RAR-related orphan receptor alpha

RAR-related orphan receptor A
PDB rendering based on 1n83.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1N83​, 1S0X​, 4S15​
Identifiers
Symbols	RORA ; NR1F1; ROR1; ROR2; ROR3; RZR-ALPHA; RZRA
External IDs	OMIM: 600825 MGI: 104661 HomoloGene: 56594 IUPHAR: 598 ChEMBL: 5868 GeneCards: RORA Gene
Gene ontology Molecular function • RNA polymerase II regulatory region sequence-specific DNA binding • core promoter sequence-specific DNA binding • transcription corepressor binding • transcription coactivator binding • DNA binding • transcription factor activity, sequence-specific DNA binding • steroid hormone receptor activity • RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding • protein binding • beta-catenin binding • transcription factor binding • oxysterol binding • zinc ion binding • sequence-specific DNA binding • transcription factor activity, direct ligand regulated sequence-specific DNA binding Cellular component • nucleus • nucleoplasm Biological process • angiogenesis • regulation of transcription, DNA-templated • transcription initiation from RNA polymerase II promoter • xenobiotic metabolic process • nitric oxide biosynthetic process • circadian rhythm • regulation of smoothened signaling pathway • gene expression • positive regulation of vascular endothelial growth factor production • regulation of glucose metabolic process • regulation of steroid metabolic process • cerebellar Purkinje cell differentiation • cerebellar granule cell precursor proliferation • intracellular receptor signaling pathway • circadian regulation of gene expression • cellular response to sterol • muscle cell differentiation • positive regulation of circadian rhythm • regulation of macrophage activation • negative regulation of I-kappaB kinase/NF-kappaB signaling • steroid hormone mediated signaling pathway • negative regulation of fat cell differentiation • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • cGMP metabolic process • negative regulation of inflammatory response • regulation of transcription involved in cell fate commitment • triglyceride homeostasis • cellular response to interleukin-1 • cellular response to tumor necrosis factor • cellular response to hypoxia • T-helper 17 cell differentiation • regulation of cholesterol homeostasis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6095	19883
Ensembl	ENSG00000069667	ENSMUSG00000032238
UniProt	P35398	P51448
RefSeq (mRNA)	NM_002943	NM_001289916
RefSeq (protein)	NP_002934	NP_001276845
Location (UCSC)	Chr 15: 60.49 – 61.23 Mb	Chr 9: 68.65 – 69.39 Mb
PubMed search

RAR-related orphan receptor alpha (RORα), also known as NR1F1 (nuclear receptor subfamily 1, group F, member 1) is a nuclear receptor that in humans is encoded by the RORA gene.^[1] RORα participates in the transcriptional regulation of some genes involved in circadian rhythm.^[2]

Discovery

The first three human isoforms of RORα were initially cloned and characterized as nuclear receptors in 1994 by Giguère and colleagues, when their structure and function were first studied.^[3]

In the early 2000s, various studies demonstrated that RORα displays rhythmic patterns of expression in a circadian cycle in the liver, kidney, retina, and lung.^[4] Of interest, it was around this time that RORα abundance was found to be circadian in the mammalian suprachiasmatic nucleus.^[5] RORα is necessary for normal circadian rhythms in mice,^[6] demonstrating its importance in chronobiology.

Structure

The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors.^[6] In humans, 4 isoforms of RORα have been identified, which are generated via alternative splicing and promoter usage, and exhibit differential tissue-specific expression. The protein structure of RORα consists of four canonical functional groups: an N-terminal (A/B) domain, a DNA-binding domain containing two zinc fingers, a hinge domain, and a C-terminal ligand-binding domain. Within the ROR family, the DNA-binding domain is highly conserved, and the ligand-binding domain is only moderately conserved.^[4] Different isoforms of RORα have different binding specificities and strengths of transcriptional activity.^[1]

Regulation of circadian rhythm

The core mammalian circadian clock is a negative feedback loop which consists of Per1/Per2, Cry1/Cry2, Bmal1, and Clock.^[5] This feedback loop is stabilized through another loop involving the transcriptional regulation of Bmal1.^[7] Transactivation of Bmal1 is regulated through the upstream ROR/REV-ERB Response Element (RRE) in the Bmal1 promoter, to which RORα and REV-ERBα bind.^[7] This stabilizing regulatory loop itself is induced by the Bmal1/Clock heterodimer, which induces transcription of RORα and REV-ERBα.^[5] RORα, which activates transcription of Bmal1, and REV-ERBα, which represses transcription of Bmal1, compete to bind to the RRE.^[7] This feedback loop regulating the expression of Bmal1 is thought to stabilize the core clock mechanism, helping to buffer it against changes in the environment.^[7]

