The pleiotropic actions of vitamin D

Abstract

General knowledge of the role of vitamin D3 in human physiology has been shaped by its discovery as a preventive agent of nutritional rickets, a defect in bone development due to inadequate uptake of dietary calcium. Studies on the function of the hormonal form of vitamin D3, 1alpha,25-dihydroxyvitamin D3, have been greatly accelerated by the molecular cloning and structural analysis of the vitamin D3 receptor, which is a ligand-activated regulator of gene transcription. Molecular genetic techniques including genomics have helped reveal that 1alpha,25-dihydroxyvitamin D3 can control more than calcium homeostasis. It has widespread effects on cellular differentiation and proliferation, and can modulate immune responsiveness, and central nervous system function. Moreover, accumulating epidemiological and molecular evidence suggests that 1alpha,25-dihydroxyvitamin D3 acts as a chemopreventive agent against several malignancies including cancers of the prostate and colon. Here, we survey the most-recent findings and discuss their implications for the potential therapeutic uses of vitamin D analogues.

Induction of kinase suppressor of RAS-1(KSR-1) gene by 1, α25-dihydroxyvitamin D3 in human leukemia HL60 cells through a vitamin D response element in the 5′-flanking region

“…Whereas previous promoter deletion analyses have identified VDREs in 1,25D-responsive promoters that are highly degenerate (Lin and White, 2004), the element identified here (GGTgCAtatAGGTCA) differs from the VDRE DR3 consensus of PuG(G/T)TCAn3PuG(G/T)TCA by only Since 'supershifting' antibodies to VDR and RXR isoforms are currently not available, the identity of the proteins bound to the 'KSR-1 VDRE' was investigated by using antibodies to these proteins, which block their binding to DNA. As Figure 4d shows, the gel run longer than the standard time used for the gels shown in Figure 4a and c achieved separation of two complexes.…”

“…VDR/RXR heterodimers bind to cognate vitamin D response elements (VDREs) in the promoter regions of 1,25D target genes (Lin and White, 2004). High affinity VDREs are composed of direct repeat of hexanucleotide PuG(G/T)TCA half-sites separated by 3 bp (DR3 elements).…”

Direct and Indirect Induction by 1,25-Dihydroxyvitamin D3 of the NOD2/CARD15-Defensin β2 Innate Immune Pathway Defective in Crohn Disease

“…Vitamin D has a range of physiological activities (1) and has emerged recently as a direct regulator of immune system function in humans (2,3). It is obtained from limited dietary sources and ultraviolet B-induced conversion of 7-dehydrocholesterol to vitamin D 3 in skin (1).…”

“…It is obtained from limited dietary sources and ultraviolet B-induced conversion of 7-dehydrocholesterol to vitamin D 3 in skin (1). Hormonal 1, dihydroxyvitamin D 3 (1,25D) 2 is produced by hepatic generation of 25-hydroxvitamin D 3 (25D), the major circulating metabolite, followed by CYP27B1-catalyzed 1␣-hydroxylation in kidney and peripheral tissues (1,4,5). Notably, activated macrophages and dendritic cells express CYP27B1 (2, 3), which, unlike the renal enzyme, is regulated primarily by immune inputs.…”

“…Notably, activated macrophages and dendritic cells express CYP27B1 (2, 3), which, unlike the renal enzyme, is regulated primarily by immune inputs. 1,25D signals through its cognate VDR nuclear receptor (1,6), which binds DNA as a heterodimer with retinoid X receptors to vitamin D-response elements (VDREs), direct repeats of PuG(G/T)TCA motifs separated by 3 bp (DR3) (1).…”