Nuclear receptor 4A1

The nuclear receptor 4A1 (NR4A1 for "nuclear receptor subfamily 4 group A member 1") also known as Nur77, TR3, and NGFI-B is a protein that in humans is encoded by the NR4A1 gene.^[5][6]

NR4A1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2QW4, 3V3E, 3V3Q, 4JGV, 4KZI, 4KZJ, 4KZM, 4RZE, 4RZF, 4RZG, 4RE8, 4REE, 4REF, 4WHF, 4WHG
Identifiers
Aliases	NR4A1, GFRP1, HMR, N10, NAK-1, NGFIB, NP10, NUR77, TR3, nuclear receptor subfamily 4 group A member 1, NH41
External IDs	OMIM: 139139; MGI: 1352454; HomoloGene: 1612; GeneCards: NR4A1; OMA:NR4A1 - orthologs
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q13.13 Start 52,022,832 bp[1] End 52,059,507 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15|15 F1 Start 101,152,150 bp[2] End 101,172,676 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gastric mucosa left uterine tube gallbladder left ovary tibial nerve popliteal artery tibial arteries right ovary muscle of thigh vena cava Top expressed in granulocyte adrenal gland plantaris muscle triceps brachii muscle vastus lateralis muscle tibialis anterior muscle extensor digitorum longus muscle muscle of thigh parotid gland medial head of gastrocnemius muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding sequence-specific DNA binding DNA-binding transcription factor activity zinc ion binding DNA-binding transcription activator activity, RNA polymerase II-specific metal ion binding steroid hormone receptor activity nuclear receptor activity protein binding protein heterodimerization activity DNA-binding transcription factor activity, RNA polymerase II-specific RNA polymerase II transcription regulatory region sequence-specific DNA binding RNA polymerase II cis-regulatory region sequence-specific DNA binding glucocorticoid receptor binding Cellular component nuclear membrane nucleoplasm nucleus cytoplasm cytosol transcription regulator complex Biological process regulation of transcription, DNA-templated positive regulation of endothelial cell proliferation negative regulation of cell cycle cellular response to fibroblast growth factor stimulus transcription, DNA-templated cell migration involved in sprouting angiogenesis endothelial cell chemotaxis cellular response to corticotropin-releasing hormone stimulus cellular response to vascular endothelial growth factor stimulus transcription initiation from RNA polymerase II promoter fat cell differentiation regulation of type B pancreatic cell proliferation signal transduction steroid hormone mediated signaling pathway positive regulation of transcription by RNA polymerase II intracellular receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3164 15370 Ensembl ENSG00000123358 ENSMUSG00000023034 UniProt P22736 P12813 RefSeq (mRNA) NM_001202233 NM_001202234 NM_002135 NM_173157 NM_173158 NM_010444 RefSeq (protein) NP_001189162 NP_001189163 NP_002126 NP_775180 NP_002126.2 NP_775180.1 NP_034574 Location (UCSC) Chr 12: 52.02 – 52.06 Mb Chr 15: 101.15 – 101.17 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Nuclear receptor 4A1 (NR4A1) is a member of the NR4A nuclear receptor family^[7] of intracellular transcription factors.^[6][8] NR4A1 is involved in cell cycle mediation, inflammation and apoptosis.^[9]

Nuclear receptor 4A1 plays a key role in mediating inflammatory responses in macrophages.^[9] In addition, subcellular localization of the NR4A1 protein appears to play a key role in the survival and death of cells.^[10]

Expression is inducible by phytohemagglutinin in human lymphocytes and by serum stimulation of arrested fibroblasts. Translocation of the protein from the nucleus to mitochondria induces apoptosis. Multiple alternatively spliced variants, encoding the same protein, have been identified.^[5]

Structure

The NR4A1 gene contains seven exons. An amino terminal transactivation domain is encoded in exon 2, a DNA-binding domain in exons 3 and 4, and dimerisation and a ligand-binding domain is exons 5 to 7.^[11]

