Glucocorticoid receptor-interacting protein-1 and receptor-associated coactivator-3 differentially interact with the vitamin D receptor (VDR) and regulate VDR-retinoid X receptor transcriptional cross-talk

The vitamin D-3 receptor (VDR) is a ubiquitously expressed nuclear hormone receptor, and its ligand, calcitriol, has diverse biological effects. The e xtent to which transcriptional coactivators are involved in modulating tiss ue-specific functions of the VDR is unclear. Hence, the current studies inv estigated the role of p160 coactivators in regulating VDR function and inte raction with RXR. Two p160 coactivators, glucocorticoid receptor-interactin g protein-1 (GRIP1) and receptor-associated coactivator-3 (RAC3), which are expressed in an inverse fashion in cell lines representative of calcitriol target tissues, interacted directly with the VDR, both in vitro and in yea st cells, but only in the presence of calcitriol. Deletional analyses of VD R indicated that GRIP1 and RAC3 required an intact VDR activation function (AF-2) domain for efficient interaction as well as additional but distinct regions of the VDR. Coexpression experiments in yeast cells indicated that both GRIP1 and RACE coassemble with the VDR to form an active transcription al complex. They also form ternary complexes with VDR homodimers and VDR:RX R alpha heterodimers. In mammalian cells, GRIP1 augmented VDR activation of the osteocalcin promoter, whereas RAC3 enhanced VDR activation indirectly through RXR. These data suggest different coactivators regulate VDR functio n via distinct mechanisms and support the hypothesis that the VDR recruits different coactivators depending on specific gene and cellular contexts.