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Title: The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor

Abstract

Testicular receptors 2 and 4 (TR2/4) constitute a subgroup of orphan nuclear receptors that play important roles in spermatogenesis, lipid and lipoprotein regulation, and the development of the central nervous system. Currently, little is known about the structural features and the ligand regulation of these receptors. Here we report the crystal structure of the ligand-free TR4 ligand binding domain, which reveals an autorepressed conformation. The ligand binding pocket of TR4 is filled by the C-terminal half of helix 10, and the cofactor binding site is occupied by the AF-2 helix, thus preventing ligand-independent activation of the receptor. However, TR4 exhibits constitutive transcriptional activity on multiple promoters, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, or ligand binding substantially reduce the transcriptional activity of this receptor. Importantly, both retinol and retinoic acid are able to promote TR4 to recruit coactivators and to activate a TR4-regulated reporter. These findings demonstrate that TR4 is a ligand-regulated nuclear receptor and suggest that retinoids might have a much wider regulatory role via activation of orphan receptors such as TR4.

Authors:
; ; ; ; ; ; ; ;  [1];  [2]
  1. (Michigan-Med)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHOTHER
OSTI Identifier:
1022280
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. Biol. Chem.; Journal Volume: 286; Journal Issue: (4) ; 01, 2011
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Zhou, X. Edward, Suino-Powell, Kelly M., Xu, Yong, Chan, Cee-Wah, Tanabe, Osamu, Kruse, Schoen W., Reynolds, Ross, Engel, James Douglas, Xu, H. Eric, and Van Andel). The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor. United States: N. p., 2015. Web. doi:10.1074/jbc.M110.168740.
Zhou, X. Edward, Suino-Powell, Kelly M., Xu, Yong, Chan, Cee-Wah, Tanabe, Osamu, Kruse, Schoen W., Reynolds, Ross, Engel, James Douglas, Xu, H. Eric, & Van Andel). The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor. United States. doi:10.1074/jbc.M110.168740.
Zhou, X. Edward, Suino-Powell, Kelly M., Xu, Yong, Chan, Cee-Wah, Tanabe, Osamu, Kruse, Schoen W., Reynolds, Ross, Engel, James Douglas, Xu, H. Eric, and Van Andel). Mon . "The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor". United States. doi:10.1074/jbc.M110.168740.
@article{osti_1022280,
title = {The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor},
author = {Zhou, X. Edward and Suino-Powell, Kelly M. and Xu, Yong and Chan, Cee-Wah and Tanabe, Osamu and Kruse, Schoen W. and Reynolds, Ross and Engel, James Douglas and Xu, H. Eric and Van Andel)},
abstractNote = {Testicular receptors 2 and 4 (TR2/4) constitute a subgroup of orphan nuclear receptors that play important roles in spermatogenesis, lipid and lipoprotein regulation, and the development of the central nervous system. Currently, little is known about the structural features and the ligand regulation of these receptors. Here we report the crystal structure of the ligand-free TR4 ligand binding domain, which reveals an autorepressed conformation. The ligand binding pocket of TR4 is filled by the C-terminal half of helix 10, and the cofactor binding site is occupied by the AF-2 helix, thus preventing ligand-independent activation of the receptor. However, TR4 exhibits constitutive transcriptional activity on multiple promoters, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, or ligand binding substantially reduce the transcriptional activity of this receptor. Importantly, both retinol and retinoic acid are able to promote TR4 to recruit coactivators and to activate a TR4-regulated reporter. These findings demonstrate that TR4 is a ligand-regulated nuclear receptor and suggest that retinoids might have a much wider regulatory role via activation of orphan receptors such as TR4.},
doi = {10.1074/jbc.M110.168740},
journal = {J. Biol. Chem.},
number = (4) ; 01, 2011,
volume = 286,
place = {United States},
year = {Mon Nov 30 00:00:00 EST 2015},
month = {Mon Nov 30 00:00:00 EST 2015}
}
  • While Bcl-2 plays an important role in cell apoptosis, its relationship to the orphan nuclear receptors remains unclear. Here we report that mouse embryonic fibroblast (MEF) cells prepared from TR4-deficient (TR4{sup -} {sup /-}) mice are more susceptible to UV-irradiation mediated apoptosis compared to TR4-Wildtype (TR4 {sup +/+}) littermates. Substantial increasing TR4{sup -} {sup /-} MEF apoptosis to UV-irradiation was correlated to the down-regulation of Bcl-2 RNA and protein expression and collaterally increased caspase-3 activity. Furthermore, this TR4-induced Bcl-2 gene expression can be suppressed by co-transfection with TR4 coregulators, such as androgen receptor (AR) and receptor-interacting protein 140 (RIP140) inmore » a dose-dependent manner. Together, our results demonstrate that TR4 might function as an apoptosis modulator through induction of Bcl-2 gene expression.« less