The protein has an atypical ligand-binding domain that is unlike the classical ligand-binding domain in most nuclear receptors. The classical domain contains a ligand-receiving pocket and co-activator site, both of which are lacking in the NR4A family. Whereas most nuclear receptors have a hydrophobic surface that results in a cleft, NR4A1 has a hydrophilic surface.^[7]

Cofactors interact with Nuclear receptor 4A1 at a hydrophobic region between helices 11 and 12 to modulate transcription.^[7]

Function

Along with the two other NR4A family members, NR4A1 is expressed in macrophages following inflammatory stimuli. This process is mediated by the NF-κB (nuclear factor-kappa B) complex, a ubiquitous transcription factor involved in cellular response to stress.^[9]

Nuclear receptor 4A1 can be induced by many physiological and physical stimuli. These include physiological stimuli such as "fatty acids, stress, prostaglandins, growth factors, calcium, inflammatory cytokines, peptide hormones, phorbol esters, and neurotransmitters" and physical stimuli including "magnetic fields, mechanical agitation (causing fluid shear stress), and membrane depolarization".^[7] No endogenous ligands that bind to NR4A1 have yet been identified, so modulation occurs at the level of protein expression and posttranslational modification.Besides these, NR4A1 can mediate T cell function, the transcription factor NR4A1 is stably expressed at high levels in tolerant T cells. Overexpression of Nuclear receptor 4A1 inhibits effector T cell differentiation, whereas deletion of NR4A1 overcomes T cell tolerance and exaggerates effector function, as well as enhancing immunity against tumor and chronic virus. Mechanistically, NR4A1 is preferentially recruited to binding sites of the transcription factor AP-1, where it represses effector gene expression by inhibiting AP-1 function. NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes.^[12]

There are several ligands that directly bind NR4A1, including cytosporone B, celastrol, and certain polyunsaturated fatty acids. These NR4A1 ligands bind at various NR4A1 sites and show activities that are dependent on ligand structure and cell context. These NR4A1 ligands may have relevance to treatment of cancer, metabolic disease, inflammation, and endometriosis.^[13] NR4A1 may play a role in Drug-induced gingival overgrowth associated with exposure to phenytoin, nifedipine, and cyclosporine A.^[14]

Biochemistry

Nuclear receptor 4A1 binds as a monomer or homodimer to response element NBRE^[15] and as a homodimer to NurRE.^[16] It is also capable of heterodimerising with COUP-TF (an orphan nuclear receptor) and retinoid X receptor (RXR) in mediating transcription in response to retinoids.^[17]

The binding sites on the response elements for NR4A1, which are common to the two other members of the NR4A family, are:^[7]

• NBRE - 5’-A/TAAAGGTCA,
• NurRE - a AAAT(G/A)(C/T)CA repeat,
• RXR - DX, a motif.

Evolution and homology

Nuclear receptor 4A1 has the systematic HUGO gene symbol NR4A1. It belongs to a group of three closely related orphan receptors, the NR4A family (NR4A). The other two members are Nuclear receptor 4A2 (NR4A2) and Nuclear receptor 4A3 (NR4A3).

Nuclear receptor 4A1 has a high degree of structural similarity with other family members at the DNA-binding domain with 91-95% sequence conservation. The C-terminal ligand-binding domain is conserved to a lesser extent at 60% and the N-terminal AB region is not conserved, differing in each member.^[7]

The three members are similar in biochemistry and function. They are immediate early genes activated in a ligand-independent manner that bind at the homologous sites on response elements.^[11]

Nuclear receptor 4A1 and the rest of the NR4A family are structurally similar to other nuclear receptor superfamily members, but contain an extra intron. The DNA-binding domain at exons 3 and 4 of the NR4A1 gene is conserved among all members of the nuclear receptor.^[11]

NR4A1 has homologous genes in a range of species including neuronal growth factor-induced clone B in rats, Nur77 in mice and TR3 in humans.^[18]

Pathology

Along with 16 other genes, NR4A1 is a signature gene in the metastasis of some primary solid tumours. It is downregulated in this process.^[19]

