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Title: Identification of Natural ROR;#947; Ligands that Regulate the Development of Lymphoid Cells

Authors:
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  1. (TTU)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1222811
Resource Type:
Journal Article
Resource Relation:
Journal Name: Cell Metab.; Journal Volume: 21; Journal Issue: (3) ; 02, 2015
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Santori, Fabio R., Huang, Pengxiang, van de Pavert, Serge A., Douglass, Jr., Eugene F., Leaver, David J., Haubrich, Brad A., Keber, Rok, Lorbek, Gregor, Konijn, Tanja, Rosales, Brittany N., Rozman, Damjana, Horvat, Simon, Rahier, Alain, Mebius, Reina E., Rastinejad, Fraydoon, Nes, W. David, Littman, Dan R., Sanford-Burnham), VU-MED), CNRS-UMR), Ljubljana), and NYUSM). Identification of Natural ROR;#947; Ligands that Regulate the Development of Lymphoid Cells. United States: N. p., 2016. Web. doi:10.1016/j.cmet.2015.01.004.
Santori, Fabio R., Huang, Pengxiang, van de Pavert, Serge A., Douglass, Jr., Eugene F., Leaver, David J., Haubrich, Brad A., Keber, Rok, Lorbek, Gregor, Konijn, Tanja, Rosales, Brittany N., Rozman, Damjana, Horvat, Simon, Rahier, Alain, Mebius, Reina E., Rastinejad, Fraydoon, Nes, W. David, Littman, Dan R., Sanford-Burnham), VU-MED), CNRS-UMR), Ljubljana), & NYUSM). Identification of Natural ROR;#947; Ligands that Regulate the Development of Lymphoid Cells. United States. doi:10.1016/j.cmet.2015.01.004.
Santori, Fabio R., Huang, Pengxiang, van de Pavert, Serge A., Douglass, Jr., Eugene F., Leaver, David J., Haubrich, Brad A., Keber, Rok, Lorbek, Gregor, Konijn, Tanja, Rosales, Brittany N., Rozman, Damjana, Horvat, Simon, Rahier, Alain, Mebius, Reina E., Rastinejad, Fraydoon, Nes, W. David, Littman, Dan R., Sanford-Burnham), VU-MED), CNRS-UMR), Ljubljana), and NYUSM). Tue . "Identification of Natural ROR;#947; Ligands that Regulate the Development of Lymphoid Cells". United States. doi:10.1016/j.cmet.2015.01.004.
@article{osti_1222811,
title = {Identification of Natural ROR;#947; Ligands that Regulate the Development of Lymphoid Cells},
author = {Santori, Fabio R. and Huang, Pengxiang and van de Pavert, Serge A. and Douglass, Jr., Eugene F. and Leaver, David J. and Haubrich, Brad A. and Keber, Rok and Lorbek, Gregor and Konijn, Tanja and Rosales, Brittany N. and Rozman, Damjana and Horvat, Simon and Rahier, Alain and Mebius, Reina E. and Rastinejad, Fraydoon and Nes, W. David and Littman, Dan R. and Sanford-Burnham) and VU-MED) and CNRS-UMR) and Ljubljana) and NYUSM)},
abstractNote = {},
doi = {10.1016/j.cmet.2015.01.004},
journal = {Cell Metab.},
number = (3) ; 02, 2015,
volume = 21,
place = {United States},
year = {Tue Jul 05 00:00:00 EDT 2016},
month = {Tue Jul 05 00:00:00 EDT 2016}
}
  • The retinoic acid-related orphan receptor {gamma} (ROR{gamma}) has important roles in development and metabolic homeostasis. Although the biological functions of ROR{gamma} have been studied extensively, no ligands for ROR{gamma} have been identified, and no structure of ROR{gamma} has been reported. In this study, we showed that hydroxycholesterols promote the recruitment of coactivators by ROR{gamma} using biochemical assays. We also report the crystal structures of the ROR{gamma} ligand-binding domain bound with hydroxycholesterols. The structures reveal the binding modes of various hydroxycholesterols in the ROR{gamma} pocket, with the receptors all adopting the canonical active conformation. Mutations that disrupt the binding of hydroxycholesterolsmore » abolish the constitutive activity of ROR{gamma}. Our observations suggest an important role for the endogenous hydroxycholesterols in modulating ROR{gamma}-dependent biological processes.« less
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  • Retinoic acid receptor-related orphan receptor-{alpha} (ROR{alpha}) (NR1F1) is an orphan nuclear receptor with a potential role in metabolism. Previous studies have shown that ROR{alpha} regulates transcription of the murine Apolipoprotein AI gene and human Apolipoprotein CIII genes. In the present study, we present evidence that ROR{alpha} also induces transcription of the human Apolipoprotein AV gene, a recently identified apolipoprotein associated with triglyceride levels. Adenovirus-mediated overexpression of ROR{alpha} increased the endogenous expression of ApoAV in HepG2 cells and ROR{alpha} also enhanced the activity of an ApoAV promoter construct in transiently transfected HepG2 cells. Deletion and mutation studies identified three AGGTCA motifsmore » in the ApoAV promoter that mediate ROR{alpha} transactivation, one of which overlaps with a previously identified binding site for PPAR{alpha}. Together, these results suggest a novel mechanism whereby ROR{alpha} modulates lipid metabolism and implies ROR{alpha} as a potential target for the treatment of dyslipidemia and atherosclerosis.« less
  • ROR-alpha is a nuclear receptor, activity of which can be modulated by natural or synthetic ligands. Due to its possible involvement in, and potential therapeutic target for atherosclerosis, we aimed to identify ROR-alpha target genes in monocytic and endothelial cell lines. We performed chromatin immunoprecipitation (ChIP) followed by tiling array (ChIP-on-chip) for ROR-alpha in monocytic cell line THP1 and endothelial cell line HUVEC. Following bioinformatic analysis of the array data, we tested four candidate genes in terms of dependence of their expression level on ligand-mediated ROR-alpha activity, and two of them in terms of promoter occupancy by ROR-alpha. Bioinformatic analysesmore » of ChIP-on-chip data suggested that ROR-alpha binds to genomic regions near the transcription start site (TSS) of more than 3000 genes in THP1 and HUVEC. Potential ROR-alpha target genes in both cell types seem to be involved mainly in membrane receptor activity, signal transduction and ion transport. While SPP1 and IKBKA were shown to be direct target genes of ROR-alpha in THP1 monocytes, inflammation related gene HMOX1 and heat shock protein gene HSPA8 were shown to be potential target genes of ROR-alpha. Our results suggest that ROR-alpha may regulate signaling receptor activity, and transmembrane transport activity through its potential target genes. ROR-alpha seems also to play role in cellular sensitivity to environmental substances like arsenite and chloroprene. Although, the expression analyses have shown that synthetic ROR-alpha ligands can modulate some of potential ROR-alpha target genes, functional significance of ligand-dependent modulation of gene expression needs to be confirmed with further analyses.« less
  • The suppressor activity of the spleen cells from bone marrow chimeras prepared with total-lymphoid irradiation was analyzed in vitro. The chimeric spleen cells lacked responsiveness to host-type, but not to third-party, antigens in the mixed-leukocyte reaction (MLR) as judged by (3H)thymidine incorporation and the generation of cytolytic cells. When the donor-type chimeric spleen cells were used as cocultured cells in the MLR, modest nonspecific suppression of (3H)thymidine incorporation and potent antigen-specific suppression of the generation of the cytolytic cells was observed. The donor-type suppressor cells may play an important role in preventing graft-versus-host disease in vivo.