The Vitamin D Receptor and RXR Heteropartner Cooperate via Synergistic Activation to Control Target Gene Expression

Vitamin D is a fat-soluble vitamin that is essential for maintaining cellular growth and development. The biologically active form of vitamin D, 1,25-dihydroxycholecalciferol (1,25D), binds to the vitamin D receptor (VDR), a nuclear protein that mediates 1,25D actions. 1,25D binding to VDR also triggers heterodimerization with the retinoid X receptor (RXR) and the VDR-RXR heterocomplex then binds to vitamin D response elements (VDREs) to modulate target gene expression. In the present study, we probed RXR-specific ligands (rexinoids) for their potential role in activating VDR-RXR by employing luciferase reporter plasmids that contain distinct VDREs in human embryonic kidney cells (HEK-293). When cells were transfected with or without VDR/RXR expression plasmids and a direct repeat VDRE (XDR3), treatment with either 1,25D alone, or with RXR-specific ligands such as bexarotene (Bex) or novel Bex analogs alone, showed modest transcriptional activity of the luciferase reporter gene. However, VDR-RXR-mediated activity was significantly increased in the presence of both RXR and VDR ligands. Similar results were obtained using an everted repeat VDRE (PER6). These results suggest that rexinoids alone either: 1) bind and partially activates VDR and/or 2) that when rexinoids binds to RXR, the liganded RXR can partially activates unliganded VDR. Thus, when both ligands are present, the significantly elevated heterodimer activity implicates a synergistic effect via a dual ligand activation process. VDR-RXR is thought to be a nonpermissive heterodimer, which can be activated only by the “primary” (VDR) ligand, but our novel results suggest that VDR may in fact possess permissive behavior and be activated by either RXR or VDR ligands. In summary, this study illuminates a coordinated interaction between VDR and RXR in transcriptional regulation of vitamin D target genes.