Interactions

Nuclear receptor 4A1 has been shown to interact with:

• AKT1,^[20]
• Bcl-2,^[21]
• HIF1A,^[22]
• Nuclear receptor co-repressor 2,^[23]
• Promyelocytic leukemia protein,^[24]
• Retinoid X receptor alpha,^[21] and
• Von Hippel-Lindau tumor suppressor.^[22]

References

1. GRCh38: Ensembl release 89: ENSG00000123358 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000023034 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: NR4A1 nuclear receptor subfamily 4, group A, member 1".
6. Chang C, Kokontis J, Liao SS, Chang Y (1989). "Isolation and characterization of human TR3 receptor: a member of steroid receptor superfamily". Journal of Steroid Biochemistry. 34 (1–6): 391–395. doi:10.1016/0022-4731(89)90114-3. PMID 2626032.
7. Maxwell MA, Muscat GE (2006). "The NR4A subgroup: immediate early response genes with pleiotropic physiological roles". Nuclear Receptor Signaling. 4: e002. doi:10.1621/nrs.04002. PMC 1402209. PMID 16604165.
8. Milbrandt J (May 1988). "Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene". Neuron. 1 (3): 183–188. doi:10.1016/0896-6273(88)90138-9. PMID 3272167. S2CID 41639878.
9. Pei L, Castrillo A, Tontonoz P (April 2006). "Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77". Molecular Endocrinology. 20 (4): 786–794. doi:10.1210/me.2005-0331. PMID 16339277.
10. Zhang XK (January 2007). "Targeting Nur77 translocation". Expert Opinion on Therapeutic Targets. 11 (1): 69–79. doi:10.1517/14728222.11.1.69. PMID 17150035. S2CID 2217539.
11. Saucedo-Cardenas O, Kardon R, Ediger TR, Lydon JP, Conneely OM (March 1997). "Cloning and structural organization of the gene encoding the murine nuclear receptor transcription factor, NURR1". Gene. 187 (1): 135–139. doi:10.1016/S0378-1119(96)00736-6. PMID 9073077.
12. Liu X, Wang Y, Lu H, Li J, Yan X, Xiao M, et al. (March 2019). "Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction". Nature. 567 (7749): 525–529. Bibcode:2019Natur.567..525L. doi:10.1038/s41586-019-0979-8. PMC 6507425. PMID 30814730.
13. Safe S, Shrestha R, Mohankumar K (December 2021). "Orphan nuclear receptor 4A1 (NR4A1) and novel ligands". Essays in Biochemistry. 65 (6): 877–886. doi:10.1042/EBC20200164. PMC 11410023. PMID 34096590. S2CID 235360253.
14. Hatano S, Matsuda S, Okanobu A, Furutama D, Memida T, Kajiya M, et al. (July 2021). "The role of nuclear receptor 4A1 (NR4A1) in drug-induced gingival overgrowth". FASEB Journal. 35 (7): e21693. doi:10.1096/fj.202100032R. PMID 34109683. S2CID 235393903.
15. Hiromura M, Suizu F, Narita M, Kinowaki K, Noguchi M (September 2006). "Identification of nerve growth factor-responsive element of the TCL1 promoter as a novel negative regulatory element". The Journal of Biological Chemistry. 281 (38): 27753–27764. doi:10.1074/jbc.M602420200. hdl:2115/14759. PMID 16835233.
16. Philips A, Lesage S, Gingras R, Maira MH, Gauthier Y, Hugo P, Drouin J (October 1997). "Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells". Molecular and Cellular Biology. 17 (10): 5946–5951. doi:10.1128/MCB.17.10.5946. PMC 232442. PMID 9315652.
17. Han YH, Cao X, Lin B, Lin F, Kolluri SK, Stebbins J, et al. (May 2006). "Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt". Oncogene. 25 (21): 2974–2986. doi:10.1038/sj.onc.1209358. PMID 16434970.
18. Wei T, Geiser AG, Qian HR, Su C, Helvering LM, Kulkarini NH, et al. (April 2007). "DNA microarray data integration by ortholog gene analysis reveals potential molecular mechanisms of estrogen-dependent growth of human uterine fibroids". BMC Women's Health. 7: 5. doi:10.1186/1472-6874-7-5. PMC 1852551. PMID 17407572.
19. Ramaswamy S, Ross KN, Lander ES, Golub TR (January 2003). "A molecular signature of metastasis in primary solid tumors". Nature Genetics. 33 (1): 49–54. doi:10.1038/ng1060. PMID 12469122. S2CID 12059602.
20. Pekarsky Y, Hallas C, Palamarchuk A, Koval A, Bullrich F, Hirata Y, et al. (March 2001). "Akt phosphorylates and regulates the orphan nuclear receptor Nur77". Proceedings of the National Academy of Sciences of the United States of America. 98 (7): 3690–3694. Bibcode:2001PNAS...98.3690P. doi:10.1073/pnas.051003198. PMC 31113. PMID 11274386.
21. Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, et al. (February 2004). "Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3". Cell. 116 (4): 527–540. doi:10.1016/S0092-8674(04)00162-X. PMID 14980220.
22. Kim BY, Kim H, Cho EJ, Youn HD (February 2008). "Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation". Experimental & Molecular Medicine. 40 (1): 71–83. doi:10.3858/emm.2008.40.1.71. PMC 2679322. PMID 18305400.
23. Sohn YC, Kwak E, Na Y, Lee JW, Lee SK (November 2001). "Silencing mediator of retinoid and thyroid hormone receptors and activating signal cointegrator-2 as transcriptional coregulators of the orphan nuclear receptor Nur77". The Journal of Biological Chemistry. 276 (47): 43734–43739. doi:10.1074/jbc.M107208200. PMID 11559707.
24. Wu WS, Xu ZX, Ran R, Meng F, Chang KS (May 2002). "Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions". Oncogene. 21 (24): 3925–3933. doi:10.1038/sj.onc.1205491. PMID 12032831. S2CID 23367035.

