期刊
EMBO JOURNAL
卷 23, 期 7, 页码 1598-1608出版社
WILEY
DOI: 10.1038/sj.emboj.7600157
关键词
bHLH-type activator; co-regulator; nuclear receptor; transrepression; vitamin D
Vitamin D receptor (VDR) is essential for ligand-induced gene repression of 25(OH)D-3 1alpha-hydroxylase (1alpha(OH)ase) in mammalian kidney, while this gene expression is activated by protein kinase A (PKA) signaling downstream of the parathyroid hormone action. The mapped negative vitamin D response element (1alphanVDRE) in the human 1alpha(OH)ase gene promoter (around 530 bp) was distinct from those of the reported DR3-like nVDREs, composed of two E-box-like motifs. Unlike the reported nVDREs, no direct binding of VDR/RXR heterodimer to 1alphanVDRE was detected. A bHLH-type factor, designated VDIR, was identified as a direct sequence-specific activator of 1alphanVDRE. The transactivation function of VDIR was further potentiated by activated-PKA signaling through phosphorylation of serine residues in the transactivation domains, with the recruitment of a p300 histone acetyltransferase co-activator. The ligand-dependent association of VDR/RXR heterodimer with VDIR bound to 1alphanVDRE caused the dissociation of p300 co-activators from VDIR, and the association of HDAC co-repressor complex components resulting in ligand-induced transrepression. Thus, the present study deciphers a novel mechanism of ligand-induced transrepression by nuclear receptor via co-regulator switching.
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