Emerging concepts on the biologic role and mechanism of action of 1,25-dihydroxyvitamin D3

Abstract

The biologic actions of 1,25-(OH)2D3 are diverse, ranging from a major role in the regulation of mineral homeostasis in intestine, kidney, and bone to the control of such fundamental processes as myeloid progenitor cell differentiation. The central character in this action is the 1,25-(OH)2D3 receptor, a protein whose activity is focused at the level of the genome. The function of this polypeptide, by analogy with other steroid receptors, is to interact in a sequence-specific manner with unique regulatory elements of DNA, which serve to modify the activity of their respective promoters. The exact manner in which receptor binding to these sequences precipitates promoter activity is unclear. It is, however, a direct result of the structural organization of the steroid receptors, which represent a class of transcriptional controlling proteins. The deduced primary sequences emanating from the molecular cloning of estrogen, progesterone, glucocorticoid, and 1,25-(OH)2D3 receptors has revealed several important structure-function relationships. These include the identification of a highly conserved cysteine-rich domain that may interact with DNA and a steroid-binding domain that is hydrophobic and is located at the carboxy terminus of the protein. The similarity of this domain among heterologous steroid receptor species implies that each of these proteins belongs to a common gene family whose functional activities are similar if not identical. It is this structure within the 1,25-(OH)2D3 receptor that provides conclusive evidence that 1,25-(OH)2D3 is a steroid hormone that via its receptor modifies the activity of hormone-sensitive genes.