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RAR-related orphan receptor alpha

From Wikipedia, the free encyclopedia

"RORA" redirects here. For other uses, see Rora (disambiguation).
RORA
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesRORA, NR1F1, ROR1, ROR2, ROR3, RZR-ALPHA, RZRA, RAR related orphan receptor A, IDDECA
External IDsOMIM: 600825; MGI: 104661; HomoloGene: 56594; GeneCards: RORA; OMA:RORA - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6095

19883

Ensembl

ENSG00000069667

ENSMUSG00000032238

UniProt

P35398

P51448

RefSeq (mRNA)

NM_002943
NM_134260
NM_134261
NM_134262

NM_013646
NM_001289916
NM_001289917

RefSeq (protein)

NP_002934
NP_599022
NP_599023
NP_599024

NP_001276845
NP_001276846
NP_038674

Location (UCSC)Chr 15: 60.49 – 61.23 MbChr 9: 68.56 – 69.3 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5] RORα participates in the transcriptional regulation of some genes involved in circadian rhythm.[6] In mice, RORα is essential for development of cerebellum[7][8] through direct regulation of genes expressed in Purkinje cells.[9] It also plays an essential role in the development of type 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient.[10][11] In addition, although present in normal numbers, the ILC3 and Th17 cells from RORα deficient mice are defective for cytokine production.[12]

Discovery

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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.[13]

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.[14] Of interest, it was around this time that RORα abundance was found to be circadian in the mammalian suprachiasmatic nucleus.[15] RORα is necessary for normal circadian rhythms in mice,[16] demonstrating its importance in chronobiology.

Structure

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The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors.[16] 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.[14] Different isoforms of RORα have different binding specificities and strengths of transcriptional activity.[5]

Regulation of circadian rhythm

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The core mammalian circadian clock is a negative feedback loop which consists of Per1/Per2, Cry1/Cry2, Bmal1, and Clock.[15] This feedback loop is stabilized through another loop involving the transcriptional regulation of Bmal1.[17] 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.[17] This stabilizing regulatory loop itself is induced by the Bmal1/Clock heterodimer, which induces transcription of RORα and REV-ERBα.[15] RORα, which activates transcription of Bmal1, and REV-ERBα, which represses transcription of Bmal1, compete to bind to the RRE.[17] 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.[17]

Mechanism

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Specific association with ROR elements (RORE) in regulatory regions is necessary for RORα's function as a transcriptional activator.[18] 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.[16]

Homology

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RORα, RORβ, and RORγ are all transcriptional activators recognizing ROR-response elements.[19] ROR-alpha is expressed in a variety of cell types and is involved in regulating several aspects of development, inflammatory responses, and lymphocyte development.[20] The RORα isoforms (RORα1 through RORα3) arise via alternative RNA processing, with RORα2 and RORα3 sharing an amino-terminal region different from RORα1.[5] 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.[20]

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.[5]

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.[17] PDP1 and VRI constitute a feedback loop and are functional homologs of ROR and REV-ERB in mammals.[17]

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.[5]

Interactions

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As a drug target

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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.[13]

