VDR-Alien:: a novel, DNA-selective vitamin D3 receptor-corepressor partnership

The vitamin D receptor (VDR) is a transcription factor that transmits incoming 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 mechanisms of transcriptional repression via the VDR are less well understood. This study documents VDR-dependent transcriptional repression largely via histone deacetylase (HDAC) activity. Direct, ligand-sensitive protein-protein interaction of the VDR with the nuclear receptor corepressor (NCoR) and a novel corepressor, called Alien, was demonstrated to be comparable but independent of the VDR AF-2 transactivation domain. Functional assays indicated that Alien, but not NCoR, displays selectivity for different VDRE structures for transferring these repressive effects into gene regulatory activities. Moreover, superrepression via Alien was found to be affected only in part by HDAC inhibitors such as trichostatin A. Finally, for a dissociation of VDR-Alien complexes in vitro and in vivo, higher ligand concentrations were needed than for a dissociation of VDR-NCoR complexes. This suggests that Alien and NCoR are using different interfaces for interaction with the VDR and different pathways for mediating superrepression, which in turn characterizes Alien as a representative of a new class of corepressors. Taken together, association of the VDR with corepressor proteins provides a further level of transcriptional regulation, which is emerging as a complex network of protein-protein interaction-mediated control.