RAR-related orphan receptor alpha: Difference between revisions

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Latest revision as of 12:40, 9 January 2019

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] In mice, RORα is essential for development of cerebellum^[3]^[4] through direct regulation of genes expressed in Purkinje cells.^[5] It also plays an essential role in the development of type 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient.^[6]^[7] In addition, although present in normal numbers, the ILC3 and Th17 cells from RORα deficient mice are defective for cytokine production.^[8]

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.^[9]

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.

Structure

The 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 rhythm

The core mammalian circadian clock is a negative feedback loop which consists of Per1/Per2, Cry1/Cry2, Bmal1, and Clock.^[11] This feedback loop is stabilized through another loop involving the transcriptional regulation of Bmal1.^[13] 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.^[13] This stabilizing regulatory loop itself is induced by the Bmal1/Clock heterodimer, which induces transcription of RORα and REV-ERBα.^[11] RORα, which activates transcription of Bmal1, and REV-ERBα, which represses transcription of Bmal1, compete to bind to the RRE.^[13] 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.^[13]

Mechanism

Specific association with ROR elements (RORE) in regulatory regions is necessary for RORα’s function as a transcriptional activator.^[14] 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]

Homology

RORα, RORβ, and RORγ are all transcriptional activators recognizing ROR-response elements.^[15] ROR-alpha is expressed in a variety of cell types and is involved in regulating several aspects of development, inflammatory responses, and lymphocyte development.^[16] 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.^[16]

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.^[13] PDP1 and VRI constitute a feedback loop and are functional homologs of ROR and REV-ERB in mammals.^[13]

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.^[12]
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.^[10]
  - 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.^[10]
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.^[17]
Sumoylation: UBE21/UBC9: Ubiquitin-conjugating enzyme I interacts with RORs, but its effect is not yet known.^[12]
Phosphorylation:
- Phosphorylation of RORα1, which inhibits its transcriptional activity, is induced by Protein Kinase C.^[10]
- ERK2: Extracellular signal-regulated kinase-2 also phosphorylates RORα.^[18]
ATXN1: ATXN1 and RORα form part of a protein complex in Purkinje cells.^[12]
FOXP3: FOXP3 directly represses the transcriptional activity of RORs.^[12]
NME1: ROR has been shown to specifically interact with NME1.^[19]
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.^[9]

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 ^1.4 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.
↑ ^2.0 ^2.1 ^2.2 "Entrez Gene: RORA RAR-related orphan receptor A".
↑ Sidman RL, Lane PW, Dickie MM (August 1962). "Staggerer, a new mutation in the mouse affecting the cerebellum". Science. 137 (3530): 610–2. doi:10.1126/science.137.3530.610. PMID 13912552.
↑ 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 (February 1996). "Disruption of the nuclear hormone receptor RORalpha in staggerer mice". Nature. 379 (6567): 736–9. doi:10.1038/379736a0. PMID 8602221.
↑ Gold DA, Baek SH, Schork NJ, Rose DW, Larsen DD, Sachs BD, Rosenfeld MG, Hamilton BA (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.
↑ 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.
↑ Gold MJ, Antignano F, Halim TY, Hirota JA, Blanchet MR, Zaph C, Takei F, McNagny KM (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.
↑ Lo BC, Gold MJ, Hughes MR, Antignano F, Valdez Y, Zaph C, Harder KW, McNagny KM (2 September 2016). "The orphan nuclear receptor RORα and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn's disease". Science Immunology. 1 (3): eaaf8864–eaaf8864. doi:10.1126/sciimmunol.aaf8864.
↑ ^9.0 ^9.1 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.
↑ ^10.0 ^10.1 ^10.2 ^10.3 ^10.4 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: 205–47. doi:10.1016/S0079-6603(01)69048-2. PMID 11550795.
↑ ^11.0 ^11.1 ^11.2 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.
↑ ^12.0 ^12.1 ^12.2 ^12.3 ^12.4 ^12.5 ^12.6 Jetten AM. "Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism". Nuclear Receptor Signaling. 7: e003. doi:10.1621/nrs.07003. PMC 2670432. PMID 19381306.
↑ ^13.0 ^13.1 ^13.2 ^13.3 ^13.4 ^13.5 Emery P, Reppert SM (August 2004). "A rhythmic Ror". Neuron. 43 (4): 443–6. doi:10.1016/j.neuron.2004.08.009. PMID 15312644.
↑ 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.
↑ 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.
↑ ^16.0 ^16.1 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.
↑ 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.
↑ 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.
↑ 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.

