| 词条 | RAR-related orphan receptor alpha |
| 释义 |
DiscoveryThe 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.[8] 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.[10] Of interest, it was around this time that RORα abundance was found to be circadian in the mammalian suprachiasmatic nucleus.[11] RORα is necessary for normal circadian rhythms in mice,[12] demonstrating its importance in chronobiology. StructureThe protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors.[12] 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.[10] Different isoforms of RORα have different binding specificities and strengths of transcriptional activity.[1] Regulation of circadian rhythmThe core mammalian circadian clock is a negative feedback loop which consists of Per1/Per2, Cry1/Cry2, Bmal1, and Clock.[9] This feedback loop is stabilized through another loop involving the transcriptional regulation of Bmal1.[10] 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.[10] This stabilizing regulatory loop itself is induced by the Bmal1/Clock heterodimer, which induces transcription of RORα and REV-ERBα.[9] RORα, which activates transcription of Bmal1, and REV-ERBα, which represses transcription of Bmal1, compete to bind to the RRE.[10] 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.[10] MechanismSpecific association with ROR elements (RORE) in regulatory regions is necessary for RORα’s function as a transcriptional activator.[11] 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.[12] HomologyRORα, RORβ, and RORγ are all transcriptional activators recognizing ROR-response elements.[12] ROR-alpha is expressed in a variety of cell types and is involved in regulating several aspects of development, inflammatory responses, and lymphocyte development.[13] 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.[13] 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.[10] PDP1 and VRI constitute a feedback loop and are functional homologs of ROR and REV-ERB in mammals.[10] 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
As a drug targetBecause 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.[8] See also
References1. ^1 2 3 4 {{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 = Sidman RL, Lane PW, Dickie MM | title = Staggerer, a new mutation in the mouse affecting the cerebellum | journal = Science | volume = 137 | issue = 3530 | pages = 610–2 | date = August 1962 | pmid = 13912552 | doi=10.1126/science.137.3530.610}} 3. ^{{cite journal | vauthors = Hamilton BA, Frankel WN, Kerrebrock AW, Hawkins TL, FitzHugh W, Kusumi K, Russell LB, Mueller KL, van Berkel V, Birren BW, Kruglyak L, Lander ES | title = Disruption of the nuclear hormone receptor RORalpha in staggerer mice | journal = Nature | volume = 379 | issue = 6567 | pages = 736–9 | date = February 1996 | pmid = 8602221 | doi = 10.1038/379736a0 }} 4. ^{{cite journal | vauthors = Gold DA, Baek SH, Schork NJ, Rose DW, Larsen DD, Sachs BD, Rosenfeld MG, Hamilton BA | title = RORalpha coordinates reciprocal signaling in cerebellar development through sonic hedgehog and calcium-dependent pathways | journal = Neuron | volume = 40 | issue = 6 | pages = 1119–31 | date = December 2003 | pmid = 14687547 | pmc = 2717708 | doi=10.1016/s0896-6273(03)00769-4}} 5. ^{{cite journal | vauthors = Halim TY, MacLaren A, Romanish MT, Gold MJ, McNagny KM, Takei F | title = Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation | journal = Immunity | volume = 37 | issue = 3 | pages = 463–74 | date = September 2012 | pmid = 22981535 | doi = 10.1016/j.immuni.2012.06.012 }} 6. ^{{cite journal | vauthors = Gold MJ, Antignano F, Halim TY, Hirota JA, Blanchet MR, Zaph C, Takei F, McNagny KM | title = Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures | journal = The Journal of Allergy and Clinical Immunology | volume = 133 | issue = 4 | pages = 1142–8 | date = April 2014 | pmid = 24679471 | doi = 10.1016/j.jaci.2014.02.033 }} 7. ^{{cite journal|last1=Lo|first1=Bernard C.