RAR-related orphan receptor-β

Nomenclature: RAR-related orphan receptor-β

Systematic Nomenclature: NR1F2

Family: 1F. Retinoic acid-related orphans

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 459 9q22 RORB RAR-related orphan receptor B 5
Mouse 459 19B Rorb RAR-related orphan receptor beta 14
Rat 459 1q43 Rorb RAR-related orphan receptor B 3
Previous and Unofficial Names
RZRB
ROR-β
RORβ
RZRβ
NR1F2
ROR-BETA
LOC309288
Rorb_predicted
RAR-related orphan receptor beta
RAR-related orphan receptor beta (predicted)
nuclear receptor ROR-beta
nuclear receptor RZR-beta
nuclear receptor subfamily 1 group F member 2
retinoid-related orphan receptor-beta
transcription factor
RZR-beta
Rorbeta
Database Links
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
NURSA Receptor
OMIM
PharmGKB Gene
PhosphoSitePlus
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  The orphan nuclear receptor RORbeta - incomplex with ATRA
PDB Id:  1N4H
Ligand:  tretinoin   This ligand is endogenous
Resolution:  2.1Å
Species:  Rat
References:  13
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
tretinoin Hs Agonist - - 13
[13]
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
ALRT 1550 Hs Antagonist 6.8 pKi 13
pKi 6.8 [13]
tretinoin Hs Antagonist 6.55 pKi 13
pKi 6.55 [13]
all-trans-4-oxo-retinoic acid Hs Antagonist 6.1 pKi 13
pKi 6.1 [13]
ALRT 1550 Hs Antagonist 10.4 pIC50 13
pIC50 10.4 [13]
tretinoin Hs Antagonist 9.82 pIC50 13
pIC50 9.82 [13]
all-trans-4-oxo-retinoic acid Hs Antagonist 9.3 pIC50 13
pIC50 9.3 [13]
Antagonist Comments
A recent study identified all trans retinoic acid, its 4-oxo metabolites and one of its synthetic analogues (ALRT 1550) as bona fide ligand for RORβ. Interestingly, this study show that binding of these ligands to RORβ LBD results in a decrease of its transcriptional activity. The values given here represent the IC50 of the substance in a functional assay based on inhibition of RORβ activity in a reporter assay in HT22 cells. The in vivo relevance of these data is still unclear.
DNA Binding
Structure:  Monomer, Homodimer
HRE core sequence:  T/A A/T T/A C A/T A/GGGTCA
Response element:  Half site
DNA Binding Comments
RORβ binds as a monomer to ROREs but activates transcription only when two properly spaced ROREs are present. No clear homodimer formation has been seen for RORβ.
Co-binding Partners
Name Interaction Effect Reference
Nm23-2 Physical 10
Main Co-regulators
Name Activity Specific Ligand dependent AF-2 dependent Comments References
NRIP2 Co-repressor No No Yes 6
NCOR1 Co-activator No No Yes 12
NCOR1 Co-repressor Yes Yes Yes 9
Main Co-regulators Comments
NRIP2 inhibits receptor-mediated gene expression in an AF2-D-dependent manner presumably by interfering with coactivator binding. By docking to the holo-LBD of nuclear receptors, NRIP2 might displace coactivators and result in suppression of the transcriptional activity of liganded nuclear receptors. Therefore, NRIP2 might fall into the same category of coregulatory proteins such as RIP140, which is described to suppress the activation of certain agonist-bound hormone receptors.
Main Target Genes
Name Species Effect Technique Comments References
ARNTL Human Activated Transient transfection, EMSA, Others ROR beta, alpha and gamma are involved in the molecular mechanism supporting the circadian pacemaker. It have been shown that the bHLH PAS protein product of ARNTL (Bmal1) expression is directly regulated by RORs and Rev erbs which compete for the same response element. 7
Tissue Distribution
Brain
Species:  Human
Technique:  in situ hybridisation, Northern blot, Western blotting, Other
References:  1,4,11
Tissue Distribution Comments
RORβ is uniquely expressed in brain. Most of its transcripts are found as a large 10 kb mRNA species and a minor fraction is detected at 2.4 kb. In spleen a RORβ transcript of 1 kb is detected. The nature of this transcript is not known. The distribution of RORβ transcript was studied in rat both by competitive PCR and by in situ hybridisation and confirmed the specific expression in brain. Strong expression was found in pineal gland, hypothalamus, and thalamus. RORβ is also expressed in eye, spinal cord and pituitary. In eye, RORβ was shown to be expressed in retinal progenitor cells in the embryonic rat retina and to be important in regulating retinal progenitor proliferation. Interestingly, it has been shown that RORβ mRNA level oscillate along a circadian rhythm in retina and in pineal gland in mouse, consistent with a role in the regulation of circadian rhythm.
Physiological Consequences of Altering Gene Expression
RORβ knock-out mice
Species:  Mouse
Tissue: 
Technique:  Knockout
References:  1
Physiological Consequences of Altering Gene Expression Comments
The knock-out strain corresponds to the now lost vacillan strain. They display a typical duck-like gait, a transient inability for males to reproduce and a severe disorganisation of the retina and complete blindness. Furthermore, they exhibit a slightly abnormal circadian rhythm: although their rhythmicity is still entrained by light-dark cycle, under constant conditions they display an extended period of free-running rhythmicity suggesting that this gene influences circadian rhythm.
Phenotypes, Alleles and Disease Models Mouse data from MGI