External links

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

[Giguère_1994-1] 1.0 ^1.1 ^1.2 ^1.3 ^1.4 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.

[entrez-2] 2.0 ^2.1 ^2.2 "Entrez Gene: RORA RAR-related orphan receptor A".

[3] Sidman RL, Lane PW, Dickie MM (August 1962). "Staggerer, a new mutation in the mouse affecting the cerebellum". Science. 137 (3530): 610–2. doi:10.1126/science.137.3530.610. PMID 13912552.

[4] 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 (February 1996). "Disruption of the nuclear hormone receptor RORalpha in staggerer mice". Nature. 379 (6567): 736–9. doi:10.1038/379736a0. PMID 8602221.

[5] Gold DA, Baek SH, Schork NJ, Rose DW, Larsen DD, Sachs BD, Rosenfeld MG, Hamilton BA (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.

[6] 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.

[7] Gold MJ, Antignano F, Halim TY, Hirota JA, Blanchet MR, Zaph C, Takei F, McNagny KM (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.

[8] Lo BC, Gold MJ, Hughes MR, Antignano F, Valdez Y, Zaph C, Harder KW, McNagny KM (2 September 2016). "The orphan nuclear receptor RORα and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn's disease". Science Immunology. 1 (3): eaaf8864–eaaf8864. doi:10.1126/sciimmunol.aaf8864.

[REV-ERB_and_ROR_nuclear_receptors_as_drug_targets-9] 9.0 ^9.1 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.

[The_ROR_nuclear_orphan_receptor_subfamily:_critical_regulators_of_multiple_biological_processes-10] 10.0 ^10.1 ^10.2 ^10.3 ^10.4 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: 205–47. doi:10.1016/S0079-6603(01)69048-2. PMID 11550795.

[Molecular_components_of_the_mammalian_circadian_clock-11] 11.0 ^11.1 ^11.2 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.

[Retinoid-related_orphan_receptors_(RORs):_critical_roles_in_development,_immunity,_circadian_rhythm,_and_cellular_metabolism-12] 12.0 ^12.1 ^12.2 ^12.3 ^12.4 ^12.5 ^12.6 Jetten AM. "Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism". Nuclear Receptor Signaling. 7: e003. doi:10.1621/nrs.07003. PMC 2670432. PMID 19381306.

[A_Rhythmic_ROR-13] 13.0 ^13.1 ^13.2 ^13.3 ^13.4 ^13.5 Emery P, Reppert SM (August 2004). "A rhythmic Ror". Neuron. 43 (4): 443–6. doi:10.1016/j.neuron.2004.08.009. PMID 15312644.

[Potential_roles_of_ROR-α_in_[[Circulatory_system|cardiovascular]]_[[endocrinology]]-14] 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.

[Nuclear_Receptors_Rock_Around_the_Clock-15] 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.

[Isoform-Specific_Inhibition_of_RORα-Mediated_Transcriptional_Activation_by_Human_FOXP31-16] 16.0 ^16.1 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.

[Retinoid-related_Orphan_Receptors_(RORs):_Roles_in_Cellular_Differentiation_and_Development-17] 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.

[RORα_Suppresses_Breast_Tumor_Invasion_by_Inducing_SEMA3F_Expression-18] 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.

[pmid8858107-19] 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.

