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Molecular and Cellular Biology, February 1999, p. 1190-1201, Vol. 19, No. 2
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Cell-Free Degradation of p27kip1, a G1 Cyclin-Dependent Kinase Inhibitor, Is Dependent on CDK2 Activity and the Proteasome

Hoang Nguyen,1 Diana M. Gitig,1 and Andrew Koff1,2,*

Program in Molecular Biology and Cell Biology and Genetics, Cornell University Graduate School of Medical Sciences,1 and Memorial Sloan-Kettering Cancer Center,2 New York, New York 10021

Received 11 August 1998/Returned for modification 1 October 1998/Accepted 27 October 1998

Entry into S phase is dependent on the coordinated activation of CDK4,6 and CDK2 kinases. Once a cell commits to S phase, there must be a mechanism to ensure the irreversibility of this decision. The activity of these kinases is inhibited by their association with p27. In many cells, p27 plays a major role in the withdrawal from the cell cycle in response to environmental cues. Thus, it is likely that p27 is a target of the machinery required to ensure the irreversibility of S-phase entry. We have been interested in understanding the mechanisms regulating p27 at the G1/S transition. In this report, we define a cell-free degradation system which faithfully recapitulates the cell cycle phase-specific degradation of p27. We show that this reaction is dependent on active CDK2 activity, suggesting that CDK2 activity is directly required for p27 degradation. In addition to CDK2, other S-phase-specific factors are required for p27 degradation. At least some of these factors are ubiquitin and proteasome dependent. We discuss the relationships between CDK2 activity, ubiquitin-dependent, and possibly ubiquitin-independent proteasomal activities in S-phase extracts as related to p27.

* Corresponding author. Mailing address: RRL917D, Box 207, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Phone: (212) 639-2354. Fax: (212) 639-2861. E-mail: a-koff{at}ski.mskcc.org.

Molecular and Cellular Biology, February 1999, p. 1190-1201, Vol. 19, No. 2
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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