Molecular mechanism of vitamin D receptor action

The vitamin D system is unique in that distinct calcium homeostatic functio ns and cell growth regulatory activities are mediated through a single liga nd, calcitriol, acting through a specific receptor exhibiting ubiquitous ti ssue expression, the vitamin D receptor (VDR). The VDR is a member of a sup erfamily of nuclear steroid hormone receptors which regulate gene transcrip tion by interacting with response elements in gene promoters. Structure-fun ction analysis of the VDR protein has defined distinct domains involved in DNA binding, ligand binding, receptor dimerisation and gene transactivation , including a C-terminal activation function domain (AF-2) that is importan t for cofactor interaction. A model for regulation of gene transcription by the VDR is evolving and proposes VDR interaction with various components o f the basal transcriptional machinery, including newly defined coactivators and corepressors, which may act to regulate gene transcription by altering histone acetylation and chromatin structure. This review describes the Vit amin D endocrine system and the role of the VDR in regulating this system, including the molecular basis for the diverse actions of synthetic calcitri ol analogues in the treatment of autoimmune disease and cancer.