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@@ Line 1: / Line 1: @@
-<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
+{{Redirect|RORA||Rora (disambiguation)}}
-{{PBB_Controls
+{{Infobox_gene}}
-| update_page = yes
+'''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]].<ref name="Giguère_1994">{{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 }}</ref> RORα participates in the transcriptional regulation of some genes involved in [[circadian rhythm]].<ref name="entrez"/> In mice, RORα is essential for development of cerebellum<ref>{{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}}</ref><ref>{{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  }}</ref> through direct regulation of genes expressed in Purkinje cells.<ref>{{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}}</ref> It also plays an essential role in the development of type 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient.<ref>{{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 }}</ref><ref>{{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 }}</ref>  In addition, although present in normal numbers, the  ILC3 and Th17 cells from RORα deficient mice are defective for cytokine production.<ref>{{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 }}</ref>
-| require_manual_inspection = no
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-| update_summary = no
-| update_citations = yes
-}}
-<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
+== Discovery ==
-{{GNF_Protein_box
- | image = PBB_Protein_RORA_image.jpg
- | image_source = [[Protein_Data_Bank|PDB]] rendering based on 1n83.
- | PDB = {{PDB2|1n83}}, {{PDB2|1s0x}}
- | Name = RAR-related orphan receptor A
- | HGNCid = 10258
- | Symbol = RORA
- | AltSymbols =; ROR1; ROR2; MGC119326; MGC119329; NR1F1; ROR3; RZRA
- | OMIM = 600825
- | ECnumber =
- | Homologene = 56594
- | MGIid = 104661
- | GeneAtlas_image1 = PBB_GE_RORA_210479_s_at_tn.png
- | GeneAtlas_image2 = PBB_GE_RORA_210426_x_at_tn.png
- | Function = {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0003707 |text = steroid hormone receptor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0043565 |text = sequence-specific DNA binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}
- | Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
- | Process = {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006809 |text = nitric oxide biosynthetic process}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0043030 |text = regulation of macrophage activation}} {{GNF_GO|id=GO:0046068 |text = cGMP metabolic process}}
- | Orthologs = {{GNF_Ortholog_box
-    | Hs_EntrezGene = 6095
-    | Hs_Ensembl = ENSG00000069667
-    | Hs_RefseqProtein = NP_002934
-    | Hs_RefseqmRNA = NM_002943
-    | Hs_GenLoc_db =
-    | Hs_GenLoc_chr = 15
-    | Hs_GenLoc_start = 58576755
-    | Hs_GenLoc_end = 59308709
-    | Hs_Uniprot = P35398
-    | Mm_EntrezGene = 19883
-    | Mm_Ensembl = ENSMUSG00000032238
-    | Mm_RefseqmRNA = XM_903197
-    | Mm_RefseqProtein = XP_908290
-    | Mm_GenLoc_db =
-    | Mm_GenLoc_chr = 9
-    | Mm_GenLoc_start = 68452971
-    | Mm_GenLoc_end = 69178125
-    | Mm_Uniprot = Q3U1P4
-  }}
-}}
-'''RAR-related orphan receptor alpha''' ('''ROR-alpha'''), also known as '''NR1F1''' (nuclear receptor subfamily 1, group F, member 1) is a [[nuclear receptor]] encoded by the {{gene|RORA}} gene.
-<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
+The first three human isoforms of RORα were initially [[Molecular cloning|cloned]] and characterized as nuclear receptors in 1994 by Giguère and colleagues, when their structure and function were first studied.<ref name="REV-ERB and ROR nuclear receptors as drug targets">{{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 }}</ref>
-{{PBB_Summary
-| section_title =
