true1996-10-012024-03-27212RORA_MOUSEDisruption of the nuclear hormone receptor RORalpha in staggerer mice.Hamilton B.A.Frankel W.N.Kerrebrock A.W.Hawkins T.L.Fitzhugh W.Kusumi K.Russell L.B.Mueller K.L.Vanberkel V.Birren B.W.Kruglyak L.Lander E.S.doi:10.1038/379736a01996Nature379736-739NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1)C57BL/6JCerebellumRZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers.Carlberg C.Hooft van Huijsduijnen R.Staple J.K.Delamarter J.F.Becker-Andre M.doi:10.1210/mend.8.6.79354911994Mol. Endocrinol.8757-770NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4)SkinThe structural integrity of ROR alpha isoforms is mutated in staggerer mice: cerebellar coexpression of ROR alpha1 and ROR alpha4.Matysiak-Scholze U.Nehls M.C.doi:10.1006/geno.1997.47571997Genomics4378-84NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4)VARIANT SG 275-HIS--LYS-314 DELAn orphan nuclear receptor, mROR alpha, and its spatial expression in adult mouse brain.Matsui T.Sashihara S.Oh Y.Waxman S.G.doi:10.1016/0169-328x(95)00126-d1995Brain Res. Mol. Brain Res.33217-226NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4)BrainThe status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).The MGC Project Teamdoi:10.1101/gr.25965042004Genome Res.142121-2127NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4)FVB/NMammary glandLubec G.Kang S.U.2007-04UniProtKBPROTEIN SEQUENCE OF 39-61IDENTIFICATION BY MASS SPECTROMETRYTranscriptional regulation of apolipoprotein C-III gene expression by the orphan nuclear receptor RORalpha.Raspe E.Duez H.Gervois P.Fievet C.Fruchart J.C.Besnard S.Mariani J.Tedgui A.Staels B.doi:10.1074/jbc.m0049822002001J. Biol. Chem.2762865-2871FUNCTION IN TRIGLYCERIDE METABOLISMDNA-BINDINGCHARACTERIZATION OF VARIANT SG PHENOTYPERORalpha coordinates reciprocal signaling in cerebellar development through sonic hedgehog and calcium-dependent pathways.Gold D.A.Baek S.H.Schork N.J.Rose D.W.Larsen D.D.Sachs B.D.Rosenfeld M.G.Hamilton B.A.doi:10.1016/s0896-6273(03)00769-42003Neuron401119-1131FUNCTION IN CEREBELLAR DEVELOPMENTDEVELOPMENTAL STAGEINTERACTION WITH CTNNB1CHARACTERIZATION OF VARIANT SG PHENOTYPEThe orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1.Akashi M.Takumi T.doi:10.1038/nsmb9252005Nat. Struct. Mol. Biol.12441-448FUNCTION IN CIRCADIAN RHYTHMSCHARACTERIZATION OF VARIANT SG PHENOTYPETranscriptional coactivator PGC-1alpha integrates the mammalian clock and energy metabolism.Liu C.Li S.Liu T.Borjigin J.Lin J.D.doi:10.1038/nature057672007Nature447477-481INTERACTION WITH PPARGC1AGene expression profiling reveals a regulatory role for ROR alpha and ROR gamma in phase I and phase II metabolism.Kang H.S.Angers M.Beak J.Y.Wu X.Gimble J.M.Wada T.Xie W.Collins J.B.Grissom S.F.Jetten A.M.doi:10.1152/physiolgenomics.00098.20072007Physiol. Genomics31281-294FUNCTION IN METABOLISM REGULATIONCHARACTERIZATION OF VARIANT SG PHENOTYPETISSUE SPECIFICITYIdentification of oxysterol 7alpha-hydroxylase (Cyp7b1) as a novel retinoid-related orphan receptor alpha (RORalpha) (NR1F1) target gene and a functional cross-talk between RORalpha and liver X receptor (NR1H3).Wada T.Kang H.S.Angers M.Gong H.Bhatia S.Khadem S.Ren S.Ellis E.Strom S.C.Jetten A.M.Xie W.doi:10.1124/mol.107.0407412008Mol. Pharmacol.73891-899FUNCTION IN METABOLISM REGULATIONCHARACTERIZATION OF VARIANT SG PHENOTYPEDNA-BINDINGThe emerging role of nuclear receptor RORalpha and its crosstalk with LXR in xeno- and endobiotic gene regulation.Wada T.Kang H.S.Jetten A.M.Xie W.doi:10.3181/0802-mr-502008Exp. Biol. Med.2331191-1201REVIEW OF FUNCTION IN METABOLISM REGULATIONT helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.Yang X.O.Pappu B.P.Nurieva R.Akimzhanov A.Kang H.S.Chung Y.Ma