Nuclear receptor 4A2

NR4A2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1OVL
Identifiers
Aliases	NR4A2, HZF-3, NOT, NURR1, RNR1, TINUR, nuclear receptor subfamily 4 group A member 2
External IDs	OMIM: 601828; MGI: 1352456; HomoloGene: 4509; GeneCards: NR4A2; OMA:NR4A2 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) Band 2q24.1 Start 156,324,437 bp End 156,342,348 bp
Gene location (Mouse) Chr. Chromosome 2 (mouse) Band 2 C1.1|2 31.66 cM Start 56,996,842 bp End 57,014,015 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in mucosa of paranasal sinus gastric mucosa trachea spinal ganglia cartilage tissue mucosa of urinary bladder cardia seminal vesicula trigeminal ganglion tail of epididymis Top expressed in habenula ventral tegmental area parotid gland Region I of hippocampus proper substantia nigra lobe of cerebellum cerebellar vermis subiculum epithelium of stomach submandibular gland More reference expression data BioGPS More reference expression data
Gene ontology Molecular function retinoid X receptor binding protein homodimerization activity sequence-specific DNA binding beta-catenin binding DNA-binding transcription activator activity, RNA polymerase II-specific steroid hormone receptor activity RNA polymerase II transcription regulatory region sequence-specific DNA binding protein binding glucocorticoid receptor binding DNA-binding transcription factor activity zinc ion binding metal ion binding DNA binding protein heterodimerization activity nuclear receptor activity RNA polymerase II cis-regulatory region sequence-specific DNA binding DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component cytoplasm nucleus nucleoplasm nuclear speck transcription regulator complex Biological process dopaminergic neuron differentiation cellular response to oxidative stress response to hypoxia response to amphetamine nervous system development neuron maturation steroid hormone mediated signaling pathway central nervous system projection neuron axonogenesis regulation of transcription, DNA-templated central nervous system neuron differentiation negative regulation of apoptotic signaling pathway cellular response to corticotropin-releasing hormone stimulus positive regulation of transcription, DNA-templated regulation of respiratory gaseous exchange regulation of dopamine metabolic process adult locomotory behavior regulation of gene expression habenula development positive regulation of catalytic activity fat cell differentiation post-embryonic development dopamine biosynthetic process transcription initiation from RNA polymerase II promoter negative regulation of neuron apoptotic process canonical Wnt signaling pathway general adaptation syndrome neuron differentiation signal transduction dopamine metabolic process transcription, DNA-templated intracellular receptor signaling pathway neuron migration negative regulation of transcription by RNA polymerase II positive regulation of transcription by RNA polymerase II cellular response to extracellular stimulus midbrain dopaminergic neuron differentiation gene expression transcription by RNA polymerase II Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4929 18227 Ensembl ENSG00000153234 ENSMUSG00000026826 UniProt P43354 Q06219 RefSeq (mRNA) NM_006186 NM_173171 NM_173172 NM_173173 NM_001139509 NM_013613 RefSeq (protein) NP_006177 NP_775265 NP_006177.1 NP_001132981 NP_038641 Location (UCSC) Chr 2: 156.32 – 156.34 Mb Chr 2: 57 – 57.01 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

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 and schizophrenia. 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.

This protein is thought to be critical to development of the dopamine phenotype in the midbrain, as mice without NURR1 are lacking expression of this phenotype. This is further confirmed by studies showing that when forcing NURR1 expression in naïve precursor cells, there is complete dopamine phenotype gene expression.

While NURR1 is a key protein, there are other factors required as research shows that solely expressing NURR1 fails to stimulate this phenotypic gene expression. One of these suggested factors is winged-helix transcription factor 2 (Foxa2). Studies have found these two factors to be within the same region of developing dopaminergic neurons, both of these factors were present in order to have expression for the dopamine phenotype.

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.

Structure

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.

Applications

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. Therefore, Nurr1 modulation may be promising for generation of dopaminergic neurons for Parkinson’s disease research, yet implantation of these induced cells as therapy treatments, has had limited results.