-| summary_text = The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. It can bind as a monomer or as a homodimer to hormone response elements upstream of several genes to enhance the expression of those genes. The specific functions of this protein are not known, but it has been shown to interact with NM23-2, a nucleoside diphosphate kinase involved in organogenesis and differentiation, as well as with NM23-1, the product of a tumor [[metastasis suppressor]] candidate gene. Four transcript variants encoding different isoforms have been described for this gene.<ref name="entrez">{{cite web | title = Entrez Gene: RORA RAR-related orphan receptor A| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6095| accessdate = }}</ref>
-}}
-==References==
+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]].<ref name="The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes" /> Of interest, it was around this time that RORα abundance was found to be circadian in the mammalian [[suprachiasmatic nucleus]].<ref name="Molecular components of the mammalian circadian clock" /> RORα is necessary for normal [[circadian rhythm]]s in [[Mouse|mice]],<ref name="Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism" /> demonstrating its importance in [[chronobiology]].
-{{reflist|2}}
-==Further reading==
+== Structure ==
-{{refbegin | 2}}
-{{PBB_Further_reading
+The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors.<ref name="Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism" /> In humans, 4 [[Protein isoform|isoforms]] of RORα have been identified, which are generated via alternative [[RNA splicing|splicing]] and [[Promoter (genetics)|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 [[Protein domain|domain]] containing two [[zinc finger]]s, a hinge domain, and a [[C-terminus|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.<ref name="The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes" /> Different isoforms of RORα have different binding specificities and strengths of [[Transcription (genetics)|transcriptional]] activity.<ref name="Giguère_1994" />
-| citations =
-*{{cite journal  | author=Giguère V, Beatty B, Squire J, ''et al.'' |title=The orphan nuclear receptor ROR alpha (RORA) maps to a conserved region of homology on human chromosome 15q21-q22 and mouse chromosome 9. |journal=Genomics |volume=28 |issue= 3 |pages= 596-8 |year= 1996 |pmid= 7490103 |doi= 10.1006/geno.1995.1197 }}
+== Regulation of circadian rhythm ==
-*{{cite journal  | author=Steinhilber D, Brungs M, Werz O, ''et al.'' |title=The nuclear receptor for melatonin represses 5-lipoxygenase gene expression in human B lymphocytes. |journal=J. Biol. Chem. |volume=270 |issue= 13 |pages= 7037-40 |year= 1995 |pmid= 7706239 |doi=  }}
-*{{cite journal  | author=Forman BM, Chen J, Blumberg B, ''et al.'' |title=Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors. |journal=Mol. Endocrinol. |volume=8 |issue= 9 |pages= 1253-61 |year= 1995 |pmid= 7838158 |doi=  }}
+The core [[mammal]]ian circadian clock is a [[negative feedback]] loop which consists of [[PER1|Per1/Per2]], [[Cryptochrome|Cry1/Cry2]], [[ARNTL|Bmal1]], and [[CLOCK|Clock]].<ref name="Molecular components of the mammalian circadian clock">{{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 }}</ref> This feedback loop is stabilized through another loop involving the transcriptional regulation of ''Bmal1''.<ref name="A Rhythmic ROR">{{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 }}</ref> [[Transactivation]] of ''Bmal1'' is regulated through the upstream ROR/REV-ERB [[Response element|Response Element]] (RRE) in the ''Bmal1'' promoter, to which RORα and [[Rev-ErbA alpha|REV-ERBα]] bind.<ref name="A Rhythmic ROR" /> This stabilizing regulatory loop itself is induced by the Bmal1/Clock [[Protein dimer|heterodimer]], which induces transcription of ''RORα'' and ''REV-ERBα''.<ref name="Molecular components of the mammalian circadian clock" /> RORα, which activates transcription of ''Bmal1'', and REV-ERBα, which represses transcription of ''Bmal1'', compete to bind to the RRE.<ref name="A Rhythmic ROR" /> 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 (biophysical)|environment]].<ref name="A Rhythmic ROR" />
-*{{cite journal  | author=Becker-André M, André E, DeLamarter JF |title=Identification of nuclear receptor mRNAs by RT-PCR amplification of conserved zinc-finger motif sequences. |journal=Biochem. Biophys. Res. Commun. |volume=194 |issue= 3 |pages= 1371-9 |year= 1993 |pmid= 7916608 |doi=  }}
-*{{cite journal  | author=Giguère V, Tini M, Flock G, ''et al.'' |title=Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. |journal=Genes Dev. |volume=8 |issue= 5 |pages= 538-53 |year= 1994 |pmid= 7926749 |doi=  }}
+== Mechanism ==
-*{{cite journal  | author=Carlberg C, Hooft van Huijsduijnen R, Staple JK, ''et al.'' |title=RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers. |journal=Mol. Endocrinol. |volume=8 |issue= 6 |pages= 757-70 |year= 1994 |pmid= 7935491 |doi=  }}
-*{{cite journal  | author=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=Biochem. Biophys. Res. Commun. |volume=227 |issue= 1 |pages= 82-7 |year= 1996 |pmid= 8858107 |doi= 10.1006/bbrc.1996.1471 }}
+Specific association with ROR elements (RORE) in regulatory regions is necessary for RORα’s function as a transcriptional activator.<ref name="Potential roles of ROR-α in [[Circulatory system|cardiovascular]] [[endocrinology]]">{{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 }}</ref> 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.<ref name="Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism" />
-*{{cite journal  | author=Lau P, Bailey P, Dowhan DH, Muscat GE |title=Exogenous expression of a dominant negative RORalpha1 vector in muscle cells impairs differentiation: RORalpha1 directly interacts with p300 and myoD. |journal=Nucleic Acids Res. |volume=27 |issue= 2 |pages= 411-20 |year= 1999 |pmid= 9862959 |doi=  }}
-*{{cite journal  | author=Atkins GB, Hu X, Guenther MG, ''et al.'' |title=Coactivators for the orphan nuclear receptor RORalpha. |journal=Mol. Endocrinol. |volume=13 |issue= 9 |pages= 1550-7 |year= 1999 |pmid= 10478845 |doi=  }}
+== Homology ==
-*{{cite journal  | author=Meyer T, Kneissel M, Mariani J, Fournier B |title=In vitro and in vivo evidence for orphan nuclear receptor RORalpha function in bone metabolism. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue= 16 |pages= 9197-202 |year= 2000 |pmid= 10900268 |doi= 10.1073/pnas.150246097 }}
-*{{cite journal  | author=Gawlas K, Stunnenberg HG |title=Differential binding and transcriptional behaviour of two highly related orphan receptors, ROR alpha(4) and ROR beta(1). |journal=Biochim. Biophys. Acta |volume=1494 |issue= 3 |pages= 236-41 |year= 2001 |pmid= 11121580 |doi=  }}
+RORα, [[RAR-related orphan receptor beta|RORβ]], and RORγ are all transcriptional activators recognizing ROR-response elements.<ref name="Nuclear Receptors Rock Around the Clock">{{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 }}</ref> ROR-alpha is expressed in a variety of cell types and is involved in regulating several aspects of development, [[Inflammatory response|inflammatory]] responses, and [[lymphocyte]] development.<ref name="Isoform-Specific Inhibition of RORα-Mediated Transcriptional Activation by Human FOXP31">{{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 }}</ref> The RORα isoforms (RORα1 through RORα3) arise via alternative RNA processing, with RORα2 and RORα3 sharing an amino-terminal region different from RORα1.<ref name="Giguère_1994" /> 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 [[thymocyte|thymopoeisis]].<ref name="Isoform-Specific Inhibition of RORα-Mediated Transcriptional Activation by Human FOXP31" />
-*{{cite journal  | author=Delerive P, Chin WW, Suen CS |title=Identification of Reverb(alpha) as a novel ROR(alpha) target gene. |journal=J. Biol. Chem. |volume=277 |issue= 38 |pages= 35013-8 |year= 2002 |pmid= 12114512 |doi= 10.1074/jbc.M202979200 }}
-*{{cite journal  | author=Moretti RM, Marelli MM, Motta M, Limonta P |title=Role of the orphan nuclear receptor ROR alpha in the control of the metastatic behavior of androgen-independent prostate cancer cells. |journal=Oncol. Rep. |volume=9 |issue= 5 |pages= 1139-43 |year= 2003 |pmid= 12168086 |doi=  }}
+The DNA-binding domains of the DHR3 orphan receptor in ''Drosophila'' shows especially close [[Homology (biology)|homology]] within [[amino]] and [[carboxy]] regions adjacent to the second zinc finger region in RORα, suggesting that this group of [[Residue (chemistry)|residues]] is important for the proteins' functionalities.<ref name="Giguère_1994" />
-*{{cite journal  | author=Raspè E, Mautino G, Duval C, ''et al.'' |title=Transcriptional regulation of human Rev-erbalpha gene expression by the orphan nuclear receptor retinoic acid-related orphan receptor alpha. |journal=J. Biol. Chem. |volume=277 |issue= 51 |pages= 49275-81 |year= 2003 |pmid= 12377782 |doi= 10.1074/jbc.M206215200 }}
-*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
+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.<ref name="A Rhythmic ROR" /> PDP1 and VRI constitute a [[feedback loop]] and are functional homologs of ROR and REV-ERB in mammals.<ref name="A Rhythmic ROR" />
-*{{cite journal  | author=Kallen J, Schlaeppi JM, Bitsch F, ''et al.'' |title=Crystal structure of the human RORalpha Ligand binding domain in complex with cholesterol sulfate at 2.2 A. |journal=J. Biol. Chem. |volume=279 |issue= 14 |pages= 14033-8 |year= 2004 |pmid= 14722075 |doi= 10.1074/jbc.M400302200 }}
-*{{cite journal  | author=Migita H, Satozawa N, Lin JH, ''et al.'' |title=RORalpha1 and RORalpha4 suppress TNF-alpha-induced VCAM-1 and ICAM-1 expression in human endothelial cells. |journal=FEBS Lett. |volume=557 |issue= 1-3 |pages= 269-74 |year= 2004 |pmid= 14741380 |doi=  }}
+Direct orthologs of this gene have been identified in mice and humans.
-*{{cite journal  | author=Miki N, Ikuta M, Matsui T |title=Hypoxia-induced activation of the retinoic acid receptor-related orphan receptor alpha4 gene by an interaction between hypoxia-inducible factor-1 and Sp1. |journal=J. Biol. Chem. |volume=279 |issue= 15 |pages= 15025-31 |year= 2004 |pmid= 14742449 |doi= 10.1074/jbc.M313186200 }}
-*{{cite journal  | author=Migita H, Morser J, Kawai K |title=Rev-erbalpha upregulates NF-kappaB-responsive genes in vascular smooth muscle cells. |journal=FEBS Lett. |volume=561 |issue= 1-3 |pages= 69-74 |year= 2004 |pmid= 15013753 |doi= 10.1016/S0014-5793(04)00118-8 }}
+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 (molecular biology)|sense]] strand while those of the RORα2 amino-terminal exon are on the antisense strand.<ref name="Giguère_1994" />
-*{{cite journal  | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
-}}
+== Interactions ==
+*DNA: RORα binds to the P-box of the RORE.<ref name="Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism">{{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}}</ref>
+*[[Co-activator]]s:
+**[[SRC-1]], [[Calcium-binding protein|CBP]], [[EP300|p300]], TRIP-l, TRIP-230, transcription intermediary protein-1 ([[TRIM24|TIF-1]]), peroxisome proliferator-binding protein (PBP), and [[GRIP1 (gene)|GRIP-1]] physically interact with RORα.<ref name="The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes">{{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 }}</ref>
+***LXXLL motif: ROR interacts with SRC-1, GRIP-l, CBP, and p300 via the [[Transcription coregulator|LXXLL]] (L=Leucine, X=any amino acid) motifs on these proteins.<ref name="The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes" />
+*[[Ubiquitin]]ation: RORα is targeted for the [[proteasome]] by ubiquitination. A [[Corepressor|co-repressor]], Hairless, stabilizes RORα by protecting it from this process, which also represses RORα.<ref name="Retinoid-related Orphan Receptors (RORs): Roles in Cellular Differentiation and Development">{{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 }}</ref>
+*[[SUMO protein|Sumoylation]]: UBE21/UBC9: Ubiquitin-conjugating enzyme I interacts with RORs, but its effect is not yet known.<ref name="Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism" />
+*[[Phosphorylation]]:
+**Phosphorylation of RORα1, which inhibits its transcriptional activity, is induced by [[Protein Kinase C]].<ref name="The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes" />
+**[[MAPK1|ERK2]]: [[Extracellular]] signal-regulated kinase-2 also phosphorylates RORα.<ref name="RORα Suppresses Breast Tumor Invasion by Inducing SEMA3F Expression">{{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 }}</ref>
+*[[Ataxin 1|ATXN1]]: ATXN1 and RORα form part of a protein complex in [[Purkinje cells]].<ref name="Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism" />
+*[[FOXP3]]: FOXP3 directly represses the transcriptional activity of RORs.<ref name="Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism" />
+*[[NME1]]: ROR has been shown to specifically interact with NME1.<ref name="pmid8858107">{{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 }}</ref>
+*[[NME2|NM23-2]]: NM23-2 is a nucleoside diphosphate [[kinase]] involved in organogenesis and differentiation.<ref name="entrez">{{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 = }}</ref>
+*[[NME1|NM23-1]]: NM23-1 is the product of a tumor [[metastasis suppressor]] candidate gene.<ref name="entrez"/>
+== 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]], [[Developmental biology|development]], [[Immunity (medical)|immunity]], and circadian rhythm, they show potential as [[Biological target|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 [[RAR-related orphan receptor gamma|RORγ]] inverse [[agonist]]s that suppress [[Reporter gene|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.<ref name="REV-ERB and ROR nuclear receptors as drug targets" />
+== See also ==
+* [[RAR-related orphan receptor]]
+* [[Rev-ErbA alpha|REV-ERBα]]
+* [[Aromatase deficiency]]
+== References ==
+{{reflist|33em}}
+== Further reading ==
+{{refbegin|33em}}
+* {{cite journal | vauthors = Giguère V, Beatty B, Squire J, Copeland NG, Jenkins NA | title = The orphan nuclear receptor ROR alpha (RORA) maps to a conserved region of homology on human chromosome 15q21-q22 and mouse chromosome 9 | journal = Genomics | volume = 28 | issue = 3 | pages = 596–8 | date = August 1995 | pmid = 7490103 | doi = 10.1006/geno.1995.1197 }}
+* {{cite journal | vauthors = Steinhilber D, Brungs M, Werz O, Wiesenberg I, Danielsson C, Kahlen JP, Nayeri S, Schräder M, Carlberg C | title = The nuclear receptor for melatonin represses 5-lipoxygenase gene expression in human B lymphocytes | journal = The Journal of Biological Chemistry | volume = 270 | issue = 13 | pages = 7037–40 | date = March 1995 | pmid = 7706239 | doi = 10.1074/jbc.270.13.7037 }}
+* {{cite journal | vauthors = Forman BM, Chen J, Blumberg B, Kliewer SA, Henshaw R, Ong ES, Evans RM | title = Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors | journal = Molecular Endocrinology | volume = 8 | issue = 9 | pages = 1253–61 | date = September 1994 | pmid = 7838158 | doi = 10.1210/me.8.9.1253 }}
+* {{cite journal | vauthors = Becker-André M, André E, DeLamarter JF | title = Identification of nuclear receptor mRNAs by RT-PCR amplification of conserved zinc-finger motif sequences | journal = Biochemical and Biophysical Research Communications | volume = 194 | issue = 3 | pages = 1371–9 | date = August 1993 | pmid = 7916608 | doi = 10.1006/bbrc.1993.1976 }}
+* {{cite journal | vauthors = Carlberg C, Hooft van Huijsduijnen R, Staple JK, DeLamarter JF, Becker-André M | title = RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers | journal = Molecular Endocrinology | volume = 8 | issue = 6 | pages = 757–70 | date = June 1994 | pmid = 7935491 | doi = 10.1210/me.8.6.757 }}
+* {{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 }}
+* {{cite journal | vauthors = Lau P, Bailey P, Dowhan DH, Muscat GE | title = Exogenous expression of a dominant negative RORalpha1 vector in muscle cells impairs differentiation: RORalpha1 directly interacts with p300 and myoD | journal = Nucleic Acids Research | volume = 27 | issue = 2 | pages = 411–20 | date = January 1999 | pmid = 9862959 | pmc = 148194 | doi = 10.1093/nar/27.2.411 }}
