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J. Biol. Chem., Vol. 280, Issue 14, 14130-14137, April 8, 2005

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Nongenotropic, Anti-Apoptotic Signaling of 1,25(OH)₂-Vitamin D₃ and Analogs through the Ligand Binding Domain of the Vitamin D Receptor in Osteoblasts and Osteocytes

MEDIATION BY Src, PHOSPHATIDYLINOSITOL 3-, AND JNK KINASES^*

Anthony M. Vertino, Craig M. Bula, Jin-Ran Chen, Maria Almeida, Li Han, Teresita Bellido, Stavroula Kousteni, Anthony W. Norman, and Stavros C. Manolagas¶

From the Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, and the Central Arkansas Veterans Health Care System, Little Rock, Arkansas 72205 and the Department of Biochemistry and Division of Biomedical Sciences, University of California, Riverside, California 92521

Because sex steroids regulate the life span of bone cells by modulating cytoplasmic kinase activity via a nongenotropic action of their classical receptors, we have explored the possibility that the vitamin D nuclear receptor (VDR) might exhibit similar nongenotropic actions. We report that the conformationally flexible full VDR agonist, 1,25(OH)₂-vitamin D₃ (1,25(OH)₂D₃), and the 6-s-cis-locked 1,25(OH)₂-lumisterol₃ (JN) analog, also acting through the VDR but with poor transcriptional activity, protected murine osteoblastic or osteocytic cells from apoptosis. This effect was reproduced in HeLa cells transiently transfected with either wild type VDR or a mutant consisting of only the VDR ligand binding domain. The VDR ligand binding domain bound [³H]1,25(OH)₂D₃ as effectively as wild type VDR but did not induce vitamin D response element-mediated transcription. The anti-apoptotic effects of 1,25(OH)₂D₃ and the 6-s-cis-locked 1,25(OH)₂-lumisterol₃ analog in calvaria cells were blocked by three cytoplasmic kinase inhibitors: Src kinase inhibitor 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1), phosphatidylinositol 3 kinase inhibitor Wortmannin, and the JNK kinase inhibitor SP600125. However, inhibition of p38 with SB203580 or ERK with either U0126 or a transfected dominant negative MEK did not interfere with these anti-apoptotic actions. Further, 1,25(OH)₂D₃ induced rapid (5 min) association of VDR with Src kinase in OB-6 cells. Finally, actinomycin D or cycloheximide prevented the anti-apoptotic effect of 1,25(OH)₂D₃, indicating that transcriptional events are also required. These findings suggest that nongenotropic modulation of kinase activity is also a general property of the VDR and that ligands that activate nongenotropic signals, but lack transcriptional activity, display different biological profiles from the steroid hormone 1,25(OH)₂D₃.

Received for publication, September 17, 2004 , and in revised form, December 30, 2004.

^* This work was supported by National Institutes of Health Grants PO1-AG13918 (to S. C. M.) and KO2-AR02127 (to T. B.) and by the Department of Veterans Affairs (Veterans Affairs Merit Review grant and Research Enhancement award (to S. C. M.)). The work conducted in the A. W. Norman laboratory was supported by National Institutes of Health Grant DK-09012-37. 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: Division of Endocrinology and Metabolism and the Center for Osteoporosis and Metabolic Bone Disease, University of Arkansas for Medical Sciences, 4301 W. Markham St., Slot 587, Little Rock, AR 72205. Tel.: 501-686-5130; Fax: 501-686-8148; E-mail: manolagasstavros{at}uams.edu.

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