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
Ll. Issa et al., 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, ENDOCRINOL, 142(4), 2001, pp. 1606-1615
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.