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J. Biol. Chem., Vol. 280, Issue 32, 29282-29288, August 12, 2005

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Cdk2-dependent Inhibition of p21 Stability via a C-terminal Cyclin-binding Motif^*

Hongyan Zhu, Linghu Nie, and Carl G. Maki¶

From the Department of Radiation and Cellular Oncology, Center for Molecular Oncology, University of Chicago, Chicago, Illinois 60637

p21 is a member of the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors that includes p21, p27, and p57. Recent studies have suggested that Cdk2 activity may promote p21 degradation through a pathway similar to that for p27, although the mechanism by which this occurs has not been clarified. In the current report, co-expression with cyclin E and Cdk2 stabilized p21 in a manner that required the CDK-binding site of p21 and a cyclin-binding site (cy1) located in the p21 N terminus. Strikingly, however, a kinase-dead Cdk2 mutant stabilized p21 to a greater extent than did wild-type Cdk2, consistent with the notion that Cdk2 activity can destabilize p21. The ability of wild-type Cdk2 to destabilize p21 required a potential Cdk2 phosphorylation site in p21 at serine 130 and an intact cyclin-binding motif (cy2) in the p21 C terminus. Finally, p21 was phosphorylated by Cdk2 at Ser-130 in vitro, and this ability of Cdk2 to phosphorylate p21 was dependent, in large part, on the presence of cy2. These results support a model in which active Cdk2 destabilizes p21 via the cy2 cyclin-binding motif and p21 phosphorylation.

Received for publication, July 1, 2004 , and in revised form, June 17, 2005.

^* 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.

^¶ To whom correspondence should be addressed: Dept. of Radiation and Cellular Oncology, Center for Molecular Oncology, University of Chicago, 5841 S. Maryland Ave., MC1105 Rm. G-06, Chicago, IL 60637. Tel.: 773-834-3791; E-mail: cmaki{at}rover.uchicago.edu.

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