Document Detail


The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes.
MedLine Citation:
PMID:  11550795     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The nuclear receptor superfamily, a group of structurally related, ligand-dependent transcription factors, includes a large number of orphan receptors for which no ligand has yet been identified. These proteins function as key regulators of many physiological processes that occur during embryonic development and in the adult. The retinoid-related orphan receptors (RORs) alpha, beta, and gamma comprise one nuclear orphan receptor gene subfamily. RORs exhibit a modular structure that is characteristic for nuclear receptors; the DNA-binding domain is highly conserved and the ligand-binding domain is moderately conserved among RORs. By a combination of alternative promoter usage and exon splicing, each ROR gene generates several isoforms that differ only in their amino terminus. RORs bind as monomers to specific ROR response elements (ROREs) consisting of the consensus core motif AGGTCA preceded by a 5-bp A/T-rich sequence. RORE-dependent transcriptional activation by RORs is cell type-specific and mediated through interactions with nuclear cofactors. RORs have been shown to interact with certain corepressors as well as coactivators, suggesting that RORs are not constitutively active but that their activity is under some regulatory control. RORs likely can assume at least two different conformations: a repressive state, which allows interaction with corepressor complexes, and an active state, which promotes binding of coactivator complexes. Whether the transition between these two states is regulated by ligand binding and/or by phosphorylation remains to be determined. Ca2+/calmodulin-dependent kinase IV (CaMKIV) can dramatically enhance ROR-mediated transcriptional activation. This stimulation involves CaMKIV-mediated phosphorylation not of RORs, but likely of specific nuclear cofactors that interact with RORs. RORalpha is widely expressed. In the cerebellum, its expression is limited to the Purkinje cells. RORalpha-/- mice and the natural RORalpha-deficient staggerer mice exhibit severe cerebellar ataxia due to a defect in Purkinje cell development. In addition, these mice have thin long bones, suggesting a role for RORalpha in bone metabolism, and develop severe atherosclerosis when placed on a high-fat diet. Expression of RORbeta is very restricted. RORbeta is highly expressed in different parts of the neurophotoendocrine system, the pineal gland, the retina, and suprachiasmatic nuclei, suggesting a role in the control of circadian rhythm. This is supported by observations showing alterations in circadian behavior in RORbeta-/- mice. RORgamma, which is most highly expressed in the thymus, plays an important role in thymopoiesis. Thymocytes from RORgamma-/- mice undergo accelerated apoptosis. The induction of apoptosis is, at least in part, due to a down-regulation of the expression of the antiapoptotic gene Bcl-XL. In addition to the thynic phenotype, RORgamma-/- mice lack lymph nodes, indicating that RORgamma is essential for lymph node organogenesis. Overexpression of RORgamma has been shown to inhibit T cell receptor-mediated apoptosis in T cell hybridomas and to repress the induction of Fas-ligand and interleukin 2. These studies demonstrate that RORs play critical roles in the regulation of a variety of physiological processes. Further characterization of the mechanisms of action of RORs will not only lead to the identification of ROR target genes and provide additional insight into their normal physiological functions, but will also determine their roles in disease.
Authors:
A M Jetten; S Kurebayashi; E Ueda
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Progress in nucleic acid research and molecular biology     Volume:  69     ISSN:  0079-6603     ISO Abbreviation:  Prog. Nucleic Acid Res. Mol. Biol.     Publication Date:  2001  
Date Detail:
Created Date:  2001-09-11     Completed Date:  2001-10-25     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0102753     Medline TA:  Prog Nucleic Acid Res Mol Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  205-47     Citation Subset:  IM    
Affiliation:
Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, North Carolina 27709, USA. jetten@niehs.nih.gov
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Apoptosis
Cloning, Molecular
Gene Expression
Hematopoiesis
Humans
Ligands
Mice
Mice, Knockout
Molecular Sequence Data
Nuclear Receptor Subfamily 1, Group F, Member 1
Nuclear Receptor Subfamily 1, Group F, Member 2
Nuclear Receptor Subfamily 1, Group F, Member 3
Phenotype
Receptors, Cell Surface / chemistry,  genetics,  physiology
Receptors, Cytoplasmic and Nuclear / chemistry,  genetics*,  physiology*
Receptors, Retinoic Acid*
Receptors, Thyroid Hormone*
Sequence Homology, Amino Acid
Trans-Activators / chemistry,  genetics,  physiology
Chemical
Reg. No./Substance:
0/Ligands; 0/Nuclear Receptor Subfamily 1, Group F, Member 1; 0/Nuclear Receptor Subfamily 1, Group F, Member 2; 0/Nuclear Receptor Subfamily 1, Group F, Member 3; 0/RORA protein, human; 0/RORB protein, human; 0/RORC protein, human; 0/Receptors, Cell Surface; 0/Receptors, Cytoplasmic and Nuclear; 0/Receptors, Retinoic Acid; 0/Receptors, Thyroid Hormone; 0/Rorb protein, mouse; 0/Rorc protein, mouse; 0/Trans-Activators

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