Mechanism

Specific association with ROR elements (RORE) in regulatory regions is necessary for RORα’s function as a transcriptional activator.^[8] RORα achieves this by specific binding to a consensus core motif in RORE, RGGTCA. This interaction is possible through the association of RORα’s first zinc finger with the core motif in the major groove, the P-box, and the association of its C-terminal extension with the AT-rich region in the 5’ region of RORE.^[6]

Homology

RORα, RORβ, and RORγ are all transcriptional activators recognizing ROR-response elements.^[9] ROR-alpha is expressed in a variety of cell types and is involved in regulating several aspects of development, inflammatory responses, and lymphocyte development.^[10] The RORα isoforms (RORα1 through RORα3) arise via alternative RNA processing, with RORα2 and RORα3 sharing an amino-terminal region different from RORα1.^[1] In contrast to RORα, RORβ is expressed in Central Nervous System (CNS) tissues involved in processing sensory information and in generating circadian rhythms while RORγ is critical in lymph node organogenesis and thymopoeisis.^[10]

The DNA-binding domains of the DHR3 orphan receptor in Drosophila shows especially close homology within amino and carboxy regions adjacent to the second zinc finger region in RORα, suggesting that this group of residues is important for the proteins' functionalities.^[1]

PDP1 and VRI in Drosophila regulate circadian rhythm's by competing for the same binding site, the VP box, similarly to how ROR and REV-ERB competitively bind to RRE.^[7] PDP1 and VRI constitute a feedback loop and are functional homologs of ROR and REV-ERB in mammals.^[7]

Direct orthologs of this gene have been identified in mice and humans.

Human cytochrome c pseudogene HC2 and RORα share overlapping genomic organization with the HC2 pseudogene located within the RORα2 transcription unit. The nucleotide and deduced amino acid sequences of cytochrome c-processed pseudogene are on the sense strand while those of the RORα2 amino-terminal exon are on the antisense strand.^[1]

Interactions

• DNA: RORα binds to the P-box of the RORE.^[6]
• Co-activators:
  • SRC-1, CBP, p300, TRIP-l, TRIP-230, transcription intermediary protein-1 (TIF-1), peroxisome proliferator-binding protein (PBP), and GRIP-1 physically interact with RORα.^[4]
    • LXXLL motif: ROR interacts with SRC-1, GRIP-l, CBP, and p300 via the LXXLL (L=Leucine, X=any amino acid) motifs on these proteins.^[4]
• Ubiquitination: RORα is targeted for the proteasome by ubiquitination. A co-repressor, Hairless, stabilizes RORα by protecting it from this process, which also represses RORα.^[11]
• Sumoylation: UBE21/UBC9: Ubiquitin-conjugating enzyme I interacts with RORs, but its effect is not yet known.^[6]
• Phosphorylation:
  • Phosphorylation of RORα1, which inhibits its transcriptional activity, is induced by Protein Kinase C.^[4]
  • ERK2: Extracellular signal-regulated kinase-2 also phosphorylates RORα.^[12]
• ATXN1: ATXN1 and RORα form part of a protein complex in Purkinje cells.^[6]
• FOXP3: FOXP3 directly represses the transcriptional activity of RORs.^[6]
• NME1: ROR has been shown to specifically interact with NME1.^[13]
• NM23-2: NM23-2 is a nucleoside diphosphate kinase involved in organogenesis and differentiation.^[2]
• NM23-1: NM23-1 is the product of a tumor metastasis suppressor candidate gene.^[2]

As a drug target

Because RORα and REV-ERBα are nuclear receptors that share the same target genes and are involved in processes that regulate metabolism, development, immunity, and circadian rhythm, they show potential as drug targets. Synthetic ligands have a variety of potential therapeutic uses, and can be used to treat diseases such as diabetes, atherosclerosis, autoimmunity, and cancer. T0901317 and SR1001, two synthetic ligands, have been found to be RORα and RORγ inverse agonists that suppress reporter activity and have been shown to delay onset and clinical severity of multiple sclerosis and other Th17 cell-mediated autoimmune diseases. SR1078 has been discovered as a RORα and RORγ agonist that increases the expression of G6PC and FGF21, yielding the therapeutic potential to treat obesity and diabetes as well as cancer of the breast, ovaries, and prostate. SR3335 has also been discovered as a RORα inverse agonist.^[3]

