RAR-related orphan receptor

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RAR-related orphan receptor A (alpha)
Identifiers
Symbol RORA
Alt. symbols RZRA, ROR1, ROR2, ROR3, NR1F1
Entrez 6095
HUGO 10258
OMIM 600825
PDB 1N83
RefSeq NM_002943
UniProt P35398
Other data
Locus Chr. 15 q21-q22
RAR-related orphan receptor B (beta)
Identifiers
Symbol RORB
Alt. symbols RZRB, NR1F2, ROR-BETA
Entrez 6096
HUGO 10259
OMIM 601972
PDB 1NQ7
RefSeq NM_006914
UniProt Q92753
Other data
Locus Chr. 9 q22
RAR-related orphan receptor C (gamma)
Identifiers
Symbol RORC
Alt. symbols RZRG, RORG, NR1F3, TOR
Entrez 6097
HUGO 10260
OMIM 602943
RefSeq NM_005060
UniProt P51449
Other data
Locus Chr. 1 q21

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, , and 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[edit]

While the identify of natural ligands for the RORs remains controversial, similar to the liver X receptors (LXRs), it appears that the RORs are activated 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[6] 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.[7] 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.[8]

Tissue distribution[edit]

RORα, RORβ, and RORγ are primarily expressed the following tissues:[6]

  • 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[edit]

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

As drug targets[edit]

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]

References[edit]

  1. ^ 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. 
  2. ^ Hirose T, Smith RJ, Jetten AM (December 1994). "ROR gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle". Biochemical and Biophysical Research Communications. 205 (3): 1976–83. doi:10.1006/bbrc.1994.2902. PMID 7811290. 
  3. ^ 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. 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. 
  4. ^ a b c d e Solt LA, Burris TP (December 2012). "Action of RORs and their ligands in (patho)physiology". Trends in Endocrinology and Metabolism. 23 (12): 619–27. doi:10.1016/j.tem.2012.05.012. PMC 3500583Freely accessible. PMID 22789990. 
  5. ^ Santori FR (2015). "Nuclear hormone receptors put immunity on sterols". European Journal of Immunology. 45 (10): 2730–41. doi:10.1002/eji.201545712. PMC 4651655Freely accessible. PMID 26222181. 
  6. ^ a b Zhang Y, Luo XY, Wu DH, Xu Y (January 2015). "ROR nuclear receptors: structures, related diseases, and drug discovery". Acta Pharmacologica Sinica. 36 (1): 71–87. doi:10.1038/aps.2014.120. PMC 4571318Freely accessible. PMID 25500868. 
  7. ^ Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, Moras D, Schüle R (October 2003). "All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta". Nature Structural Biology. 10 (10): 820–5. doi:10.1038/nsb979. PMID 12958591. 
  8. ^ Wiesenberg I, Missbach M, Kahlen JP, Schräder M, Carlberg C (February 1995). "Transcriptional activation of the nuclear receptor RZR alpha by the pineal gland hormone melatonin and identification of CGP 52608 as a synthetic ligand". Nucleic Acids Research. 23 (3): 327–33. doi:10.1093/nar/23.3.327. PMC 306679Freely accessible. PMID 7885826. 
  9. ^ Jetten AM (December 2004). "Recent advances in the mechanisms of action and physiological functions of the retinoid-related orphan receptors (RORs)". Current Drug Targets. Inflammation and Allergy. 3 (4): 395–412. doi:10.2174/1568010042634497. PMID 15584888. 
  10. ^ Jetten AM, Joo JH (2006). "Retinoid-related Orphan Receptors (RORs): Roles in Cellular Differentiation and Development". Advances in Developmental Biology (Amsterdam, Netherlands). 16: 313–355. doi:10.1016/S1574-3349(06)16010-X. PMC 2312092Freely accessible. PMID 18418469. 
  11. ^ Feng S, Xu S, Wen Z, Zhu Y (2015). "Retinoic acid-related orphan receptor RORβ, circadian rhythm abnormalities and tumorigenesis (Review)". International Journal of Molecular Medicine. 35 (6): 1493–500. doi:10.3892/ijmm.2015.2155. PMID 25816151. 
  12. ^ Cyr P, Bronner SM, Crawford JJ (2016). "Recent progress on nuclear receptor RORγ modulators". Bioorganic & Medicinal Chemistry Letters. 26 (18): 4387–93. doi:10.1016/j.bmcl.2016.08.012. PMID 27542308. 
  13. ^ Bronner SM, Zbieg JR, Crawford JJ (2017). "RORγ antagonists and inverse agonists: a patent review". Expert Opinion on Therapeutic Patents. 27 (1): 101–112. doi:10.1080/13543776.2017.1236918. PMID 27629281. 

Further reading[edit]

External links[edit]