Abstract
Vitamin D receptor (VDR) is essential for ligand-induced gene repression of 25(OH)D3 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 1nVDRE. 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.
Publication types
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Research Support, Non-U.S. Gov't
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Retracted Publication
MeSH terms
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25-Hydroxyvitamin D3 1-alpha-Hydroxylase / genetics*
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25-Hydroxyvitamin D3 1-alpha-Hydroxylase / metabolism
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Amino Acid Sequence
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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Cell Line
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Cyclic AMP-Dependent Protein Kinases / metabolism
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E1A-Associated p300 Protein
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Gene Expression Regulation*
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Helix-Loop-Helix Motifs*
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Humans
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Ligands
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Mice
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Molecular Sequence Data
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Nuclear Proteins / metabolism
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Promoter Regions, Genetic
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Protein Structure, Secondary
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Rats
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Receptors, Calcitriol / genetics
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Receptors, Calcitriol / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Retinoid X Receptors / genetics
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Retinoid X Receptors / metabolism
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Signal Transduction / physiology
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Trans-Activators / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Two-Hybrid System Techniques
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Vitamin D Response Element*
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Ligands
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Nuclear Proteins
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Receptors, Calcitriol
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Recombinant Fusion Proteins
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Repressor Proteins
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Retinoid X Receptors
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Tcf3 protein, mouse
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Trans-Activators
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Transcription Factors
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25-Hydroxyvitamin D3 1-alpha-Hydroxylase
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E1A-Associated p300 Protein
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Ep300 protein, mouse
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Ep300 protein, rat
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Cyclic AMP-Dependent Protein Kinases