L.Shah B.Panopoulos A.D.Schluns K.S.Watowich S.S.Tian Q.Jetten A.M.Dong C.doi:10.1016/j.immuni.2007.11.0162008Immunity2829-39FUNCTION IN T(H)17 CELLS DIFFERENTIATIONINDUCTION BY IL6 AND TGFB1TISSUE SPECIFICITYThe orphan nuclear receptor, RORalpha, regulates gene expression that controls lipid metabolism: staggerer (SG/SG) mice are resistant to diet-induced obesity.Lau P.Fitzsimmons R.L.Raichur S.Wang S.C.Lechtken A.Muscat G.E.doi:10.1074/jbc.m7105262002008J. Biol. Chem.28318411-18421FUNCTION IN LIPID METABOLISM REGULATIONTISSUE SPECIFICITYCHARACTERIZATION OF VARIANT SG PHENOTYPEAbsence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease.Chopra A.R.Louet J.F.Saha P.An J.Demayo F.Xu J.York B.Karpen S.Finegold M.Moore D.Chan L.Newgard C.B.O'Malley B.W.doi:10.1126/science.11648472008Science3221395-1399INTERACTION WITH NCOA2Retinoic acid receptor-related orphan receptor alpha regulates a subset of cone genes during mouse retinal development.Fujieda H.Bremner R.Mears A.J.Sasaki H.doi:10.1111/j.1471-4159.2008.05739.x2009J. Neurochem.10891-101FUNCTIONDEVELOPMENTAL STAGECHARACTERIZATION OF VARIANT SGThe orphan nuclear receptor RORalpha restrains adipocyte differentiation through a reduction of C/EBPbeta activity and perilipin gene expression.Ohoka N.Kato S.Takahashi Y.Hayashi H.Sato R.doi:10.1210/me.2008-02772009Mol. Endocrinol.23759-771FUNCTION IN ADIPOGENESISINTERACTION WITH CEBPBDEVELOPMENTAL STAGERetinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism.Jetten A.M.doi:10.1621/nrs.070032009Nucl. Recept. Signal.73-35REVIEW ON FUNCTIONInteraction of MAGED1 with nuclear receptors affects circadian clock function.Wang X.Tang J.Xing L.Shi G.Ruan H.Gu X.Liu Z.Wu X.Gao X.Xu Y.doi:10.1038/emboj.2010.342010EMBO J.291389-1400INTERACTION WITH MAGED1The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors.Schmutz I.Ripperger J.A.Baeriswyl-Aebischer S.Albrecht U.doi:10.1101/gad.5641102010Genes Dev.24345-357INTERACTION WITH PER2Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands.Wang Y.Kumar N.Solt L.A.Richardson T.I.Helvering L.M.Crumbley C.Garcia-Ordonez R.D.Stayrook K.R.Zhang X.Novick S.Chalmers M.J.Griffin P.R.Burris T.P.doi:10.1074/jbc.m109.0806142010J. Biol. Chem.2855013-5025FUNCTION IN GLUCOSE METABOLISM REGULATIONIDENTIFICATION OF LIGANDSModulation of clock gene expression by the transcriptional coregulator receptor interacting protein 140 (RIP140).Poliandri A.H.Gamsby J.J.Christian M.Spinella M.J.Loros J.J.Dunlap J.C.Parker M.G.doi:10.1177/07487304114015792011J. Biol. Rhythms26187-199FUNCTIONINTERACTION WITH NRIP1Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand.Solt L.A.Kumar N.Nuhant P.Wang Y.Lauer J.L.Liu J.Istrate M.A.Kamenecka T.M.Roush W.R.Vidovic D.Schuerer S.C.Xu J.Wagoner G.Drew P.D.Griffin P.R.Burris T.P.doi:10.1038/nature100752011Nature472491-494FUNCTION IN T(H)17 CELLS DIFFERENTIATIONINDUCTION BY IL6 AND TGFB1INTERACTION WITH NCOR1 AND NCOA2IDENTIFICATION OF LIGANDSCryptochromes mediate rhythmic repression of the glucocorticoid receptor.Lamia K.A.Papp S.J.Yu R.T.Barish G.D.Uhlenhaut N.H.Jonker J.W.Downes M.Evans R.M.doi:10.1038/nature107002011Nature480552-556INTERACTION WITH CRY1RORgamma directly regulates the circadian expression of clock genes and downstream targets in vivo.Takeda Y.Jothi R.Birault V.Jetten A.M.doi:10.1093/nar/gks6302012Nucleic Acids Res.408519-8535FUNCTION IN CIRCADIAN RHYTHMSTISSUE SPECIFICITYSUBCELLULAR LOCATIONDNA-BINDINGINDUCTIONAction of RORs and their ligands in (patho)physiology.Solt L.A.Burris T.P.doi:10.1016/j.tem.2012.05.0122012Trends Endocrinol. Metab.23619-627REVIEW ON FUNCTION AND LIGANDSPivotal role of Rho-associated kinase 2 in generating the intrinsic circadian rhythm of vascular contractility.Saito T.Hirano