Two nuclear signalling pathways for vitamin D

Abstract

The dihydroxylated form of vitamin D3 (1,25-dihydroxy-D3)mediates a biological response by binding to intracellular receptors which belong to the steroid receptor superfamily. These receptors act as ligand-dependent transcription factors that bind to specific DNA sequences (reviewed in refs 6-9). We have identified two classes of vitamin D response elements that are activated either by the vitamin D receptor (VDR) alone or by heterodimers of VDR and the retinoid-X receptor-alpha (RXR-alpha). The motif GGGTGA arranged as a direct repeat with a spacing of six nucleotides or as a palindrome without spacing, or as an inverted palindrome with a 12-nucleotide spacing, confers vitamin D inducibility mediated by VDR alone. A second class of response elements, composed of directly repeated pairs of motifs (GGTCCA, AGGTCA, or GGGTGA) spaced by three nucleotides, is synergistically activated by RXR and VDR, but only in the presence of both ligands. Thus, the RXR ligand and the nature of the response element determine whether a nuclear receptor is co-regulated by RXR.

Regulation of vitamin D receptor function in MEN1-related parathyroid adenomas

“…Similar to our previous observations, overexpression of menin increased ligand-induced transcription to almost threefold, depending on the amount of menin that was co-transfected ( Figure 2A) (Dreijerink et al, 2006). VDR binds to its response elements as a heterodimer with the retinoid X receptor (RXR) (Carlberg et al, 1993). To determine if menin can also interact with RXR, additional luciferase experiments were performed.…”

Large-scale expression and purification of the human vitamin D receptor and its ligand-binding domain for structural studies

“…For example, it was reported that VDR expressed in baculovirus and yeast was unable to interact directly with VDREs ; these results were interpreted to mean that VDR cannot form homodimers [25,27]. In a study that used gel-shift assays, purified VDRs were shown to bind to the osteopontin VDRE in the absence of RXR ; however, RXR was required for binding to osteoclasin VDRE [35], whereas opposite results were obtained in a study in which VDR translated in itro was used [36]. The conflicting results are likely to be due to differences in sample quality and purity as well as in methodology.…”

Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway

“…It has been demonstrated that RXR is silent in the RXR/VDR heterodimers on binding to the DR3 (direct repeats spaced by 3 nucleotides) response element [25]. However, additive or synergistic transcriptional activation has been observed when RXR/VDR heterodimers bind to particular response elements (osteopontin vitamin D response element and DR3) in different cells (human breast cancer cell line MCF-7 and Drosophila SL-3 cells) [30], suggesting that the role of RXR in VDR-mediated transactivation is gene-and cell line-specific. It has been demonstrated that RXR is an essential partner of VDR and actively participates in VDR-dependent gene expression [31].…”