Nuclear receptor related-1 protein
|Nuclear receptor subfamily 4, group A, member 2|
PDB rendering based on 1cit.
|Symbols||; HZF-3; NOT; NURR1; RNR1; TINUR|
|External IDs||IUPHAR: ChEMBL: GeneCards:|
|RNA expression pattern|
The Nuclear receptor related 1 protein (NURR1) also known as NR4A2 (nuclear receptor subfamily 4, group A, member 2) is a protein that in humans is encoded by the NR4A2 gene. NURR1 is a member of the nuclear receptor family of intracellular transcription factors.
NURR1 plays a key role in the maintenance of the dopaminergic system of the brain. Mutations in this gene have been associated with disorders related to dopaminergic dysfunction, including Parkinson's disease, schizophrenia, and manic depression. Misregulation of this gene may be associated with rheumatoid arthritis. Four transcript variants encoding four distinct isoforms have been identified for this gene. Additional alternate splice variants may exist, but their full-length nature has not been determined.
Nurr1 and Inflammation
Research has been conducted on Nurr1’s role in inflammation, and may provide important information in treating disorders caused by dopaminergic neuron disease. Inflammation in the CNS can result from activated microglia (macrophage analogs for the central nervous system) and other pro-inflammatory factors, such as bacterial lipopolysaccharide (LPS). LPS binds to toll-like receptors (TLR), which induces inflammatory gene expression by promoting signal-dependent transcription factors. To determine which cells are dopaminergic, experiments measured the enzyme tyrosine hydroxylase (TH), which is needed for dopamine synthesis. It has been shown that Nurr1 protects dopaminergic neurons from LPS-induced inflammation, by reducing inflammatory gene expression in microglia and astrocytes. When a short hairpin for Nurr1 was expressed in microglia and astrocytes, these cells produced inflammatory mediators, such as TNFa, NO synthase and IL-1β, supporting the conclusion that reduced Nurr1 promotes inflammation and leads to cell death of dopaminergic neurons. Nurr1 interacts with the transcription factor complex NF-κB-p65 on the inflammatory gene promoters. However, Nurr1 is dependent on other factors to be able to participate in these interactions. Nurr1 needs to be sumoylated and its co-regulating factor, glycogen synthase kinase 3, needs to be phosphorylated for these interactions to occur. Sumolyated Nurr1 recruits CoREST, a complex made of several proteins that assembles chromatin-modifying enzymes. The Nurr1/CoREST complex inhibits transcription of inflammatory genes.
One investigation conducted research on the structure and found that Nurr1 does not contain a ligand-binding cavity but a patch filled with hydrophobic side chains. Non-polar amino acid residues of Nurr1’s co-regulators, SMRT and NCoR, bind to this hydrophobic patch. Analysis of tertiary structure has shown that the binding surface of the ligand-binding domain is located on the grooves of the 11th and 12th alpha helices. This study also found essential structural components of this hydrophobic patch, to be the three amino acids residues, F574, F592, L593; mutation of any these three inhibits LBD activity.
Nurr1 induces tyrosine hydroxylase (TH) expression, which eventually leads to differentiation into dopaminergic neurons. Nurr1 has been demonstrated to induce differentiation in CNS precursor cells in vitro but they require additional factors to reach full maturity and dopaminergic differentiation. This is promising for generation of dopaminergic neurons for Parkinson’s disease research, yet implantation of these induced cells as therapy treatments, has had limited results.
Nuclear receptor related 1 protein has been shown to interact with:
- Okabe T, Takayanagi R, Imasaki K, Haji M, Nawata H, Watanabe T (1995). "cDNA cloning of a NGFI-B/nur77-related transcription factor from an apoptotic human T cell line". J. Immunol. 154 (8): 3871–9. PMID 7706727.
- Sacchetti P, Carpentier R, Ségard P, Olivé-Cren C, Lefebvre P (2006). "Multiple signaling pathways regulate the transcriptional activity of the orphan nuclear receptor NURR1". Nucleic Acids Res. 34 (19): 5515–27. doi:10.1093/nar/gkl712. PMC 1636490. PMID 17020917.
- "Entrez Gene: NR4A2 nuclear receptor subfamily 4, group A, member 2".
- Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK (2009). "Nurr1/CoREST Pathway in Microglia and Astrocytes Protects Dopaminergic Neurons from Inflammation-Induced Death". Cell 137 (1): 47–59. doi:10.1016/j.cell.2009.01.038. PMC 2754279. PMID 19345186.
- Codina A, Benoit G, Gooch JT, Neuhaus D, Perlmann T, Schwabe JW (2004). "Identification of a novel co-regulator interaction surface on the ligand binding domain of Nurr1 using NMR footprinting". J Biol Chem 279 (51): 53338–53345. doi:10.1074/jbc.M409096200. PMID 15456745.
- Kim JY, Koh HC, Lee JY, Chang MY, Kim YC, Chung HY, Son H, Lee YS, Studer L, McKay R, Lee SH (June 2003). "Dopaminergic neuronal differentiation from rat embryonic neural precursors by Nurr1 overexpression". J. Neurochem. 85 (6): 1443–54. doi:10.1046/j.1471-4159.2003.01780.x. PMID 12787064.