See also

• RAR-related orphan receptor
• REV-ERBα

References

1. Giguère V, Tini M, Flock G, Ong E, Evans RM, Otulakowski G (Mar 1994). "Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors". Genes & Development 8 (5): 538–553. doi:10.1101/gad.8.5.538. PMID 7926749.
2. "Entrez Gene: RORA RAR-related orphan receptor A".
3. Kojetin DJ, Burris TP (Mar 2014). "REV-ERB and ROR nuclear receptors as drug targets". Nature Reviews. Drug Discovery 13 (3): 197–216. doi:10.1038/nrd4100. PMID 24577401.
4. Jetten AM, Kurebayashi S, Ueda E (2001). "The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes". Progress in Nucleic Acid Research and Molecular Biology 69: 205–247. doi:10.1016/S0079-6603(01)69048-2. PMID 11550795.
5. Ko CH, Takahashi JS (Oct 2006). "Molecular components of the mammalian circadian clock". Human Molecular Genetics. 15 Spec No 2 (2): R271–R277. doi:10.1093/hmg/ddl207. PMID 16987893.
6. Jetten AM. "Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism". Nuclear Receptor Signaling 4. doi:10.1621/nrs.07003.
7. Emery P, Reppert SM (Aug 2004). "A rhythmic Ror". Neuron 43 (4): 443–446. doi:10.1016/j.neuron.2004.08.009. PMID 15312644.
8. Laitinen S, Staels B (2003). "Potential roles of ROR-alpha in cardiovascular endocrinology". Nuclear Receptor Signaling 1. doi:10.1621/nrs.01011. PMC 1402228. PMID 16604183.
9. Zhao X, Cho H, Yu RT, Atkins AR, Downes M, Evans RM (May 2014). "Nuclear receptors rock around the clock". EMBO Reports 15 (5): 518–528. doi:10.1002/embr.201338271. PMC 4210094. PMID 24737872.
10. Du J, Huang C, Zhou B, Ziegler SF (Apr 2008). "Isoform-specific inhibition of ROR alpha-mediated transcriptional activation by human FOXP3". Journal of Immunology 180 (7): 4785–4792. doi:10.4049/jimmunol.180.7.4785. PMID 18354202.
11. Jetten AM, Joo JH. "Retinoid-related Orphan Receptors (RORs): Roles in Cellular Differentiation and Development". Advances in Developmental Biology 16: 313–355. doi:10.1016/S1574-3349(06)16010-X. PMC 2312092. PMID 18418469.
12. Xiong G, Wang C, Evers BM, Zhou BP, Xu R (Apr 2012). "RORα suppresses breast tumor invasion by inducing SEMA3F expression". Cancer Research 72 (7): 1728–1739. doi:10.1158/0008-5472.CAN-11-2762. PMC 3319846. PMID 22350413.
13. Paravicini G, Steinmayr M, Andre E, Becker-Andre M (October 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. doi:10.1006/bbrc.1996.1471. PMID 8858107.

