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J. Biol. Chem., Vol. 281, Issue 33, 24058-24069, August 18, 2006

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Skp2 Contains a Novel Cyclin A Binding Domain That Directly Protects Cyclin A from Inhibition by p27^Kip1*

Peng Ji, Luba Goldin¹, Hao Ren², Daqian Sun, Daniele Guardavaccaro³, Michele Pagano, and Liang Zhu, Recipient of the Irma T. Hirschl Career Scientist Award⁴

From the Department of Developmental and Molecular Biology, the Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461 and Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, New York 10016

Skp2 is well known as the F-box protein of the SCF^Skp2·Roc1 complex targeting p27 for ubiquitylation. Skp2 also forms complexes with cyclin A, which is particularly abundant in cancer cells due to frequent Skp2 overexpression, but the mechanism and significance of this interaction remain unknown. Here, we report that Skp2-cyclin A interaction is mediated by novel interaction sequences on both Skp2 and cyclin A, distinguishing it from the well known RXL-hydrophobic patch interaction between cyclins and cyclin-binding proteins. Furthermore, a short peptide derived from the mapped cyclin A binding sequences of Skp2 can block Skp2-cyclin A interaction but not p27-cyclin A interaction, whereas a previously identified RXL peptide can block p27-cyclin A interaction but not Skp2-cyclin A interaction. Functionally, Skp2-cyclin A interaction is separable from Skp2 ability to mediate p27 ubiquitylation. Rather, Skp2-cyclin A interaction serves to directly protect cyclin A-Cdk2 from inhibition by p27 through competitive binding. Finally, we show that disruption of cyclin A binding with point mutations in the cyclin A binding domain of Skp2 compromises the ability of overexpressed Skp2 to counter cell cycle arrest by a p53/p21-mediated cell cycle checkpoint without affecting its ability to cause degradation of cellular p27 and p21. These findings reveal a new functional mechanism of Skp2 and a new regulatory mechanism of cyclin A.

Received for publication, March 31, 2006 , and in revised form, June 14, 2006.

^* This work was supported by grants from the NCI and NIDDK (to L. Z.) and NCI and NIGMS, National Institutes of Health (to M. P.). The Albert Einstein Comprehensive Cancer Research Center and Liver Research Center provided core facility support. 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.

¹ A trainee of the National Institutes of Health Cell Biology Training grant at Albert Einstein College of Medicine.

² Present address: Department of Microbiology, Second Military Medical University, Shanghai 200433, China.

³ Supported by an Emerald Foundation grant.

⁴ To whom correspondence should be addressed: Dept. of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Rm. U-521, Bronx, NY 10461. Tel.: 718-430-3320; Fax: 718-430-8975; E-mail: lizhu{at}aecom.yu.edu.

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