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J. Biol. Chem., Vol. 279, Issue 24, 25260-25267, June 11, 2004

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p27^Kip1 Stabilization and G₁ Arrest by 1,25-Dihydroxyvitamin D₃ in Ovarian Cancer Cells Mediated through Down-regulation of Cyclin E/Cyclin-dependent Kinase 2 and Skp1-Cullin-F-box Protein/Skp2 Ubiquitin Ligase^*

Pengfei Li, Chunrong Li, Xiuhua Zhao, Xiaohong Zhang, Santo V. Nicosia, and Wenlong Bai¶

From the Departments of Pathology and Interdisciplinary Oncology, University of South Florida College of Medicine and Programs of Molecular Oncology and Drug Discovery and the Program of Molecular Oncology, H. Lee Moffitt Cancer Center Tampa, Florida 33612-4799

p27^Kip1 (p27) is a tumor suppressor whose stability is controlled by proteasome-mediated degradation, a process directed in part by cyclin-dependent kinase 2 (CDK2)-mediated phosphorylation of p27 at Thr¹⁸⁷ and its subsequent interaction with the Skp1-Cullin-F-box protein/Skp2 (Skp2) ubiquitin ligase. The present study shows that 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) arrests ovarian cancer cells in G₁ by stabilizing the p27 protein. 1,25(OH)₂D₃ initiates a chain of events by decreasing the amounts of cyclin E and cyclin E-associated CDK2 activity. As a result, p27 phosphorylation at Thr¹⁸⁷ and consequently the interaction with Skp2 are decreased. 1,25(OH)₂D₃ also increases p27 stability by decreasing the abundance of Skp2. It is the combined effect of 1,25(OH)₂D₃ on both the CDK2-dependent phosphorylation of p27, and thus its affinity for Skp2, and Skp2 expression that dramatically increases the stability of the p27 protein. Similar to its effects in ovarian cancer cells, 1,25(OH)₂D₃ induces p27 accumulation in wild type mouse embryo fibroblasts and arrests wild type but not p27-null mouse embryo fibroblasts in G₁. Stable expression of Skp2 in OVCAR3 cells diminishes the G₁ arrest and decreases the growth response to 1,25(OH)₂D₃. Taken together, the results of this study identify p27 as the key mediator of 1,25(OH)₂D₃-induced growth suppression in G₁ and show that the hormone achieves this by decreasing the activity of CDK2 and reducing the abundance of Skp2, which act together to degrade p27.

Received for publication, October 7, 2003 , and in revised form, April 5, 2004.

^* This work was supported by New Investigator Award DAMD17-01-1-0731 from the United States Department of Defense Ovarian Cancer Program (to W. B.). 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 Pathology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., MDC 11, Tampa, FL 33612-4799. Tel.: 813-974-0563; Fax: 813-974-5536; E-mail: wbai{at}hsc.usf.edu.

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