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Molecular and Cellular Biology, November 1998, p. 6605-6615, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Regulation of Exit from Quiescence by p27 and Cyclin D1-CDK4

Mohamed H. Ladha, Kwang Y. Lee, Todd M. Upton,dagger Michael F. Reed,Dagger and Mark E. Ewen*

The Dana-Farber Cancer Institute and the Harvard Medical School, Boston, Massachusetts 02115

Received 30 April 1998/Returned for modification 17 June 1998/Accepted 18 August 1998

The synthesis of cyclin D1 and its assembly with cyclin-dependent kinase 4 (CDK4) to form an active complex is a rate-limiting step in progression through the G1 phase of the cell cycle. Using an activated allele of mitogen-activated protein kinase kinase 1 (MEK1), we show that this kinase plays a significant role in positively regulating the expression of cyclin D1. This was found both in quiescent serum-starved cells and in cells expressing dominant-negative Ras. Despite the observation that cyclin D1 is a target of MEK1, in cycling cells, activated MEK1, but not cyclin D1, is capable of overcoming a G1 arrest induced by Ras inactivation. Either wild-type or catalytically inactive CDK4 cooperates with cyclin D1 in reversing the G1 arrest induced by inhibition of Ras activity. In quiescent NIH 3T3 cells expressing either ectopic cyclin D1 or activated MEK1, cyclin D1 is able to efficiently associate with CDK4; however, the complex is inactive. A significant percentage of the cyclin D1-CDK4 complexes are associated with p27 in serum-starved activated MEK1 or cyclin D1 cell lines. Reduction of p27 levels by expression of antisense p27 allows for S-phase entry from quiescence in NIH 3T3 cells expressing ectopic cyclin D1, but not in parental cells.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: (617) 632-2206. E-mail: mark_ewen{at}dfci.harvard.edu.

dagger Present address: Cytomatrix, Inc., Cambridge, MA 02139.

Dagger Present address: Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.

Molecular and Cellular Biology, November 1998, p. 6605-6615, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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