|last2=Gold|first2=Matthew J.|last3=Hughes|first3=Michael R.|last4=Antignano|first4=Frann|last5=Valdez|first5=Yanet|last6=Zaph|first6=Colby|last7=Harder|first7=Kenneth W.|last8=McNagny|first8=Kelly M. | name-list-format = vanc | title = The orphan nuclear receptor RORα and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn’s disease | journal = Science Immunology | date = 2 September 2016 | volume = 1 | issue = 3 | pages = eaaf8864–eaaf8864 | doi = 10.1126/sciimmunol.aaf8864 }} 8. ^1 {{cite journal | vauthors = Kojetin DJ, Burris TP | title = REV-ERB and ROR nuclear receptors as drug targets | journal = Nature Reviews. Drug Discovery | volume = 13 | issue = 3 | pages = 197–216 | date = March 2014 | pmid = 24577401 | pmc = 4865262 | doi = 10.1038/nrd4100 }} 9. ^1 2 {{cite journal | vauthors = Ko CH, Takahashi JS | title = Molecular components of the mammalian circadian clock | journal = Human Molecular Genetics | volume = 15 Spec No 2 | issue = 2 | pages = R271-7 | date = October 2006 | pmid = 16987893 | doi = 10.1093/hmg/ddl207 | pmc = 3762864 }} 10. ^1 2 3 4 5 {{cite journal | vauthors = Emery P, Reppert SM | title = A rhythmic Ror | journal = Neuron | volume = 43 | issue = 4 | pages = 443–6 | date = August 2004 | pmid = 15312644 | doi = 10.1016/j.neuron.2004.08.009 }} 11. ^{{cite journal | vauthors = Laitinen S, Staels B | title = Potential roles of ROR-alpha in cardiovascular endocrinology | journal = Nuclear Receptor Signaling | volume = 1 | pages = e011 | year = 2003 | pmid = 16604183 | pmc = 1402228 | doi = 10.1621/nrs.01011 }} 12. ^{{cite journal | vauthors = Zhao X, Cho H, Yu RT, Atkins AR, Downes M, Evans RM | title = Nuclear receptors rock around the clock | journal = EMBO Reports | volume = 15 | issue = 5 | pages = 518–28 | date = May 2014 | pmid = 24737872 | pmc = 4210094 | doi = 10.1002/embr.201338271 }} 13. ^1 {{cite journal | vauthors = Du J, Huang C, Zhou B, Ziegler SF | title = Isoform-specific inhibition of ROR alpha-mediated transcriptional activation by human FOXP3 | journal = Journal of Immunology | volume = 180 | issue = 7 | pages = 4785–92 | date = April 2008 | pmid = 18354202 | doi = 10.4049/jimmunol.180.7.4785 }} 14. ^1 2 3 4 5 6 {{cite journal | vauthors = Jetten AM | title = Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism | journal = Nuclear Receptor Signaling | volume = 7 | pages = e003 | pmid = 19381306 | doi = 10.1621/nrs.07003 | pmc=2670432}} 15. ^1 2 3 4 {{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 | pages = 205–47 | year = 2001 | pmid = 11550795 | doi = 10.1016/S0079-6603(01)69048-2 }} 16. ^{{cite journal | vauthors = Jetten AM, Joo JH | title = Retinoid-related Orphan Receptors (RORs): Roles in Cellular Differentiation and Development | journal = Advances in Developmental Biology | volume = 16 | pages = 313–355 | pmid = 18418469 | pmc = 2312092 | doi = 10.1016/S1574-3349(06)16010-X }} 17. ^{{cite journal | vauthors = Xiong G, Wang C, Evers BM, Zhou BP, Xu R | title = RORα suppresses breast tumor invasion by inducing SEMA3F expression | journal = Cancer Research | volume = 72 | issue = 7 | pages = 1728–39 | date = April 2012 | pmid = 22350413 | pmc = 3319846 | doi = 10.1158/0008-5472.CAN-11-2762 }} 18. ^{{cite journal | vauthors = Paravicini G, Steinmayr M, André E, Becker-André M | title = The metastasis suppressor candidate nucleotide diphosphate kinase NM23 specifically interacts with members of the ROR/RZR nuclear orphan receptor subfamily | journal = Biochemical and Biophysical Research Communications | volume = 227 | issue = 1 | pages = 82–7 | date = October 1996 | pmid = 8858107 | doi = 10.1006/bbrc.1996.1471 }} 19. ^1 2 {{cite web | title = Entrez Gene: RORA RAR-related orphan receptor A| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6095| accessdate = }} Further reading{{refbegin|33em}}
External links
2 : Intracellular receptors|Transcription factors |
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