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J. Biol. Chem., Vol. 278, Issue 47, 46862-46868, November 21, 2003

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Vitamin D Inhibits G₁ to S Progression in LNCaP Prostate Cancer Cells through p27^Kip1 Stabilization and Cdk2 Mislocalization to the Cytoplasm^*

Eddy S. Yang and Kerry L. Burnstein

From the Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, Florida 33136

1,25-(OH)₂ vitamin D₃ (1,25-(OH)₂D₃) exerts antiproliferative effects via cell cycle regulation in a variety of tumor cells, including prostate. We have previously shown that in the human prostate cancer cell line LN-CaP, 1,25-(OH)₂D₃ mediates an increase in cyclin-dependent kinase inhibitor p27^Kip1 levels, inhibition of cyclin-dependent kinase 2 (Cdk2) activity, hypophosphorylation of retinoblastoma protein, and accumulation of cells in G₁. In this study, we investigated the mechanism whereby 1,25-(OH)₂D₃ increases p27 levels. 1,25-(OH)₂D₃ had no effect on p27 mRNA levels or on the regulation of a 3.5-kb fragment of the p27 promoter. The rate of p27 protein synthesis was not affected by 1,25-(OH)₂D₃ as measured by luciferase activity driven by the 5'- and 3'-untranslated regions of p27 that regulate p27 protein synthesis. Pulse-chase analysis of ³⁵S-labeled p27 revealed an increased p27 protein half-life with 1,25-(OH)₂D₃ treatment. Because Cdk2-mediated phosphorylation of p27 at Thr¹⁸⁷ targets p27 for Skp2-mediated degradation, we examined the phosphorylation status of p27 in 1,25-(OH)₂D₃-treated cells. 1,25-(OH)₂D₃ decreased levels of Thr¹⁸⁷ phosphorylated p27, consistent with inhibition of Thr¹⁸⁷ phosphorylation-dependent p27 degradation. In addition, 1,25-(OH)₂D₃ reduced Skp2 protein levels in LNCaP cells. Cdk2 is activated in the nucleus by Cdk-activating kinase through Thr¹⁶⁰ phosphorylation and by cdc25A phosphatase via Thr¹⁴ and Tyr¹⁵ dephosphorylation. Interestingly, 1,25-(OH)₂D₃ decreased nuclear Cdk2 levels as assessed by subcellular fractionation and confocal microscopy. Inhibition of Cdk2 by 1,25-(OH)₂D₃ may thus involve two mechanisms: 1) reduced nuclear Cdk2 available for cyclin binding and activation and 2) impairment of cyclin E-Cdk2-dependent p27 degradation through cytoplasmic mislocalization of Cdk2. These data suggest that Cdk2 mislocalization is central to the antiproliferative effects of 1,25-(OH)₂D₃.

Received for publication, June 16, 2003 , and in revised form, August 14, 2003.

^* This work was supported by NIEHS, National Institutes of Health Fellowship F30 ES05910-02 and the NIDDK, National Institutes of Health Grant DK45478. 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 Molecular and Cellular Pharmacology (R-189), University of Miami School of Medicine, P.O. Box 016189 (R-189), Miami, FL 33136. E-mail: kburnste{at}miami.edu.

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