Further reading

• Giguere V, Beatty B, Squire J, Copeland NG, Jenkins NA (1996). "The orphan nuclear receptor ROR alpha (RORA) maps to a conserved region of homology on human chromosome 15q21-q22 and mouse chromosome 9.". Genomics 28 (3): 596–8. doi:10.1006/geno.1995.1197. PMID 7490103.
• Steinhilber D, Brungs M, Werz O, Wiesenberg I, Danielsson C, Kahlen JP, Nayeri S, Schräder M, Carlberg C (1995). "The nuclear receptor for melatonin represses 5-lipoxygenase gene expression in human B lymphocytes.". J. Biol. Chem. 270 (13): 7037–40. doi:10.1074/jbc.270.13.7037. PMID 7706239.
• Forman BM, Chen J, Blumberg B, Kliewer SA, Henshaw R, Ong ES, Evans RM (1995). "Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors.". Mol. Endocrinol. 8 (9): 1253–61. doi:10.1210/me.8.9.1253. PMID 7838158.
• Becker-Andre M, Andre 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. doi:10.1006/bbrc.1993.1976. PMID 7916608.
• Carlberg C, Hooft van Huijsduijnen R, Staple JK, DeLamarter JF, Becker-Andre M (1994). "RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers.". Mol. Endocrinol. 8 (6): 757–70. doi:10.1210/me.8.6.757. PMID 7935491.
• Paravicini G, Steinmayr M, Andre E, Becker-Andre 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. doi:10.1006/bbrc.1996.1471. PMID 8858107.
• Lau P, Bailey P, Dowhan DH, Muscat GE (1999). "Exogenous expression of a dominant negative RORalpha1 vector in muscle cells impairs differentiation: RORalpha1 directly interacts with p300 and myoD.". Nucleic Acids Res. 27 (2): 411–20. doi:10.1093/nar/27.2.411. PMC 148194. PMID 9862959.
• Atkins GB, Hu X, Guenther MG, Rachez C, Freedman LP, Lazar MA (1999). "Coactivators for the orphan nuclear receptor RORalpha.". Mol. Endocrinol. 13 (9): 1550–7. doi:10.1210/me.13.9.1550. PMID 10478845.
• Meyer T, Kneissel M, Mariani J, Fournier B (2000). "In vitro and in vivo evidence for orphan nuclear receptor RORalpha function in bone metabolism.". Proc. Natl. Acad. Sci. U.S.A. 97 (16): 9197–202. doi:10.1073/pnas.150246097. PMC 16845. PMID 10900268.
• Gawlas K, Stunnenberg HG (2001). "Differential binding and transcriptional behaviour of two highly related orphan receptors, ROR alpha(4) and ROR beta(1).". Biochim. Biophys. Acta 1494 (3): 236–41. doi:10.1016/s0167-4781(00)00237-2. PMID 11121580.
• Delerive P, Chin WW, Suen CS (2002). "Identification of Reverb(alpha) as a novel ROR(alpha) target gene.". J. Biol. Chem. 277 (38): 35013–8. doi:10.1074/jbc.M202979200. PMID 12114512.
• Moretti RM, Montagnani Marelli M, Motta M, Limonta P (2003). "Role of the orphan nuclear receptor ROR alpha in the control of the metastatic behavior of androgen-independent prostate cancer cells.". Oncol. Rep. 9 (5): 1139–43. doi:10.3892/or.9.5.1139. PMID 12168086.
• Raspe E, Mautino G, Duval C, Fontaine C, Duez H, Barbier O, Monte D, Fruchart J, Fruchart JC, Staels B (2003). "Transcriptional regulation of human Rev-erbalpha gene expression by the orphan nuclear receptor retinoic acid-related orphan receptor alpha.". J. Biol. Chem. 277 (51): 49275–81. doi:10.1074/jbc.M206215200. PMID 12377782.
• Kallen J, Schlaeppi JM, Bitsch F, Delhon I, Fournier B (2004). "Crystal structure of the human RORalpha Ligand binding domain in complex with cholesterol sulfate at 2.2 A.". J. Biol. Chem. 279 (14): 14033–8. doi:10.1074/jbc.M400302200. PMID 14722075.
• Migita H, Satozawa N, Lin JH, Morser J, Kawai K (2004). "RORalpha1 and RORalpha4 suppress TNF-alpha-induced VCAM-1 and ICAM-1 expression in human endothelial cells.". FEBS Lett. 557 (1-3): 269–74. doi:10.1016/S0014-5793(03)01502-3. PMID 14741380.
• Miki N, Ikuta M, Matsui T (2004). "Hypoxia-induced activation of the retinoic acid receptor-related orphan receptor alpha4 gene by an interaction between hypoxia-inducible factor-1 and Sp1.". J. Biol. Chem. 279 (15): 15025–31. doi:10.1074/jbc.M313186200. PMID 14742449.
• Migita H, Morser J, Kawai K (2004). "Rev-erbalpha upregulates NF-kappaB-responsive genes in vascular smooth muscle cells.". FEBS Lett. 561 (1-3): 69–74. doi:10.1016/S0014-5793(04)00118-8. PMID 15013753.

External links

• orphan nuclear receptor ROR-gamma at the US National Library of Medicine Medical Subject Headings (MeSH)