CGP 52608

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000069667 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032238 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c d e Giguère V, Tini M, Flock G, Ong E, Evans RM, Otulakowski G (March 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): 538–53. doi:10.1101/gad.8.5.538. PMID 7926749.
  6. ^ a b c "Entrez Gene: RORA RAR-related orphan receptor A".
  7. ^ Sidman RL, Lane PW, Dickie MM (August 1962). "Staggerer, a new mutation in the mouse affecting the cerebellum". Science. 137 (3530): 610–2. Bibcode:1962Sci...137..610S. doi:10.1126/science.137.3530.610. PMID 13912552. S2CID 30733570.
  8. ^ Hamilton BA, Frankel WN, Kerrebrock AW, Hawkins TL, FitzHugh W, Kusumi K, et al. (February 1996). "Disruption of the nuclear hormone receptor RORalpha in staggerer mice". Nature. 379 (6567): 736–9. Bibcode:1996Natur.379..736H. doi:10.1038/379736a0. PMID 8602221. S2CID 4318427.
  9. ^ Gold DA, Baek SH, Schork NJ, Rose DW, Larsen DD, Sachs BD, et al. (December 2003). "RORalpha coordinates reciprocal signaling in cerebellar development through sonic hedgehog and calcium-dependent pathways". Neuron. 40 (6): 1119–31. doi:10.1016/s0896-6273(03)00769-4. PMC 2717708. PMID 14687547.
  10. ^ Halim TY, MacLaren A, Romanish MT, Gold MJ, McNagny KM, Takei F (September 2012). "Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation". Immunity. 37 (3): 463–74. doi:10.1016/j.immuni.2012.06.012. PMID 22981535.
  11. ^ Gold MJ, Antignano F, Halim TY, Hirota JA, Blanchet MR, Zaph C, et al. (April 2014). "Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures". The Journal of Allergy and Clinical Immunology. 133 (4): 1142–8. doi:10.1016/j.jaci.2014.02.033. PMID 24679471.
  12. ^ Lo BC, Gold MJ, Hughes MR, Antignano F, Valdez Y, Zaph C, et al. (September 2016). "The orphan nuclear receptor ROR alpha and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn's disease". Science Immunology. 1 (3): eaaf8864. doi:10.1126/sciimmunol.aaf8864. PMC 5489332. PMID 28670633.
  13. ^ a b Kojetin DJ, Burris TP (March 2014). "REV-ERB and ROR nuclear receptors as drug targets". Nature Reviews. Drug Discovery. 13 (3): 197–216. doi:10.1038/nrd4100. PMC 4865262. PMID 24577401.
  14. ^ a b c d e 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: 205–47. doi:10.1016/S0079-6603(01)69048-2. ISBN 978-0-12-540069-5. PMID 11550795.
  15. ^ a b c Ko CH, Takahashi JS (October 2006). "Molecular components of the mammalian circadian clock". Human Molecular Genetics. 15 Spec No 2 (2): R271-7. doi:10.1093/hmg/ddl207. PMC 3762864. PMID 16987893.
  16. ^ a b c d e f Emery P, Reppert SM (August 2004). "A rhythmic Ror". Neuron. 43 (4): 443–6. doi:10.1016/j.neuron.2004.08.009. PMID 15312644.
  17. ^ Laitinen S, Staels B (2003). "Potential roles of ROR-alpha in cardiovascular endocrinology". Nuclear Receptor Signaling. 1: e011. doi:10.1621/nrs.01011. PMC 1402228. PMID 16604183.
  18. ^ Zhao X, Cho H, Yu RT, Atkins AR, Downes M, Evans RM (May 2014). "Nuclear receptors rock around the clock". EMBO Reports. 15 (5): 518–28. doi:10.1002/embr.201338271. PMC 4210094. PMID 24737872.
  19. ^ a b Du J, Huang C, Zhou B, Ziegler SF (April 2008). "Isoform-specific inhibition of ROR alpha-mediated transcriptional activation by human FOXP3". Journal of Immunology. 180 (7): 4785–92. doi:10.4049/jimmunol.180.7.4785. PMID 18354202.
  20. ^ Xiong G, Wang C, Evers BM, Zhou BP, Xu R (April 2012). "RORα suppresses breast tumor invasion by inducing SEMA3F expression". Cancer Research. 72 (7): 1728–39. doi:10.1158/0008-5472.CAN-11-2762. PMC 3319846. PMID 22350413.
  21. ^ Paravicini G, Steinmayr M, André E, Becker-André M (October 1996). "The metastasis suppressor candidate nucleotide diphosphate kinase NM23 specifically interacts with members of the ROR/RZR nuclear orphan receptor subfamily". Biochemical and Biophysical Research Communications. 227 (1): 82–7. doi:10.1006/bbrc.1996.1471. PMID 8858107.

Further reading

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