M.Ide T.Ichiki T.Koibuchi N.Sunagawa K.Hirano K.doi:10.1161/circulationaha.112.1356082013Circulation127104-114FUNCTIONINDUCTIONProspero-related homeobox 1 (Prox1) functions as a novel modulator of retinoic acid-related orphan receptors alpha- and gamma-mediated transactivation.Takeda Y.Jetten A.M.doi:10.1093/nar/gkt4472013Nucleic Acids Res.416992-7008FUNCTIONSUBCELLULAR LOCATIONINTERACTION WITH PROX1Different initiation.Different initiation.14641 antibodies from 37 providersmouseRoraEukaryotaNuclear Receptor transcription pathwaySUMOylation of intracellular receptors0 hits in 79 CRISPR screensmouseProteinExpressed in medial geniculate body and 290 other cell types or tissuesbaseline and differentialNR_DBD_RORNR_LBD_ROR_likeErythroid Transcription Factor GATA-1, subunit ARetinoid X ReceptorNHR-like_dom_sfNR_DBD_RORNucl_hrmn_rcpt_lig-bdNuclear_hrmn_rcptROR_rcptZnf_hrmn_rcptZnf_NHR/GATANUCLEAR HORMONE RECEPTOR HR3-RELATEDNUCLEAR RECEPTOR ROR-ALPHAHormone_recepzf-C4RORNUCRECPTRSTRDHORMONERSTROIDFINGERHOLIZnF_C4Glucocorticoid receptor-like (DNA-binding domain)Nuclear receptor ligand-binding domainNR_LBDNUCLEAR_REC_DBD_1NUCLEAR_REC_DBD_2MMNuclear receptor ROR-alphaNuclear receptor RZR-alphaNuclear receptor subfamily 1 group F member 1RAR-related orphan receptor ARetinoid-related orphan receptor-alphaRoraNr1f1RzraNuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of embryonic development, cellular differentiation, immunity, circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target genes regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates genes involved in photoreceptor development including OPN1SW, OPN1SM and ARR3 and skeletal muscle development with MYOD1. Required for proper cerebellum development, regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium-mediated signal transduction. Regulates the circadian expression of several clock genes, including CLOCK, BMAL1, NPAS2 and CRY1. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORA-mediated activation of clock genes expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Regulates genes involved in lipid metabolism such as apolipoproteins APOA1, APOA5, APOC3 and PPARG. In liver, has specific and redundant functions with RORC as positive or negative modulator of expression of genes encoding phase I and phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as CYP7B1 and SULT2A1. Induces a rhythmic expression of some of these genes. In addition, interplays functionally with NR1H2 and NR1H3 for the regulation of genes involved in cholesterol metabolism. Also involved in the regulation of hepatic glucose metabolism through the modulation of G6PC1 and PCK1. In adipose tissue, plays a role as negative regulator of adipocyte differentiation, probably acting through dual mechanisms. May suppress CEBPB-dependent adipogenesis through direct interaction and PPARG-dependent adipogenesis through competition for DNA-binding. Downstream of IL6 and TGFB and synergistically with RORC isoform 2, is implicated in the lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. Involved in hypoxia signaling by interacting with and activating the transcriptional activity of HIF1A. May inhibit cell growth in response to cellular stress. May exert an anti-inflammatory role by inducing CHUK expression and inhibiting NF-kappa-B signaling.Monomer. Interacts (via the DNA-binding domain) with HIF1A; the interaction enhances HIF1A transcription under hypoxia through increasing protein stability. Interacts with CEBPB; the interaction disrupts the interaction CEBPB:EP300. Interacts with the coactivators NCOA2, PPARGC1A (via LXXLL motif), EP300 and MED1. Interacts with the corepressor NCOR1. Interacts with MAGED1 and CTNNB1. Interacts