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p27Kip1 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 LiDepartment of Pathology, University of South Florida College of Medicine and Programs of Molecular Oncology and Drug Discovery, Tampa, FL 33612, USAChunrong LiDepartments of Pathology and Interdisciplinary Oncology, University of South Florida College of Medicine and Programs of Molecular Oncology and Drug Discovery, Florida 33612-4799Xiuhua ZhaoProgram of Molecular Oncology, H. Lee Moffitt Cancer Center Tampa, Florida 33612-4799Xiaohong ZhangProgram of Molecular Oncology, H. Lee Moffitt Cancer Center Tampa, Florida 33612-4799Santo V. NicosiaDepartments of Pathology and Interdisciplinary Oncology, University of South Florida College of Medicine and Programs of Molecular Oncology and Drug Discovery, Florida 33612-4799Wenlong BaiDepartments of Pathology and Interdisciplinary Oncology, University of South Florida College of Medicine and Programs of Molecular Oncology and Drug Discovery, Florida 33612-4799

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Annotatsiya

p27Kip1 (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. p27Kip1 (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.

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DOI: 10.1074/jbc.m311052200

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