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词条 RAR-related orphan receptor
释义

  1. Ligands

  2. Tissue distribution

  3. Function

  4. As drug targets

  5. References

  6. Further reading

  7. External links

{{infobox protein | Name = RAR-related orphan receptor A (alpha) | caption = | image = | width = | HGNCid = 10258 | Symbol = RORA | AltSymbols = RZRA, ROR1, ROR2, ROR3, NR1F1 | EntrezGene = 6095 | OMIM = 600825 | RefSeq = NM_002943 | UniProt = P35398 | PDB = 1N83 | ECnumber = | Chromosome = 15 | Arm = q | Band = 21 | LocusSupplementaryData = -q22}}{{infobox protein | Name = RAR-related orphan receptor B (beta) | caption = | image = | width = | HGNCid = 10259 | Symbol = RORB | AltSymbols = RZRB, NR1F2, ROR-BETA| EntrezGene = 6096 | OMIM = 601972 | RefSeq = NM_006914 | UniProt = Q92753 | PDB = 1NQ7 | ECnumber = | Chromosome = 9 | Arm = q | Band = 22 | LocusSupplementaryData = }}{{infobox protein | Name = RAR-related orphan receptor C (gamma) |caption = | image = | width = | HGNCid = 10260 | Symbol = RORC | AltSymbols = RZRG, RORG, NR1F3, TOR | EntrezGene = 6097 | OMIM = 602943 | RefSeq = NM_005060 | UniProt = P51449 | PDB = | ECnumber = | Chromosome = 1 | Arm = q | Band = 21 | LocusSupplementaryData = }}

The RAR-related orphan receptors (RORs) are members of the nuclear receptor family of intracellular transcription factors.[1][2] There are three forms of ROR, ROR-α, -β, and -γ and each is encoded by a separate gene RORA, RORB, and RORC respectively. The RORs are somewhat unusual in that they appear to bind as monomers to hormone response elements as opposed to the majority of other nuclear receptors which bind as dimers.[3]

Ligands

While the identity of natural ligands for the RORs remains controversial, similar to the liver X receptors (LXRs), it appears that the RORs are activated by oxysterols.[4][5] Furthermore, the RORs appear to be constitutively active (absence of ligand) and that activity may be due to continuously bound natural ligands.[4] Side chain oxygenated sterols (e.g., 20α-hydroxycholesterol, 22R-hydroxycholesterol, and 25-hydroxycholesterol) are high affinity RORγ agonists[7] while sterols oxygenated at the 7-position, (e.g., (7-hydroxycholesterol and 7-ketocholesterol) function as inverse agonists for both RORa and RORγ.[4] A number of other natural substances have also been reported to bind to the RORs. These include all-trans retinoic acid binds with high affinity to ROR-β and -γ but not ROR-α.[6] Finally the RORs may function as lipid sensors and hence may play a role in the regulation of lipid metabolism.[4]

Melatonin has been claimed to be an endogenous ligand for ROR-α while CGP 52608 has been identified as a ROR-α selective synthetic ligand.[7]

Tissue distribution

RORα, RORβ, and RORγ are primarily expressed the following tissues:[8]

  • ROR-α – widely expressed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus, and brain.
  • ROR-β – expression restricted to the brain and retina.
  • ROR-γ – highly expressed in thymus (the thymus-specific isoform is referred to as RORγt), muscle, testis, pancreas, prostate, heart, and liver.

Function

The three forms of RORs fulfill a number of critical roles[9] including:

  • ROR-α – Involved in the maintenance of the circadian rhythm by positively regulating the expression of BMAL1.[4] Development of the cerebellum and lymph nodes, lipid metabolism, immune response, maintenance of bone.[10]
  • ROR-β – Circadian rhythm, bone metabolism, and retinal neurogenesis.[11]
  • ROR-γ – Lymph node development and immune response, survival of T helper 17 cells.

As drug targets

A number of synthetic RORγt inverse agonists are in various stages of drug development for the treatment of inflammatory diseases. RORγt agonists have also been proposed for use as immunooncology agents to activate the immune system to treat cancer.[12][13]

