Transrepression by a liganded nuclear receptor via a bHLH activator through co-regulator switching.
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.
Murayama
Akiko
A
Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan.
Kim
Mi-sun
MS
Yanagisawa
Junn
J
Takeyama
Ken-ichi
K
Kato
Shigeaki
S
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D050881:E1A-Associated p300 Protein; D005786:Gene Expression Regulation; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017433:Protein Structure, Secondary; D051381:Rats; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D030181:Vitamin D Response Element
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D051792:Basic Helix-Loop-Helix Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D050881:E1A-Associated p300 Protein; D008024:Ligands; D009687:Nuclear Proteins; D018167:Receptors, Calcitriol; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D015534:Trans-Activators; D014157:Transcription Factors; C075668:Tcf3 protein, mouse; C494361:Ep300 protein, mouse; C494362:Ep300 protein, rat