  • The human testicular receptor 4 (TR4) shares structural homology with members of the nuclear receptor superfamily. Some other members of this superfamily were able to regulate the transcriptional activity of the human oxytocin (OXT) promoter by binding to the first DR0 regulatory site. However, little investigation was conducted systematically in the study of the second dDR4 site of OXT proximal promoter, and the relationship between the first and the second sites of OXT promoter. Here, we demonstrated for the first time that TR4 could increase the proximal promoter activity of the human OXT gene via DR0, dDR4, and OXT (bothmore » DR0 and dDR4) elements, respectively. TR4 might induce OXT gene expression through the OXT element in a dose-dependent manner. However, there is no synergistic effect between DR0 and dDR4 elements during TR4 transactivation. Taken together, these results suggested that TR4 should be one of important regulators of OXT gene expression.« less
  • The chicken ovalbumin upstream promoter-transcription factors (COUP-TFI and II) make up the most conserved subfamily of nuclear receptors that play key roles in angiogenesis, neuronal development, organogenesis, cell fate determination, and metabolic homeostasis. Although the biological functions of COUP-TFs have been studied extensively, little is known of their structural features or aspects of ligand regulation. Here we report the ligand-free 1.48 {angstrom} crystal structure of the human COUP-TFII ligand-binding domain. The structure reveals an autorepressed conformation of the receptor, where helix {alpha}10 is bent into the ligand-binding pocket and the activation function-2 helix is folded into the cofactor binding site,more » thus preventing the recruitment of coactivators. In contrast, in multiple cell lines, COUP-TFII exhibits constitutive transcriptional activity, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, and ligand binding, substantially reduce the COUP-TFII transcriptional activity. Importantly, retinoid acids are able to promote COUP-TFII to recruit coactivators and activate a COUP-TF reporter construct. Although the concentration needed is higher than the physiological levels of retinoic acids, these findings demonstrate that COUP-TFII is a ligand-regulated nuclear receptor, in which ligands activate the receptor by releasing it from the autorepressed conformation.« less
  • TR4 is a new member of the nuclear hormone receptor family. This receptor is highly conserved in rat and human, but an in-frame insertion of 19 amino acid residues in the amino-terminal (A/B) region was found in the human, but an in-frame insertion of 19 amino acid residues in the amino-terminal (A/B) region was found in the human homolog, which we refer to as hTR4{alpha}1. which is homologous to hTR4{alpha}1 since it contains the extra 19 amino acids in the A/B region. The two rat transcripts showed a differential tissue distribution. Analysis of the exon-intron organization of the hTR4 A/Bmore » region showed that the 19-amino-acid peptide insert in hTR4{alpha}1 was encoded by a separate exon, indicating that hTR4{alpha}1 and hTR4{alpha}2 transcripts were produced by the differential usage of the exon. RT-PCR analysis revealed that both hTR4{alpha}1 and hTR4{alpha}2 were detectable in brain, placenta, and ovary. In contrast, the human ovarian cancer cell line, PA1, failed to express hTR4{alpha}1. By fluorescence in situ hybridization, we have mapped the hTR4 gene to 3p25, a region deleted in some forms of cancer. 24 refs., 6 figs., 1 tab.« less
  • Estrogen receptor-related receptor gamma (ERR{gamma}) is a member of the nuclear receptor family of transcriptional activators. To date, the target genes and physiological functions of ERR{gamma} are not well understood. In the current study, we identify that Plk2 is a novel target of ERR{gamma}. Northern blot analysis showed that overexpression of ERR{gamma} induced Plk2 expression in cancer cell lines. ERR{gamma} activated the Plk2 gene promoter, and deletion and mutational analysis of the Plk2 promoter revealed that the ERR{gamma}-response region is located between nucleotides (nt) -2327 and -2229 and -441 and -432 (relative to the transcriptional start site at +1). Electrophoreticmore » mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) analysis demonstrated that ERR{gamma} binds directly to the Plk2 promoter. Overexpression of ERR{gamma} in the presence of the mitotic inhibitor nocodazole significantly decreased apoptosis, and induced S-phase cell cycle progression through the induction of Plk2 expression. Taken together, these results demonstrated that Plk2 is a novel target of ERR{gamma}, and suggest that this interaction is crucial for cancer cell proliferation.« less