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Bone and Mineral Research Program (L.L.I., G.M.L., J.B.B., J.A.E.) and Cancer Research Program (R.L.S.), Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, New South Wales 2010, Australia
Address all correspondence and requests for reprints to: Laura L. Issa, Muscle Development Unit, Children’s Medical Research Institute, Locked Bag 23, Wentworthville, New South Wales 2145, Australia. E-mail: lissa{at}cmri.usyd.edu.au
The vitamin D3 receptor (VDR) is a ubiquitously expressed
nuclear hormone receptor, and its ligand, calcitriol, has diverse
biological effects. The extent to which transcriptional coactivators
are involved in modulating tissue-specific functions of the VDR is
unclear. Hence, the current studies investigated the role of p160
coactivators in regulating VDR function and interaction with RXR. Two
p160 coactivators, glucocorticoid receptor-interacting 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 yeast cells, but only in the presence of
calcitriol. Deletional analyses of VDR 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
RAC3 coassemble with the VDR to form an active transcriptional complex.
They also form ternary complexes with VDR homodimers and VDR:RXR
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
function via distinct mechanisms and support the hypothesis that the
VDR recruits different coactivators depending on specific gene and
cellular contexts.
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