The genomic mechanism of action of 1,25-dihydroxyvitamin D3.

The purpose of this article has been to describe recent evidence that supports the idea(62) that 1,25-(OH)2D3 acts mechanistically like that of other steroid hormones. This evidence includes the finding that a clear structural interrelationship exists between the VDR and other members of the steroid receptor gene family, the observation that the VDR is required for gene promoter transactivation, and the identification of VDREs that act in cis to mediate 1,25-(OH)2D3 response. The VDR has been found to bind in vitro specifically to these functional DNA sites. Current evidence, however, indicates that the receptor may interact at these sites not as a monomer or homodimer but rather as a heterodimer with a protein whose identity remains unknown. Future studies with regard to the mechanism of vitamin D action must be aimed at gaining additional insight into the nature of VDREs, acquiring further detail about the interaction of the VDR with these elements, identifying factors that facilitate VDR DNA binding, and determining the biochemical mechanism by which the binding of receptor to these elements leads to modulation of common transcriptional machinery. In addition, 1,25-(OH)2D3 acts to suppress a number of genes, for example collagen, calcitonin, and parathyroid hormone. Efforts to elucidate these actions are currently underway, but the mechanism by which attenuation of response occurs remains largely uncharacterized. Finally, it is possible that additional mechanisms of vitamin D action may exist. Each of these areas offers a considerable challenge to future research.