with CRY1 and PER2. Interacts (via AF-2 motif) with PROX1. Interacts with NRIP1. Isoform 4 interacts (via AF-2 motif) with isoform 1 of FOXP3 (via LXXLL motif) (By similarity).Expressed in cerebellum, heart, liver, lung, kidney, retina and brown and white adipose tissues. Expressed in the subset of mature Th17 cells.In cerebellum, expression begins at 12.5 dpc. In the developing retina, first expressed at 17 dpc in the ganglion cell layer. At P3, expressed in the inner border of the neuroblasitic border (presumptive amacrine cells). By P6, levels increase in developing cones. Expression found in the presumptive bipolar cells by P9. During adipocyte differentiation, expression gradually increases.In T(H) cells, induced upon antigen receptor ligation in the presence of IL6 and TGB1 (via STAT3). Oscillates diurnally in central nervous system. In liver, Isoform 1 oscillates diurnally but not isoform 4.The AF-2 (activation function-2) motif is required for recruiting coregulators containing LXXLL motifs.Phosphorylation by conventional PKCs in neurons inhibits transcriptional activity. Phosphorylated on Thr-183 by MAPK1/ERK1 in vitro.Sumoylated by SENP1 and SENP2. Sumoylation, promoted by PIAS2, PIAS3, PIAS4 but not PIAS1, enhances the transcriptional activity. Desumoylated by SENP1.Ubiquitinated, leading to its degradation by the proteasome. Proteasomal degradation is required for efficient transcriptional activity and is prevented by HR.Monomethylated at Lys-38 by EZH2, this creates a degron recognized by a DCX (DDB1-DCAF1/VPRBP-CUL4A-RBX1) E3 ubiquitin ligase complex.Defects in Rora are the cause of the staggerer (SG) mutant phenotype which is characterized by disturbance of Purkinje cell development and immune system functioning. This phenotype exhibits lower body weight, reduced adiposity, decreased plasma cholesterol, triglyceride and apolipoprotein CIII levels, and is resistant to diet-induced obesity. Also has abnormal circadian rhythms.Belongs to the nuclear hormone receptor family. NR1 subfamily.Truncated N-terminus.Truncated N-terminus.Nuclear receptor ROR-alpha588451523NR LBD272510Nuclear receptor73138NR C4-type93NR C4-type109133Disordered63Disordered154183AF-2506511Polar residues1936Polar residues46Basic and acidic residues169N6-methyllysine38Phosphothreonine; by MAPK1Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)240In isoform 4.MYFVIAAMKA66In SG; disturbance of Purkinje cell and muscle development, lipid metabolism, circadian behavior and immune system functioning.275314R163T180181I182ISA193194W304315G362P433HM450451N487Nfalse3false5Atxn1Maged11996-10-011588457ca6684832869114809c9190546f821c1Alpha-1MESAPAAPDPAASEPGSSGSEAAAGSRETPLTQDTGRKSEAPGAGRRQSYASSSRGISVTKKTHTSQIEIIPCKICGDKSSGIHYGVITCEGCKGFFRRSQQSNATYSCPRQKNCLIDRTSRNRCQHCRLQKCLAVGMSRDAVKFGRMSKKQRDSLYAEVQKHRMQQQQRDHQQQPGEAEPLTPTYNISANGLTELHDDLSTYMDGHTPEGSKADSAVSSFYLDIQPSPDQSGLDINGIKPEPICDYTPASGFFPYCSFTNGETSPTVSMAELEHLAQNISKSHLETCQYLREELQQITWQTFLQEEIENYQNKQREVMWQLCAIKITEAIQYVVEFAKRIDGFMELCQNDQIVLLKAGSLEVVFIRMCRAFDSQNNTVYFDGKYASPDVFKSLGCEDFISFVFEFGKSLCSMHLTEDEIALFSAFVLMSADRSWLQEKVKIEKLQQKIQLALQHVLQKNHREDGILTKLICKVSTLRALCGRHTEKLMAFKAIYPDIVRLHFPPLYKELFTSEFEPAMQIDG2Alpha-23Alpha-34Alpha-4MYFVIAAMKAQIEIIPCKICGDKSSGIHYGVITCEGCKGFFRRSQQSNATYSCPRQKNCLIDRTSRNRCQHCRLQKCLAVGMSRDAVKFGRMSKKQRDSLYAEVQKHRMQQQQRDHQQQPGEAEPLTPTYNISANGLTELHDDLSTYMDGHTPEGSKADSAVSSFYLDIQPSPDQSGLDINGIKPEPICDYTPASGFFPYCSFTNGETSPTVSMAELEHLAQNISKSHLETCQYLREELQQITWQTFLQEEIENYQNKQREVMWQLCAIKITEAIQYVVEFAKRIDGFMELCQNDQIVLLKAGSLEVVFIRMCRAFDSQNNTVYFDGKYASPDVFKSLGCEDFISFVFEFGKSLCSMHLTEDEIALFSAFVLMSADRSWLQEKVKIEKLQQKIQLALQHVLQKNHREDGILTKLICKVSTLRALCGRHTEKLMAFKAIYPDIVRLHFPPLYKELFTSEFEPAMQIDGtruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetruetrue