Mechanism of Action of 1, 25-Dihydroxyvitamin D on Target Gene Expression

Conformationally Restricted Analogs of 1α,25-Dihydroxyvitamin D3 and Its 20-Epimer: Compounds for Study of the Three-Dimensional Structure of Vitamin D Responsible for Binding to the Receptor

“…These analogs (3)(4)(5)(6) were synthesized efficiently by a stereoselective conjugate addition of organocuprate to steroidal E-and Z-22-en-24-ones as the key step. In binding to the VDR the affinities of the analogs (3)(4)(5)(6) relative to 1,25-(OH) 2 D 3 (1) were 1/60, 1/3, 20, and 1/100, respectively. These results indicate that the A region is responsible for binding of 1 to VDR and the EA region for binding of 2.…”

“…This study was conducted to clarify the conformation of vitamin D responsible for binding to those proteins. For the purpose, the side chain mobility of 1,25(OH) 2 D 3 (1) and its 20-epimer, 20-epi-1,25(OH) 2 D 3 (2), was analyzed by a systematic conformational search. The results were depicted as a three-dimensional dot map, which indicates that the side chains of the two vitamins (1 and 2) occupy different spatial regions that are separated in two areas.…”

“…1R,25-Dihydroxyvitamin D 3 [1,25(OH) 2 D 3 , 1], the hormonally active form of vitamin D, exhibits control over the expression of various genes whose products are involved in calcium and phosphorus metabolism, cellular differentiation, and regulation of the immune system. 1 These gene expressions are mediated through the nuclear vitamin D receptor (VDR), 2 a member of a nuclear receptor superfamily which behaves as transcription factors that transduce extracellular hormonal signals to target genes that contain specific enhancer sequences referred to as hormone response elements. 3 Though the molecular mechanism of gene expression is not well understood, it is clear that the binding of 1,25(OH) 2 D 3 (1) to the VDR initiates a sequence of events resulting in the activation of transcription.…”

“…1 These gene expressions are mediated through the nuclear vitamin D receptor (VDR), 2 a member of a nuclear receptor superfamily which behaves as transcription factors that transduce extracellular hormonal signals to target genes that contain specific enhancer sequences referred to as hormone response elements. 3 Though the molecular mechanism of gene expression is not well understood, it is clear that the binding of 1,25(OH) 2 D 3 (1) to the VDR initiates a sequence of events resulting in the activation of transcription. Thus, the VDR-1,25(OH) 2 D 3 complex is most directly relevant to the ultimate biological event.…”

Vitamin D-influenced gene expression via a ligand-independent, receptor-DNA complex intermediate.

“…The hormonally active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,2D3], exhibits control over the expression of a number of genes whose products are involved in calcium and phosphorus absorption in the intestine, calcium mobilization from bone, stimulation of osteoclasts to secrete particular non-matrix bone proteins, and cellular differentiation (1). In addition, the identification of a vitamin D receptor (VDR) in skin has led to investigations of vitamin D function in this tissue (2).…”