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The 1,25(OH)₂D₃-Regulated Transcription Factor MN1 Stimulates Vitamin D Receptor-Mediated Transcription and Inhibits Osteoblastic Cell Proliferation

Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106

Address all correspondence and requests for reprints to: Paul N. MacDonald, Ph.D., Department of Pharmacology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106. E-mail: pnm2{at}po.cwru.edu.

The vitamin D endocrine system is essential for maintaining mineral ion homeostasis and preserving bone density. The most bioactive form of vitamin D, 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] elicits its effects by binding to the vitamin D receptor (VDR) and regulating the transcription of target genes. In osteoblasts, the bone-forming cells of the skeleton, 1,25-(OH)₂D₃ regulates cell proliferation, differentiation, and mineralization of the extracellular matrix. Despite these well-characterized biological functions, relatively few 1,25-(OH)₂D₃ target genes have been described in osteoblasts. In this study, we characterize the regulation and function of MN1, a novel 1,25-(OH)₂D₃-induced gene in osteoblastic cells. MN1 is a nuclear protein first identified as a gene disrupted in some meningiomas and leukemias. Our studies demonstrate that MN1 preferentially stimulates VDR-mediated transcription through its ligand-binding domain and synergizes with the steroid receptor coactivator family of coactivators. Furthermore, forced expression of MN1 in osteoblastic cells results in a profound decrease in cell proliferation by slowing S-phase entry, suggesting that MN1 is an antiproliferative factor that may mediate 1,25-(OH)₂D₃-dependent inhibition of cell growth. Collectively, these data indicate that MN1 is a 1,25-(OH)₂D₃-induced VDR coactivator that also may have critical roles in modulating osteoblast proliferation.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ  |  RARα  |  RORα  |  RORβ  |  RORγ  |  VDR  |  GR

Coregulators:   TRAP220  |  CBP  |  p300  |  SKIP  |  SRC-1  |  GRIP1  |  AIB1

Ligands:   all-trans-Retinoic acid  |  Calcitriol  |  Dexamethasone  |  Thyroid hormone

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