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Research Background

Steroid Hormones

Steroid and small molecule-related hormones are largely endocrine factors that regulate almost every facet of vertebrate development, growth and adult homeostasis. They operate by controlling the transcriptional output of specific target genes at the molecular level in virtually every tissue and organ system in higher vertebrates. The activities of steroidal ligands are mediated by unique intracellular receptor proteins to which they bind with high affinity. These interactions prompt the subsequent associate of receptor-ligand complexes with the regulatory regions of genes where they function to recruit a variety of molecular machines capable of controlling the expression of target genes.  

The Vitamin D Hormone

The vitamin D hormone represents such a steroid hormone system. The hormone is famous for its role in orchestrating the regulation of calcium and phosphorus homeostasis via its actions on the intestine, kidney and bone. Thus, vitamin D deficiency leads to a reduction in circulating calcium and phosphorus levels that results ultimately in rickets, adult osteomalacia, and osteoporosis. The vitamin D hormone is less well known, but nonetheless important, for diverse actions in the skin, the regulation of immune function, control of cellular growth, and modulation of cellular differentiation. As with other steroid hormones, all of these pleiotropic activities are also mediated by a unique intracellular receptor termed the vitamin D receptor or VDR which acts within the nucleus of target cells to regulate the expression of numerous genes. Perhaps the clearest demonstration of the essentiality of the VDR in vitamin D action is the finding that singe point mutations in this receptor’s gene have been found to be responsible for a generalized vitamin D resistance syndrome in humans. Accordingly, tissues fail to respond to the vitamin D hormone despite the fact that its circulating levels in the blood are normal.

Historical Studies

Our past studies have sought to understand how the vitamin D hormone, termed 1,25-dihydroxyvitamin D3 or 1,25(OH)2D3 for short, modulates the transcriptional output of target genes and, in so doing, orchestrates the intricacies of maintaining calcium and phosphorus homeostasis in mammals. We participated in the initial characterization of 1,25(OH)2D3 as an endocrine hormone and the discovery and characterization of its receptor, cloned the VDR’s structural and chromosomal genes and developed an understanding of how the receptor operates at the molecular level on target genes. These studies facilitated our finding, described above, that genetic mutations in the VDR gene were responsible for vitamin D hormone resistance in humans. More recently, these molecular studies of the VDR have culminated in the determination of the three dimensional structure of the 1,25(OH)2D3-binding portion of the receptor through X-ray diffraction analysis. These studies have led to a more complete understanding of how the vitamin D hormone interacts within the ligand-binding pocket of the VDR.

1,25-dihydroxyvitamin D3 structure graphic
Vanhooke JL. Biochemistry. 43(14). 2004