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References

1. ^{{cite journal | vauthors = Giguère V, Tini M, Flock G, Ong E, Evans RM, Otulakowski G | title = Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors | journal = Genes & Development | volume = 8 | issue = 5 | pages = 538–53 | date = March 1994 | pmid = 7926749 | doi = 10.1101/gad.8.5.538 }}
2. ^{{cite journal | vauthors = Hirose T, Smith RJ, Jetten AM | title = ROR gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle | journal = Biochemical and Biophysical Research Communications | volume = 205 | issue = 3 | pages = 1976–83 | date = December 1994 | pmid = 7811290 | doi = 10.1006/bbrc.1994.2902 }}
3. ^{{cite journal | vauthors = Jetten AM, Kurebayashi S, Ueda E | title = The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes | journal = Progress in Nucleic Acid Research and Molecular Biology | volume = 69 | issue = | pages = 205–47 | year = 2001 | pmid = 11550795 | doi = 10.1016/S0079-6603(01)69048-2 | isbn = 978-0-12-540069-5 | series = Progress in Nucleic Acid Research and Molecular Biology }}
4. ^1 2 3 4 {{cite journal | vauthors = Solt LA, Burris TP | title = Action of RORs and their ligands in (patho)physiology | journal = Trends in Endocrinology and Metabolism | volume = 23 | issue = 12 | pages = 619–27 | date = December 2012 | pmid = 22789990 | pmc = 3500583 | doi = 10.1016/j.tem.2012.05.012 }}
5. ^{{cite journal | vauthors = Santori FR | title = Nuclear hormone receptors put immunity on sterols | journal = European Journal of Immunology | volume = 45 | issue = 10 | pages = 2730–41 | year = 2015 | pmid = 26222181 | pmc = 4651655 | doi = 10.1002/eji.201545712 }}
6. ^{{cite journal | vauthors = Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, Moras D, Schüle R | title = All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta | journal = Nature Structural Biology | volume = 10 | issue = 10 | pages = 820–5 | date = October 2003 | pmid = 12958591 | doi = 10.1038/nsb979 }}
7. ^{{cite journal | vauthors = Wiesenberg I, Missbach M, Kahlen JP, Schräder M, Carlberg C | title = Transcriptional activation of the nuclear receptor RZR alpha by the pineal gland hormone melatonin and identification of CGP 52608 as a synthetic ligand | journal = Nucleic Acids Research | volume = 23 | issue = 3 | pages = 327–33 | date = February 1995 | pmid = 7885826 | pmc = 306679 | doi = 10.1093/nar/23.3.327 }}
8. ^1 {{cite journal | vauthors = Zhang Y, Luo XY, Wu DH, Xu Y | title = ROR nuclear receptors: structures, related diseases, and drug discovery | journal = Acta Pharmacologica Sinica | volume = 36 | issue = 1 | pages = 71–87 | date = January 2015 | pmid = 25500868 | pmc = 4571318 | doi = 10.1038/aps.2014.120 }}
9. ^{{cite journal | vauthors = Jetten AM | title = Recent advances in the mechanisms of action and physiological functions of the retinoid-related orphan receptors (RORs) | journal = Current Drug Targets. Inflammation and Allergy | volume = 3 | issue = 4 | pages = 395–412 | date = December 2004 | pmid = 15584888 | doi = 10.2174/1568010042634497 }}
10. ^{{cite journal | vauthors = Jetten AM, Joo JH | title = Retinoid-related Orphan Receptors (RORs): Roles in Cellular Differentiation and Development | journal = Advances in Developmental Biology (Amsterdam, Netherlands) | volume = 16 | issue = | pages = 313–355 | year = 2006 | pmid = 18418469 | pmc = 2312092 | doi = 10.1016/S1574-3349(06)16010-X }}
11. ^{{cite journal | vauthors = Feng S, Xu S, Wen Z, Zhu Y | title = Retinoic acid-related orphan receptor RORβ, circadian rhythm abnormalities and tumorigenesis (Review) | journal = International Journal of Molecular Medicine | volume = 35 | issue = 6 | pages = 1493–500 | year = 2015 | pmid = 25816151 | doi = 10.3892/ijmm.2015.2155 | url = }}
12. ^{{cite journal | vauthors = Cyr P, Bronner SM, Crawford JJ | title = Recent progress on nuclear receptor RORγ modulators | journal = Bioorganic & Medicinal Chemistry Letters | volume = 26 | issue = 18 | pages = 4387–93 | year = 2016 | pmid = 27542308 | doi = 10.1016/j.bmcl.2016.08.012 }}
13. ^{{cite journal | vauthors = Bronner SM, Zbieg JR, Crawford JJ | title = RORγ antagonists and inverse agonists: a patent review | journal = Expert Opinion on Therapeutic Patents | volume = 27 | issue = 1 | pages = 101–112 | year = 2017 | pmid = 27629281 | doi = 10.1080/13543776.2017.1236918 }}

Further reading

{{refbegin|33em}}
  • {{cite journal | vauthors = Solt LA, Griffin PR, Burris TP | title = Ligand regulation of retinoic acid receptor-related orphan receptors: implications for development of novel therapeutics | journal = Current Opinion in Lipidology | volume = 21 | issue = 3 | pages = 204–11 | date = June 2010 | pmid = 20463469 | pmc = 5024716 | doi = 10.1097/MOL.0b013e328338ca18 }}
  • {{cite journal | vauthors = Chang MR, Rosen H, Griffin PR | title = RORs in autoimmune disease | journal = Current Topics in Microbiology and Immunology | volume = 378 | issue = | pages = 171–82 | year = 2014 | pmid = 24728598 | doi = 10.1007/978-3-319-05879-5_8 }}
{{refend}}

External links

  • {{MeshName|RAR-related+orphan+receptor+A}}
  • {{MeshName|RAR-related+orphan+receptor+B}}
  • {{MeshName|RAR-related+orphan+receptor+C}}
{{Transcription factors|g2}}{{Nuclear receptor ligands}}{{receptor-stub}}

2 : Intracellular receptors|Transcription factors
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