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Rorbtm1Mba Rorbtm1Mba/Rorbtm1Mba
involves: 129P2/OlaHsd * C57BL/6
MGI:1343464  MP:0005253 abnormal eye physiology PMID: 9670004 
Rorbtm1Mba Rorbtm1Mba/Rorbtm1Mba
involves: 129P2/OlaHsd * C57BL/6
MGI:1343464  MP:0001406 abnormal gait PMID: 9670004 
Rorbm1Btlr Rorbm1Btlr/Rorbm1Btlr
C57BL/6J-Rorb
MGI:1343464  MP:0001406 abnormal gait
Rorbtm1Mba Rorbtm1Mba/Rorbtm1Mba
involves: 129P2/OlaHsd * C57BL/6
MGI:1343464  MP:0002063 abnormal learning/memory/conditioning PMID: 9670004 
Rorbtm1Mba Rorbtm1Mba/Rorbtm1Mba
involves: 129P2/OlaHsd * C57BL/6
MGI:1343464  MP:0002066 abnormal motor capabilities/coordination/movement PMID: 9670004 
Rorbtm1Mba Rorbtm1Mba/Rorbtm1Mba
involves: 129P2/OlaHsd * C57BL/6
MGI:1343464  MP:0001325 abnormal retina morphology PMID: 9670004 
Rorbtm1Mba Rorbtm1Mba/Rorbtm1Mba
involves: 129P2/OlaHsd * C57BL/6
MGI:1343464  MP:0002566 abnormal sexual interaction PMID: 9670004 
Rorbtm1Mba Rorbtm1Mba/Rorbtm1Mba
involves: 129P2/OlaHsd * C57BL/6
MGI:1343464  MP:0002557 abnormal social/conspecific interaction PMID: 9670004 
Rorbtm1Mba Rorbtm1Mba/Rorbtm1Mba
involves: 129P2/OlaHsd * C57BL/6
MGI:1343464  MP:0005656 decreased aggression PMID: 9670004 
Rorbtm1Mba Rorbtm1Mba/Rorbtm1Mba
involves: 129P2/OlaHsd * C57BL/6
MGI:1343464  MP:0001265 decreased body size PMID: 9670004 
Rorbtm1Mba Rorbtm1Mba/Rorbtm1Mba
involves: 129P2/OlaHsd * C57BL/6
MGI:1343464  MP:0001417 decreased exploration in new environment PMID: 9670004 
Rorbtm1Mba Rorbtm1Mba/Rorbtm1Mba
involves: 129P2/OlaHsd * C57BL/6
MGI:1343464  MP:0001328 disorganized retinal layers PMID: 9670004 
Rorbtm1Mba Rorbtm1Mba/Rorbtm1Mba
involves: 129P2/OlaHsd * C57BL/6
MGI:1343464  MP:0001405 impaired coordination PMID: 9670004 
Rorbtm1Mba Rorbtm1Mba/Rorbtm1Mba
involves: 129P2/OlaHsd * C57BL/6
MGI:1343464  MP:0001513 limb grasping PMID: 9670004 
Rorbm1Btlr Rorbm1Btlr/Rorbm1Btlr
C57BL/6J-Rorb
MGI:1343464  MP:0001513 limb grasping
Rorbm1Btlr Rorbm1Btlr/Rorbm1Btlr
C57BL/6J-Rorb
MGI:1343464  MP:0001925 male infertility
Rorbtm1Mba Rorbtm1Mba/Rorbtm1Mba
involves: 129P2/OlaHsd * C57BL/6
MGI:1343464  MP:0001326 retinal degeneration PMID: 9670004 
Biologically Significant Variants
Type:  Splice variant
Species:  Mouse
Description:  nuclear receptor ROR-beta isoform 1
Amino acids:  459
Protein accession: 
References:  14
Type:  Splice variant
Species:  Mouse
Description:  nuclear receptor ROR-beta isoform 2 (ROR beta 2) differs from the canonical ROR beta in its N-terminal region. Its expression is confined to pineal gland and retina and is strongly increased at night. ROR beta 2 isoforms exhibit a more restricted DNA binding properties compared to the canonical ROR beta and is likely to regulate different sets of genes in different physiological contexts.
Amino acids:  470
Protein accession: 
References:  1-2
General Comments
A complete review of the NR1F subfamily is [8].

