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Molecular and Cellular Biology, October 2003, p. 7285-7290, Vol. 23, No. 20
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.20.7285-7290.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

p27Kip1 and p21Cip1 Are Not Required for the Formation of Active D Cyclin-cdk4 Complexes

Tapan K. Bagui, Subhra Mohapatra, Eric Haura, and W. J. Pledger*

Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida 33612

Received 27 February 2003/ Returned for modification 14 April 2003/ Accepted 9 July 2003

Our studies address questions pertaining to the regulation of D cyclin-cdk4 activity, and the following results were obtained. Conditions that increased the abundance of the D cyclins also increased the abundance of enzymatically active D cyclin-cdk4 complexes in mouse embryo fibroblasts (MEFs) lacking both p27Kip1 and p21Cip1 (p27/p21-/-). Such conditions included ectopic expression of cyclin D1 and inhibition of D cyclin degradation by the proteasome inhibitor MG132. However, as determined by treatment of wild-type MEFs with MG132, maximal accumulation of D cyclin-cdk4 complexes required p27Kip1 and p21Cip1 and coincided with the formation of inactive D cyclin-cdk4-p27Kip1 or -p21Cip1 complexes. p27Kip1 or p21Cip1 also increased the abundance of D cyclin-cdk4 complexes and reduced amounts of cdk4 activity when ectopically expressed in p27/p21-/- MEFs. Lastly, increases in the stability of the D cyclins accounted for their greater abundance in wild-type MEFs than in p27/p21-/- MEFs. We conclude that (i) D cyclin-cdk4 complexes are formed and become active in the absence of p27Kip1 and p21Cip1 and (ii) p27Kip1 and p21Cip1 maximize the accumulation but inhibit the activity of D cyclin-cdk4 complexes. We suggest that D cyclin-cdk4 complexes are more stable when bound to p27Kip1 or p21Cip1 and that formation of ternary complexes also stabilizes the D cyclins.

* Corresponding author. Mailing address: H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL 33612. Phone: (813) 979-3887. Fax: (813) 979-3893. E-mail: pledgerw{at}moffitt.usf.edu.

Molecular and Cellular Biology, October 2003, p. 7285-7290, Vol. 23, No. 20
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.20.7285-7290.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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