Further reading

• Winoto A, Littman DR (April 2002). "Nuclear hormone receptors in T lymphocytes". Cell. 109 Suppl (2): S57–S66. doi:10.1016/S0092-8674(02)00710-9. PMID 11983153.
• Engelse MA, Arkenbout EK, Pannekoek H, de Vries CJ (November 2003). "Activin and TR3 orphan receptor: two 'atheroprotective' genes as evidenced in dedicated mouse models". Clinical and Experimental Pharmacology & Physiology. 30 (11): 894–899. doi:10.1046/j.1440-1681.2003.03928.x. PMID 14678255. S2CID 11046562.
• Bondy GP (April 1991). "Phorbol ester, forskolin, and serum induction of a human colon nuclear hormone receptor gene related to the NUR 77/NGFI-B genes". Cell Growth & Differentiation. 2 (4): 203–208. PMID 1651101.
• Nakai A, Kartha S, Sakurai A, Toback FG, DeGroot LJ (October 1990). "A human early response gene homologous to murine nur77 and rat NGFI-B, and related to the nuclear receptor superfamily". Molecular Endocrinology. 4 (10): 1438–1443. doi:10.1210/mend-4-10-1438. PMID 2283997.
• Ryseck RP, Macdonald-Bravo H, Mattéi MG, Ruppert S, Bravo R (November 1989). "Structure, mapping and expression of a growth factor inducible gene encoding a putative nuclear hormonal binding receptor". The EMBO Journal. 8 (11): 3327–3335. doi:10.1002/j.1460-2075.1989.tb08494.x. PMC 401469. PMID 2555161.
• Uemura H, Mizokami A, Chang C (March 1995). "Identification of a new enhancer in the promoter region of human TR3 orphan receptor gene. A member of steroid receptor superfamily". The Journal of Biological Chemistry. 270 (10): 5427–5433. doi:10.1074/jbc.270.10.5427. PMID 7890657.
• Hirata Y, Kiuchi K, Chen HC, Milbrandt J, Guroff G (November 1993). "The phosphorylation and DNA binding of the DNA-binding domain of the orphan nuclear receptor NGFI-B". The Journal of Biological Chemistry. 268 (33): 24808–24812. doi:10.1016/S0021-9258(19)74536-0. PMID 8227042.
• Harrison DC, Roberts J, Campbell CA, Crook B, Davis R, Deen K, et al. (2000). "TR3 death receptor expression in the normal and ischaemic brain". Neuroscience. 96 (1): 147–160. doi:10.1016/S0306-4522(99)00502-3. PMID 10777386. S2CID 42030769.
• Li H, Kolluri SK, Gu J, Dawson MI, Cao X, Hobbs PD, et al. (August 2000). "Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3". Science. 289 (5482): 1159–1164. Bibcode:2000Sci...289.1159L. doi:10.1126/science.289.5482.1159. PMID 10947977.
