Agonist-triggered modulation of the activated and silent state of the vitamin D-3 receptor by interaction with co-repressors and co-activators

The nuclear receptor for the hormone 1 alpha ,25-dihydroxyvitamin D-3 (1 al pha ,25(OH)(2)D-3), VDR, regulates gene expression via a ternary complex wi th the retinoid X receptor (RXR) and a 1 alpha ,25(OH)(2)D-3 response eleme nt (VDRE). This complex mediates transcriptional repression through interac tion with co-repressor proteins, such as NCoR, and transactivation through agonist-triggered contacts with co-activator proteins, such as SRC-1. This study demonstrates that the interaction of the VDR with NCoR results in a p referential stabilization of the VDR in a non-agonistic conformation (silen t state), whereas within a complex with SRC-1 VDR is in its agonistic confo rmation (activated state). Helix 12 of the ligand-binding domain of the VDR was found to be a critical sensor for the differential stabilization of th e activated and silent state of the receptor. VDR agonists that showed simi lar sensitivity in inducing VDR-RXR-VDRE complex formation were found to me diate a different dose-dependent release of NCoR from these complexes, whic h correlates with their ability to stabilize the silent state of the VDR in the presence of NCoR. Interestingly, up to 50 % of all VDR-NCoR complexes were found to be stable even in the presence of saturating agonist concentr ations. This was confirmed by a quenching effect of overexpressed NCoR on a gonist-induced gene activity mediated by VDR-RXR heterodimers. Taken togeth er, co-activator and co-repressor proteins antagonize each other in stabili zing the activated and silent state of the receptor and modulate in this wa y the sensitivity and potency of the transcriptional activation by the liga nd-responsive transcription factor VDR. (C) 2000 Academic Press.