VDR-Alien: a novel, DNA-selective vitamin D-3 receptor-corepressor partnership

The vitamin D receptor (VDR) is a transcription factor that transmits incom ing 1,25-dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3) signaling via combined contact with coactivator proteins and specific DNA binding sites (VDREs), which ultimately results in activation of transcription. In contrast, the m echanisms of transcriptional repression via the VDR are less well understoo d. This study documents VDR-dependent transcriptional repression largely vi a histone deacetylase (HDAC) activity. Direct, ligand-sensitive protein-pro tein interaction of the VDR with the nuclear receptor corepressor (NCoR) an d a novel corepressor, called Alien, was demonstrated to be comparable but independent of the VDR AF-2 transactivation domain. Functional assays indic ated that Alien, but not NCoR, displays selectivity for different VDRE stru ctures for transferring these repressive effects into gene regulatory activ ities. Moreover, superrepression via Alien was found to be affected only in part by HDAC inhibitors such as trichostatin A. Finally, for a dissociatio n of VDR-Alien complexes in vitro and in vivo, higher ligand concentrations were needed than for a dissociation of VDR-NCoR complexes. This suggests t hat Alien and NCoR are using different interfaces for interaction with the VDR and different pathways for mediating superrepression, which in turn cha racterizes Alien as a representative of a new class of corepressors. Taken together, association of the VDR with corepressor proteins provides a furth er level of transcriptional regulation, which is emerging as a complex netw ork of protein-protein interaction-mediated control.