- Perlmann T, Jansson L (April 1995). "A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1". Genes Dev. 9 (7): 769–82. doi:10.1101/gad.9.7.769. PMID 7705655.
- Le W, Appel SH (2004). "Mutant genes responsible for Parkinson's disease.". Current Opinion in Pharmacology 4 (1): 79–84. doi:10.1016/j.coph.2003.09.005. PMID 15018843.
- Wedler B, Wüstenberg PW, Naumann G (1976). "[Treatment of hypertonus in diabetes mellitus]". Zeitschrift für die gesamte innere Medizin und ihre Grenzgebiete 30 (13): 437–42. PMID 4929.
- Perlmann T, Jansson L (1995). "A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1.". Genes Dev. 9 (7): 769–82. doi:10.1101/gad.9.7.769. PMID 7705655.
- Forman BM, Umesono K, Chen J, Evans RM (1995). "Unique response pathways are established by allosteric interactions among nuclear hormone receptors.". Cell 81 (4): 541–50. doi:10.1016/0092-8674(95)90075-6. PMID 7758108.
- Mages HW, Rilke O, Bravo R, et al. (1995). "NOT, a human immediate-early response gene closely related to the steroid/thyroid hormone receptor NAK1/TR3.". Mol. Endocrinol. 8 (11): 1583–91. doi:10.1210/me.8.11.1583. PMID 7877627.
- Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.". Gene 138 (1-2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library.". Gene 200 (1-2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Torii T, Kawarai T, Nakamura S, Kawakami H (1999). "Organization of the human orphan nuclear receptor Nurr1 gene.". Gene 230 (2): 225–32. doi:10.1016/S0378-1119(99)00064-5. PMID 10216261.
- Ichinose H, Ohye T, Suzuki T, et al. (1999). "Molecular cloning of the human Nurr1 gene: characterization of the human gene and cDNAs.". Gene 230 (2): 233–9. doi:10.1016/S0378-1119(99)00065-7. PMID 10216262.
- Chen YH, Tsai MT, Shaw CK, Chen CH (2002). "Mutation analysis of the human NR4A2 gene, an essential gene for midbrain dopaminergic neurogenesis, in schizophrenic patients.". Am. J. Med. Genet. 105 (8): 753–7. doi:10.1002/ajmg.10036. PMID 11803525.
- Ishiguro H, Okubo Y, Ohtsuki T, et al. (2002). "Mutation analysis of the retinoid X receptor beta, nuclear-related receptor 1, and peroxisome proliferator-activated receptor alpha genes in schizophrenia and alcohol dependence: possible haplotype association of nuclear-related receptor 1 gene to alcohol dependence.". Am. J. Med. Genet. 114 (1): 15–23. doi:10.1002/ajmg.1620. PMID 11840500.
- McEvoy AN, Murphy EA, Ponnio T, et al. (2002). "Activation of nuclear orphan receptor NURR1 transcription by NF-kappa B and cyclic adenosine 5'-monophosphate response element-binding protein in rheumatoid arthritis synovial tissue.". J. Immunol. 168 (6): 2979–87. doi:10.4049/jimmunol.168.6.2979. PMID 11884470.
- Xu PY, Liang R, Jankovic J, et al. (2002). "Association of homozygous 7048G7049 variant in the intron six of Nurr1 gene with Parkinson's disease.". Neurology 58 (6): 881–4. doi:10.1212/wnl.58.6.881. PMID 11914402.
- Bannon MJ, Pruetz B, Manning-Bog AB, et al. (2002). "Decreased expression of the transcription factor NURR1 in dopamine neurons of cocaine abusers.". Proc. Natl. Acad. Sci. U.S.A. 99 (9): 6382–5. doi:10.1073/pnas.092654299. PMC 122957. PMID 11959923.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Le WD, Xu P, Jankovic J, et al. (2003). "Mutations in NR4A2 associated with familial Parkinson disease.". Nat. Genet. 33 (1): 85–9. doi:10.1038/ng1066. PMID 12496759.
- Satoh J, Kuroda Y (2003). "The constitutive and inducible expression of Nurr1, a key regulator of dopaminergic neuronal differentiation, in human neural and non-neural cell lines.". Neuropathology : official journal of the Japanese Society of Neuropathology 22 (4): 219–32. doi:10.1046/j.1440-1789.2002.00460.x. PMID 12564761.
- Iwayama-Shigeno Y, Yamada K, Toyota T, et al. (2003). "Distribution of haplotypes derived from three common variants of the NR4A2 gene in Japanese patients with schizophrenia.". Am. J. Med. Genet. B Neuropsychiatr. Genet. 118 (1): 20–4. doi:10.1002/ajmg.b.10053. PMID 12627459.
- Kim KS, Kim CH, Hwang DY, et al. (2003). "Orphan nuclear receptor Nurr1 directly transactivates the promoter activity of the tyrosine hydroxylase gene in a cell-specific manner.". J. Neurochem. 85 (3): 622–34. doi:10.1046/j.1471-4159.2003.01671.x. PMID 12694388.