The Vitamin D3 1alpha-Hydroxylase Gene and Its Regulation by Active Vitamin D3

Vitamin D has a pivotal role in a many biological processes, including the maintenance of calcium homeostasis, cell differentiation and proliferation. Most of these actions are mediated by transcriptional regulation of target genes through vitamin D receptor (VDR), a member the steroid/thyroid hormone receptor superfamily. Thus, it is important to understand vitamin D biosynthesis into an active form that regulates VDR transcriptional functions. The active form of vitamin D, 1 alpha,25(OH)(2)D-3, derived by vitamin D-3 1alpha hydroxylase, 1 alpha(OH)ase in renal proximal tubule cells is a ligand for VDR. We have identified the 1 alpha(OH)ase gene, which uses a novel expression cloning method derived from VDR deficient mice that have excess amounts of active vitamin D-3 in the serum. Identification of 1 alpha(OH)ase gene had lead us to understand not only the biological significance of active vitamin D-3 synthesis, but also a novel mechanism of VDR-mediated transcriptional regulation. The gene expression of 1 alpha(OH)ase is positively and negatively regulated by parathyroid hormone (PTH) and active vitamin D-3 respectively. In this review, we describe switching between positive and negative transcriptional modulation by the VDR, together with recent findings on the mechanisms of VDR-mediated epigenetic regulation in the 1 alpha(OH)ase gene.