Functional Characterization of a Novel Type of 1α,25-Dihydroxyvitamin D3Response Element Identified in the Mouse c-fosPromoter

Abstract

The seco-steroid 1α,25-dihydroxyvitamin D3(VD) is known to inhibit cellular proliferation and to induce differentiation as well as programmed cell death (apoptosis). VD is the ligand of the transcription factor VDR, which is a member of the nuclear receptor superfamily. Primary VD responding genes contain a VD response element (VDRE), on which VDR binds as a dimeric complex. The main heterodimeric partner of VDR is the retinoid X receptor (RXR) and the majority of the known natural VDREs are formed by a direct repeat of hexameric core binding motifs spaced by 3 nucleotides. Most of the genes carrying DR3-type VDREs are associated with the hormone's classical function, which is the regulation of calcium homeostasis. Recently, it has been found that inverted palindromic arrangements spaced by 9 nucleotides also form functional VDREs. This paper reports the identification of a novel IP9-type VDRE in the mouse c-fospromoter. This elements is bound with high affinity by VDR-RXR heterodimers and responds at 10-fold lower concentrations to the potent anti-proliferative VD analogue EB1089 than to VD. This suggests that VD may be directly involved in the transcriptional regulation of the cell cycle via the activation of the c-fosgene.