• Pekarsky Y, Hallas C, Palamarchuk A, Koval A, Bullrich F, Hirata Y, et al. (March 2001). "Akt phosphorylates and regulates the orphan nuclear receptor Nur77". Proceedings of the National Academy of Sciences of the United States of America. 98 (7): 3690–3694. Bibcode:2001PNAS...98.3690P. doi:10.1073/pnas.051003198. PMC 31113. PMID 11274386.
• Sohn YC, Kwak E, Na Y, Lee JW, Lee SK (November 2001). "Silencing mediator of retinoid and thyroid hormone receptors and activating signal cointegrator-2 as transcriptional coregulators of the orphan nuclear receptor Nur77". The Journal of Biological Chemistry. 276 (47): 43734–43739. doi:10.1074/jbc.M107208200. PMID 11559707.
• Lee MO, Kang HJ, Cho H, Shin EC, Park JH, Kim SJ (November 2001). "Hepatitis B virus X protein induced expression of the Nur77 gene". Biochemical and Biophysical Research Communications. 288 (5): 1162–1168. doi:10.1006/bbrc.2001.5910. PMID 11700033.
• Slagsvold HH, Østvold AC, Fallgren AB, Paulsen RE (March 2002). "Nuclear receptor and apoptosis initiator NGFI-B is a substrate for kinase ERK2". Biochemical and Biophysical Research Communications. 291 (5): 1146–1150. doi:10.1006/bbrc.2002.6579. PMID 11883936.
• Wu WS, Xu ZX, Ran R, Meng F, Chang KS (May 2002). "Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions". Oncogene. 21 (24): 3925–3933. doi:10.1038/sj.onc.1205491. PMID 12032831. S2CID 23367035.
• Liu S, Wu Q, Ye XF, Cai JH, Huang ZW, Su WJ (June 2002). "Induction of apoptosis by TPA and VP-16 is through translocation of TR3". World Journal of Gastroenterology. 8 (3): 446–450. doi:10.3748/wjg.v8.i3.446. PMC 4656418. PMID 12046067.
• Wansa KD, Harris JM, Muscat GE (September 2002). "The activation function-1 domain of Nur77/NR4A1 mediates trans-activation, cell specificity, and coactivator recruitment". The Journal of Biological Chemistry. 277 (36): 33001–33011. doi:10.1074/jbc.M203572200. PMID 12082103.
• Chtarbova S, Nimmrich I, Erdmann S, Herter P, Renner M, Kitajewski J, Müller O (November 2002). "Murine Nr4a1 and Herpud1 are up-regulated by Wnt-1, but the homologous human genes are independent from beta-catenin activation". The Biochemical Journal. 367 (Pt 3): 723–728. doi:10.1042/BJ20020699. PMC 1222938. PMID 12153396.
• Wu Q, Liu S, Ye XF, Huang ZW, Su WJ (October 2002). "Dual roles of Nur77 in selective regulation of apoptosis and cell cycle by TPA and ATRA in gastric cancer cells". Carcinogenesis. 23 (10): 1583–1592. doi:10.1093/carcin/23.10.1583. PMID 12376465.

External links

• orphan+nuclear+receptor+NGFI-B at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• orphan+nuclear+receptor+TR3 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)