RAR-related orphan receptor alpha
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| Location (UCSC) | Chr 15: 60.49 – 61.23 Mb | Chr 9: 68.56 – 69.3 Mb | |||||||
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RAR-related orphan receptor alpha (RORα), also known as NR1F1 (nuclear receptor subfamily 1, group F, member 1) is a
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.[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
The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors.
Regulation of circadian rhythm
The core
Mechanism
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
RORα,
The DNA-binding domains of the DHR3 orphan receptor in Drosophila shows especially close
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.
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
- DNA: RORα binds to the P-box of the RORE.[16]
- Co-activators:
- 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.[21]
- Sumoylation: UBE21/UBC9: Ubiquitin-conjugating enzyme I interacts with RORs, but its effect is not yet known.[16]
- Phosphorylation:
- Purkinje cells.[16]
- FOXP3: FOXP3 directly represses the transcriptional activity of RORs.[16]
- NME1: ROR has been shown to specifically interact with NME1.[23]
- NM23-2: NM23-2 is a nucleoside diphosphate kinase involved in organogenesis and differentiation.[6]
- NM23-1: NM23-1 is the product of a tumor metastasis suppressor candidate gene.[6]
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
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000069667 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032238 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 7926749.
- ^ a b c "Entrez Gene: RORA RAR-related orphan receptor A".
- S2CID 30733570.
- S2CID 4318427.
- PMID 14687547.
- PMID 22981535.
- PMID 24679471.
- PMID 28670633.
- ^ PMID 24577401.
- ^ PMID 11550795.
- ^ PMID 16987893.
- ^ PMID 15312644.
- PMID 16604183.
- PMID 24737872.
- ^ PMID 18354202.
- PMID 22350413.
- PMID 8858107.
Further reading
- Giguère V, Beatty B, Squire J, Copeland NG, Jenkins NA (August 1995). "The orphan nuclear receptor ROR alpha (RORA) maps to a conserved region of homology on human chromosome 15q21-q22 and mouse chromosome 9". Genomics. 28 (3): 596–8. PMID 7490103.
- Steinhilber D, Brungs M, Werz O, Wiesenberg I, Danielsson C, Kahlen JP, Nayeri S, Schräder M, Carlberg C (March 1995). "The nuclear receptor for melatonin represses 5-lipoxygenase gene expression in human B lymphocytes". The Journal of Biological Chemistry. 270 (13): 7037–40. PMID 7706239.
- Forman BM, Chen J, Blumberg B, Kliewer SA, Henshaw R, Ong ES, Evans RM (September 1994). "Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors". Molecular Endocrinology. 8 (9): 1253–61. PMID 7838158.
- Becker-André M, André E, DeLamarter JF (August 1993). "Identification of nuclear receptor mRNAs by RT-PCR amplification of conserved zinc-finger motif sequences". Biochemical and Biophysical Research Communications. 194 (3): 1371–9. PMID 7916608.
- Carlberg C, Hooft van Huijsduijnen R, Staple JK, DeLamarter JF, Becker-André M (June 1994). "RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers". Molecular Endocrinology. 8 (6): 757–70. S2CID 22342101.
- 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. PMID 8858107.
- Lau P, Bailey P, Dowhan DH, Muscat GE (January 1999). "Exogenous expression of a dominant negative RORalpha1 vector in muscle cells impairs differentiation: RORalpha1 directly interacts with p300 and myoD". Nucleic Acids Research. 27 (2): 411–20. PMID 9862959.
- Atkins GB, Hu X, Guenther MG, Rachez C, Freedman LP, Lazar MA (September 1999). "Coactivators for the orphan nuclear receptor RORalpha". Molecular Endocrinology. 13 (9): 1550–7. PMID 10478845.
- Meyer T, Kneissel M, Mariani J, Fournier B (August 2000). "In vitro and in vivo evidence for orphan nuclear receptor RORalpha function in bone metabolism". Proceedings of the National Academy of Sciences of the United States of America. 97 (16): 9197–202. PMID 10900268.
- Gawlas K, Stunnenberg HG (December 2000). "Differential binding and transcriptional behaviour of two highly related orphan receptors, ROR alpha(4) and ROR beta(1)". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1494 (3): 236–41. PMID 11121580.
- Delerive P, Chin WW, Suen CS (September 2002). "Identification of Reverb(alpha) as a novel ROR(alpha) target gene". The Journal of Biological Chemistry. 277 (38): 35013–8. PMID 12114512.
- Moretti RM, Montagnani Marelli M, Motta M, Limonta P (2003). "Role of the orphan nuclear receptor ROR alpha in the control of the metastatic behavior of androgen-independent prostate cancer cells". Oncology Reports. 9 (5): 1139–43. PMID 12168086.
- Raspè E, Mautino G, Duval C, Fontaine C, Duez H, Barbier O, Monte D, Fruchart J, Fruchart JC, Staels B (December 2002). "Transcriptional regulation of human Rev-erbalpha gene expression by the orphan nuclear receptor retinoic acid-related orphan receptor alpha". The Journal of Biological Chemistry. 277 (51): 49275–81. PMID 12377782.
- Kallen J, Schlaeppi JM, Bitsch F, Delhon I, Fournier B (April 2004). "Crystal structure of the human RORalpha Ligand binding domain in complex with cholesterol sulfate at 2.2 A". The Journal of Biological Chemistry. 279 (14): 14033–8. PMID 14722075.
- Migita H, Satozawa N, Lin JH, Morser J, Kawai K (January 2004). "RORalpha1 and RORalpha4 suppress TNF-alpha-induced VCAM-1 and ICAM-1 expression in human endothelial cells". FEBS Letters. 557 (1–3): 269–74. S2CID 24388280.
- Miki N, Ikuta M, Matsui T (April 2004). "Hypoxia-induced activation of the retinoic acid receptor-related orphan receptor alpha4 gene by an interaction between hypoxia-inducible factor-1 and Sp1". The Journal of Biological Chemistry. 279 (15): 15025–31. PMID 14742449.
- Migita H, Morser J, Kawai K (March 2004). "Rev-erbalpha upregulates NF-kappaB-responsive genes in vascular smooth muscle cells". FEBS Letters. 561 (1–3): 69–74. S2CID 84456190.
External links
- orphan+nuclear+receptor+ROR-gamma at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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