoxO factors leads to reduced protein expression of the D-type cyclins D1 and D2 and is associated with an impaired capacity of CDK4 to phosphorylate and inactivate the S-phase repressor pRb. Downregulation of D-type cyclins involves a transcriptional repression mechanism and does not require p27kip1 function. Ectopic expression of cyclin D1 can partially overcome FoxO factor-induced cell cycle arrest, demonstrating that downregulation of D-type cyclins represents a physiologically relevant mechanism of FoxO-induced cell cycle inhibition.

* Corresponding author. Mailing address: Division of Molecular Biology, H8, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Phone: 31-20-512-2096. Fax: 31-20-512-2086. E-mail: r.medema{at}nki.nl.

{dagger} Present address: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093-0670.

Molecular and Cellular Biology, November 2002, p. 7842-7852, Vol. 22, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.22.7842-7852.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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