Knockout Studies

Studies have shown that heterozygous knockout mice for the NURR1 gene demonstrate reduced dopamine release. Initially this was compensated for by a decrease in the rate of dopamine reuptake; however, over time this reuptake could not make up for the reduced amount of dopamine being released. Coupled with the loss of dopamine receptor neurons, this can result in the onset of symptoms for Parkinson’s Disease.

Interactions

Nuclear receptor related 1 protein has been shown to interact with:

• Beta-catenin,
• Pituitary homeobox 3,
• Retinoic acid receptor alpha, and
• Retinoic acid receptor beta.

Further reading

• Le W, Appel SH (February 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 (July 1975). "[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 (April 1995). "A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1". Genes & Development. 9 (7): 769–82. doi:10.1101/gad.9.7.769. PMID 7705655.
• Forman BM, Umesono K, Chen J, Evans RM (May 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, Senger G, Kroczek RA (November 1994). "NOT, a human immediate-early response gene closely related to the steroid/thyroid hormone receptor NAK1/TR3". Molecular Endocrinology. 8 (11): 1583–91. doi:10.1210/me.8.11.1583. PMID 7877627.
• Maruyama K, Sugano S (January 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, Suyama A, Sugano S (October 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 (April 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, Sumi-Ichinose C, Nomura T, Hagino Y, Nagatsu T (April 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 (December 2001). "Mutation analysis of the human NR4A2 gene, an essential gene for midbrain dopaminergic neurogenesis, in schizophrenic patients". American Journal of Medical Genetics. 105 (8): 753–7. doi:10.1002/ajmg.10036. PMID 11803525.
• Ishiguro H, Okubo Y, Ohtsuki T, Yamakawa-Kobayashi K, Arinami T (January 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". American Journal of Medical Genetics. 114 (1): 15–23. doi:10.1002/ajmg.1620. PMID 11840500.
• McEvoy AN, Murphy EA, Ponnio T, Conneely OM, Bresnihan B, FitzGerald O, Murphy EP (March 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". Journal of Immunology. 168 (6): 2979–87. doi:10.4049/jimmunol.168.6.2979. PMID 11884470.
• Xu PY, Liang R, Jankovic J, Hunter C, Zeng YX, Ashizawa T, Lai D, Le WD (March 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, Whitty CJ, Michelhaugh SK, Sacchetti P, Granneman JG, Mash DC, Schmidt CJ (April 2002). "Decreased expression of the transcription factor NURR1 in dopamine neurons of cocaine abusers". Proceedings of the National Academy of Sciences of the United States of America. 99 (9): 6382–5. doi:10.1073/pnas.092654299. PMC 122957. PMID 11959923.
• Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, Vassilatis DK (January 2003). "Mutations in NR4A2 associated with familial Parkinson disease". Nature Genetics. 33 (1): 85–9. doi:10.1038/ng1066. PMID 12496759.
• Satoh J, Kuroda Y (December 2002). "The constitutive and inducible expression of Nurr1, a key regulator of dopaminergic neuronal differentiation, in human neural and non-neural cell lines". Neuropathology. 22 (4): 219–32. doi:10.1046/j.1440-1789.2002.00460.x. PMID 12564761.
• Iwayama-Shigeno Y, Yamada K, Toyota T, Shimizu H, Hattori E, Yoshitsugu K, Fujisawa T, Yoshida Y, Kobayashi T, Toru M, Kurumaji A, Detera-Wadleigh S, Yoshikawa T (April 2003). "Distribution of haplotypes derived from three common variants of the NR4A2 gene in Japanese patients with schizophrenia". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 118B (1): 20–4. doi:10.1002/ajmg.b.10053. PMID 12627459.
• Kim KS, Kim CH, Hwang DY, Seo H, Chung S, Hong SJ, Lim JK, Anderson T, Isacson O (May 2003). "Orphan nuclear receptor Nurr1 directly transactivates the promoter activity of the tyrosine hydroxylase gene in a cell-specific manner". Journal of Neurochemistry. 85 (3): 622–34. doi:10.1046/j.1471-4159.2003.01671.x. PMID 12694388.

External links

• Nurr1+nuclear+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)