Laura L. Issa

Molecular mechanism of vitamin D receptor action.

Abstract. The vitamin D system is unique in that distinct calcium homeostatic functions and cell growth regulatory activities are mediated through a single ligand, calcitriol, acting through a specific receptor exhibiting ubiquitous tissue expression, the vitamin D receptor (VDR). The VDR is a member of a superfamily of nuclear steroid hormone receptors which regulate gene transcription by interacting with response elements in gene promoters. Structure-function 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 important for cofactor interaction. A model for regulation of gene transcription by the VDR is evolving and proposes VDR interaction with various components of 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 vitamin D endocrine system and the role of the VDR in regulating this system, including the molecular basis for the diverse actions of synthetic calcitriol analogues in the treatment of autoimmune disease and cancer.

Vitamin D Analogue‐Specific Recruitment of Vitamin D Receptor Coactivators

Synthetic ligands for the vitamin D receptor (VDR) are potential therapeutic agents for metabolic, neoplastic, and autoimmune disorders. Some of these ligands have similar or more potent antiproliferative, yet reduced hypercalcemic actions, than calcitriol. However, the mechanisms for these differential actions have not been clearly defined. We hypothesized that these gene‐ and tissue‐specific effects may relate to ligand‐directed selective recruitment of transcriptional coactivators. To identify key elements in ligand structure that facilitate VDR‐coactivator interactions, the current studies assessed the ability of the VDR to recruit the coactivators GRIP1 and RAC3 following activation by a series of 20‐R‐ and 20‐S (20‐epi)‐modified analogues. The strength of VDR‐coactivator interactions was ligand‐specific and did not always correlate with ligand‐receptor binding affinity. In general, the 20‐epi analogues enhanced these interactions, whereas the 20‐R‐modified analogues were less effective than calcitriol. The 16‐ene,23‐yne modification and fluorinated substituents to the side‐chain attenuated interaction with coactivators. The enhanced ability of the VDR to recruit GRIP1 following activation by the 20‐epi analogues was consistent with potentiation of 20‐epi analogue‐induced transactivation of the osteocalcin gene promoter by GRIP1. Overall, the structure of the ligand side‐chain as well as its orientation seemed to affect the avidity of coactivator binding. These results suggest that selective recruitment of coactivators may contribute to gene‐ and tissue‐specific effects of vitamin D analogues.