+* {{cite journal | vauthors = Atkins GB, Hu X, Guenther MG, Rachez C, Freedman LP, Lazar MA | title = Coactivators for the orphan nuclear receptor RORalpha | journal = Molecular Endocrinology | volume = 13 | issue = 9 | pages = 1550–7 | date = September 1999 | pmid = 10478845 | doi = 10.1210/me.13.9.1550 }}
+* {{cite journal | vauthors = Meyer T, Kneissel M, Mariani J, Fournier B | title = In vitro and in vivo evidence for orphan nuclear receptor RORalpha function in bone metabolism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 16 | pages = 9197–202 | date = August 2000 | pmid = 10900268 | pmc = 16845 | doi = 10.1073/pnas.150246097 }}
+* {{cite journal | vauthors = Gawlas K, Stunnenberg HG | title = Differential binding and transcriptional behaviour of two highly related orphan receptors, ROR alpha(4) and ROR beta(1) | journal = Biochimica et Biophysica Acta | volume = 1494 | issue = 3 | pages = 236–41 | date = December 2000 | pmid = 11121580 | doi = 10.1016/s0167-4781(00)00237-2 }}
+* {{cite journal | vauthors = Delerive P, Chin WW, Suen CS | title = Identification of Reverb(alpha) as a novel ROR(alpha) target gene | journal = The Journal of Biological Chemistry | volume = 277 | issue = 38 | pages = 35013–8 | date = September 2002 | pmid = 12114512 | doi = 10.1074/jbc.M202979200 }}
+* {{cite journal | vauthors = Moretti RM, Montagnani Marelli M, Motta M, Limonta P | title = Role of the orphan nuclear receptor ROR alpha in the control of the metastatic behavior of androgen-independent prostate cancer cells | journal = Oncology Reports | volume = 9 | issue = 5 | pages = 1139–43 | year = 2003 | pmid = 12168086 | doi = 10.3892/or.9.5.1139 }}
+* {{cite journal | vauthors = Raspè E, Mautino G, Duval C, Fontaine C, Duez H, Barbier O, Monte D, Fruchart J, Fruchart JC, Staels B | title = Transcriptional regulation of human Rev-erbalpha gene expression by the orphan nuclear receptor retinoic acid-related orphan receptor alpha | journal = The Journal of Biological Chemistry | volume = 277 | issue = 51 | pages = 49275–81 | date = December 2002 | pmid = 12377782 | doi = 10.1074/jbc.M206215200 }}
+* {{cite journal | vauthors = Kallen J, Schlaeppi JM, Bitsch F, Delhon I, Fournier B | title = Crystal structure of the human RORalpha Ligand binding domain in complex with cholesterol sulfate at 2.2 A | journal = The Journal of Biological Chemistry | volume = 279 | issue = 14 | pages = 14033–8 | date = April 2004 | pmid = 14722075 | doi = 10.1074/jbc.M400302200 }}
+* {{cite journal | vauthors = Migita H, Satozawa N, Lin JH, Morser J, Kawai K | title = RORalpha1 and RORalpha4 suppress TNF-alpha-induced VCAM-1 and ICAM-1 expression in human endothelial cells | journal = FEBS Letters | volume = 557 | issue = 1–3 | pages = 269–74 | date = January 2004 | pmid = 14741380 | doi = 10.1016/S0014-5793(03)01502-3 }}
+* {{cite journal | vauthors = Miki N, Ikuta M, Matsui T | title = Hypoxia-induced activation of the retinoic acid receptor-related orphan receptor alpha4 gene by an interaction between hypoxia-inducible factor-1 and Sp1 | journal = The Journal of Biological Chemistry | volume = 279 | issue = 15 | pages = 15025–31 | date = April 2004 | pmid = 14742449 | doi = 10.1074/jbc.M313186200 }}
+* {{cite journal | vauthors = Migita H, Morser J, Kawai K | title = Rev-erbalpha upregulates NF-kappaB-responsive genes in vascular smooth muscle cells | journal = FEBS Letters | volume = 561 | issue = 1–3 | pages = 69–74 | date = March 2004 | pmid = 15013753 | doi = 10.1016/S0014-5793(04)00118-8 }}
 {{refend}}
-{{protein-stub}}
+== External links ==
-{{Transcription factors}}
+* {{MeshName|orphan+nuclear+receptor+ROR-gamma}}
+{{PDB Gallery|geneid=6095}}
+{{Transcription factors|g2}}
+{{Nuclear receptor ligands}}
 [[Category:Intracellular receptors]]
 [[Category:Transcription factors]]
-{{WikiDoc Sources}}