1,25(OH) ₂ ‐Vitamin D ₃ receptors: gene regulation and genetic circuitry

Abstract

Our understanding of how vitamin D mediates biological responses has entered a new era. It is now clear that the bulk of the biological responses supported by vitamin D occur as a consequence of its metabolism to its daughter metabolite 1 alpha,25-dihydroxyvitamin D3 (a steroid hormone). The fact that 1,25(OH)2D3 receptors are ubiquitous in tissue distribution opens the possibility for unforeseen biological functions of the vitamin D endocrine system. For example, 1,25(OH)2D3 serves as an immunoregulatory hormone and a differentiation hormone besides its classical role in mineral homeostasis. The avian 1,25)OH)2D3 receptor has recently been cloned and shown to be a member of the nuclear transacting receptor family that includes estrogen, progesterone, glucocorticoid, thyroxine (T3), aldosterone, and retinoic acid receptors. We have compiled an extensive number of RNA polymerase II-transcribed genes that are regulated by 1,25(OH)2D3. Classification of these genes on functional grounds identifies and formulates the several genetic circuits or biochemical systems in which 1,25(OH)2D3 plays an essential regulatory role. These systems include genes that govern oncogene and lymphokine expression as well as those involved in mineral homeostasis, vitamin D metabolism, and regulation of a set of replication-linked genes (c-myc, c-myb, and histone H4), which are critical for rapid cellular proliferation. An integrated analysis of the combinations of genetic circuits regulated by 1,25(OH)2D3 suggests that they may be collectively tied to a DNA replication-differentiation switch.

Regulation of murine lymphokine production in vivo. III. The lymphoid tissue microenvironment exerts regulatory influences over T helper cell function.

“…We believe that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] may represent such a hormone. 1,25-(OH)2D3 is the active hormone for which intracellular receptors are known to exist in T cells (33,34). It is a metabolite of 25-hydroxyvitamin D3, and can be produced locally by the action of lct-hydroxylase (an enzyme that is inducible in LPS-or IFN-, y-stimulated macrophages) (35,36).…”

Control of calbindin‐D28K expression in developing mouse kidney

“…Calbindin-DzeK, first isolated as a 28KD vitamin D-inducible protein in chick intestine (Wasserman and Taylor, 1966), is a member of a large family of "EF Hand" calcium-binding proteins which includes troponin C, calmodulin, parvalbumin, and SlOO (for reviews, see Van Eldik et al, 1982;Minghetti and Norman, 1988). Expressed in a variety of organs including kidney, intestine, bone, brain, pancreas, and placenta, its precise function remains the subject of speculation (Christakos et al, 1989).…”

Avian tibial dyschondroplasia: The interaction of genetic selection and dietary 1,25 ‐dihydroxycholecalciferol

“…Dietary supplementation of normal chicks with 1,25-dihydroxycholecalciferol results in stimulation of chondrocyte differentiation and, in particular, alkaline phosphatase activity (ALP) (Farquharson et al, 1992d). In most cell culture studies 1,25-dihydroxycholecalciferol stimulates ALP activity Schwartz et al, 1988;Boyan et al, 1990;Klaus et al, 1991) and modulates both TGF-(3 and c-myc protein expression (Minghetti & Norman, 1988), proteins that are both lowered in TD. It can be speculated that the actions of 1,25-dihydroxycholecalciferol on chondrocyte differentiation are mediated by TGF-P and/or c-myc protein.…”