References

Show »

1. André E, Conquet F, Steinmayr M, Stratton SC, Porciatti V, Becker-André M. (1998) Disruption of retinoid-related orphan receptor beta changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice. EMBO J.17 (14): 3867-77. [PMID:9670004]

2. André E, Gawlas K, Becker-André M. (1998) A novel isoform of the orphan nuclear receptor RORbeta is specifically expressed in pineal gland and retina. Gene216 (2): 277-83. [PMID:9729429]

3. Becker-André M, André E, DeLamarter JF. (1993) Identification of nuclear receptor mRNAs by RT-PCR amplification of conserved zinc-finger motif sequences. Biochem. Biophys. Res. Commun.194 (3): 1371-9. [PMID:7916608]

4. Becker-André M, Wiesenberg I, Schaeren-Wiemers N, André E, Missbach M, Saurat JH, Carlberg C. (1994) Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J. Biol. Chem.269 (46): 28531-4. [PMID:7961794]

5. Carlberg C, Hooft van Huijsduijnen R, Staple JK, DeLamarter JF, Becker-André M. (1994) RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers. Mol. Endocrinol.8 (6): 757-70. [PMID:7935491]

6. Greiner EF, Kirfel J, Greschik H, Huang D, Becker P, Kapfhammer JP, Schüle R. (2000) Differential ligand-dependent protein-protein interactions between nuclear receptors and a neuronal-specific cofactor. Proc. Natl. Acad. Sci. U.S.A.97 (13): 7160-5. [PMID:10860982]

7. Guillaumond F, Dardente H, Giguère V, Cermakian N. (2005) Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors. J. Biol. Rhythms20 (5): 391-403. [PMID:16267379]

8. Jetten AM. (2004) Recent advances in the mechanisms of action and physiological functions of the retinoid-related orphan receptors (RORs). Curr Drug Targets Inflamm Allergy3 (4): 395-412. [PMID:15584888]

9. Moraitis AN, Giguère V, Thompson CC. (2002) Novel mechanism of nuclear receptor corepressor interaction dictated by activation function 2 helix determinants. Mol. Cell. Biol.22 (19): 6831-41. [PMID:12215540]

10. Paravicini G, Steinmayr M, André E, Becker-André M. (1996) The metastasis suppressor candidate nucleotide diphosphate kinase NM23 specifically interacts with members of the ROR/RZR nuclear orphan receptor subfamily. Biochem. Biophys. Res. Commun.227 (1): 82-7. [PMID:8858107]

11. Schaeren-Wiemers N, André E, Kapfhammer JP, Becker-André M. (1997) The expression pattern of the orphan nuclear receptor RORbeta in the developing and adult rat nervous system suggests a role in the processing of sensory information and in circadian rhythm. Eur. J. Neurosci.9 (12): 2687-701. [PMID:9517474]

12. Stehlin C, Wurtz JM, Steinmetz A, Greiner E, Schüle R, Moras D, Renaud JP. (2001) X-ray structure of the orphan nuclear receptor RORbeta ligand-binding domain in the active conformation. EMBO J.20 (21): 5822-31. [PMID:11689423]

13. Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, Moras D, Schüle R. (2003) All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta. Nat. Struct. Biol.10 (10): 820-5. [PMID:12958591]

14. Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF et al.. (2002) Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc. Natl. Acad. Sci. U.S.A.99 (26): 16899-903. [PMID:12477932]

How to cite this page

1F. Retinoic acid-related orphans: RAR-related orphan receptor-β. Last modified on 27/11/2013. Accessed on 30/10/2014. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=599.