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 1α,25‐dihydroxyvitamin D 3 (a steroid hormone). The fact that 1,25(OH) 2 D 3 receptors are ubiquitous in tissue distribution opens the possibility for unforeseen biological functions of the vitamin D endocrine system. For example, 1,25(OH) 2 D 3 serves as an immunoregulatory hormone and a differentiation hormone besides its classical role in mineral homeostasis. The avian 1,25(OH) 2 D 3 receptor has recently been cloned and shown to be a member of the nuclear transacting receptor family that includes estrogen, progesterone, glucocorticoid, thyroxine (T 3 ), aldosterone, and retinoic acid receptors. We have compiled an extensive number of RNA polymerase II‐transcribed genes that are regulated by 1,25(OH) 2 D 3 . Classification of these genes on functional grounds identifies and formulates the several genetic circuits or biochemical systems in which 1,25(OH) 2 D 3 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) 2 D 3 suggests that they may be collectively tied to a DNA replication‐differentiation switch.— M inghetti , P. P.; N orman , A. W. 1,25(OH) 2 ‐Vitamin D 3 receptors: gene regulation and genetic circuitry. FASEB J. 2: 3043‐3053; 1988.