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Gene Review

NR4A2  -  nuclear receptor subfamily 4, group A,...

Homo sapiens

Synonyms: HZF-3, Immediate-early response protein NOT, NOT, NURR1, Nuclear receptor subfamily 4 group A member 2, ...
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Disease relevance of NR4A2


High impact information on NR4A2

  • Additionally, mutations in NR4A2 affect transcription of the gene encoding tyrosine hydroxylase [2].
  • The mutations resulted in a marked decrease in NR4A2 mRNA levels in transfected cell lines and in lymphocytes of affected individuals [2].
  • These data show that NGFI-B and NURR1 can increase the potential of RXR to modulate gene expression in a ligand-dependent manner by allowing a distinct class of direct repeats to serve as specific RXR response elements [6].
  • Because expression of both NGFI-B and NURR1 is rapidly induced by various growth factors, these findings also suggest a novel mechanism for convergence between vitamin A or retinoid and growth factor signaling pathways [6].
  • A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1 [6].

Chemical compound and disease context of NR4A2


Biological context of NR4A2


Anatomical context of NR4A2


Associations of NR4A2 with chemical compounds

  • 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 [1].
  • Originally described as a critical dopaminergic neuron growth factor receptor, NR4A2 expression is rapidly but transiently induced by PGE2 in a cAMP/protein kinase A-dependent manner [3].
  • The NR4A2 (Nurr1) gene is essential for the development and maintenance of mesencephalic DA-synthesizing neurons [15].
  • Alone or with retinoid X receptor, RXR, NR4A2 influences the expression of several genes important for human brain development and regulation [16].
  • NURR1 is known to regulate transcription of the gene encoding the cocaine-sensitive dopamine transporter (DAT) [17].

Physical interactions of NR4A2


Regulatory relationships of NR4A2

  • Furthermore, glucocorticoids dramatically suppressed cytokine- and CRH-induced synovial NURR1 mRNA [19].
  • NURR1 was abundantly expressed in the inflammatory cells of both RA and PsA synovium [19].
  • In addition, NURR1 selectively antagonizes cytokine-induced MMP-3 and -9 expression with minimal effects on MMP-2 and -13 and tissue inhibitor of matrix metalloproteinases-1 and -2 [18].
  • Consistent with this observation, cyclooxygenase-2-derived prostaglandin E(2) (PGE(2)) rapidly and potently induces NURR1 expression in chondrocytes, suggesting that this receptor may regulate PGE(2)-mediated processes in cartilage [18].

Other interactions of NR4A2

  • 1. A Val95Ala polymorphism of the RXRB gene, a Val227Ala polymorphism in the PPARA gene, and two synonymous single-nucleotide and CA repeat polymorphisms in the 5' region and 3' untranslated region of the NR4A2 gene were identified [10].
  • Markedly enhanced expression of NURR1 is observed in synovial tissue of patients with RA compared with normal subjects [1].
  • Orphan nuclear receptor Nurr1 directly transactivates the promoter activity of the tyrosine hydroxylase gene in a cell-specific manner [21].
  • Now, a total of five causative genes including NR4A2 have been identified, and others such as PARK3, -4, -6, -8, -9, -10 have been mapped as hereditary forms of familial PD [22].
  • NURR1 appears to be important for CYP11B2 transcription and is found at higher levels in glomerulosa and in APA [23].

Analytical, diagnostic and therapeutic context of NR4A2

  • Database analysis revealed a CA repeat polymorphism in the 3' UTR of NR4A2 that was confirmed by PCR [14].


  1. 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. McEvoy, A.N., Murphy, E.A., Ponnio, T., Conneely, O.M., Bresnihan, B., FitzGerald, O., Murphy, E.P. J. Immunol. (2002) [Pubmed]
  2. Mutations in NR4A2 associated with familial Parkinson disease. Le, W.D., Xu, P., Jankovic, J., Jiang, H., Appel, S.H., Smith, R.G., Vassilatis, D.K. Nat. Genet. (2003) [Pubmed]
  3. Prostaglandin E2 regulates the nuclear receptor NR4A2 in colorectal cancer. Holla, V.R., Mann, J.R., Shi, Q., DuBois, R.N. J. Biol. Chem. (2006) [Pubmed]
  4. A common NURR1 polymorphism associated with Parkinson disease and diffuse Lewy body disease. Zheng, K., Heydari, B., Simon, D.K. Arch. Neurol. (2003) [Pubmed]
  5. Expression of NOR-1 and its closely related members of the steroid/thyroid hormone receptor superfamily in human neuroblastoma cell lines. Maruyama, K., Tsukada, T., Bandoh, S., Sasaki, K., Ohkura, N., Yamaguchi, K. Cancer Lett. (1995) [Pubmed]
  6. A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Perlmann, T., Jansson, L. Genes Dev. (1995) [Pubmed]
  7. Modulation of orphan nuclear receptor NURR1 expression by methotrexate in human inflammatory joint disease involves adenosine A2A receptor-mediated responses. Ralph, J.A., McEvoy, A.N., Kane, D., Bresnihan, B., FitzGerald, O., Murphy, E.P. J. Immunol. (2005) [Pubmed]
  8. NURR1 mutations in cases of schizophrenia and manic-depressive disorder. Buervenich, S., Carmine, A., Arvidsson, M., Xiang, F., Zhang, Z., Sydow, O., Jönsson, E.G., Sedvall, G.C., Leonard, S., Ross, R.G., Freedman, R., Chowdari, K.V., Nimgaonkar, V.L., Perlmann, T., Anvret, M., Olson, L. Am. J. Med. Genet. (2000) [Pubmed]
  9. Nuclear hormone receptor NR4A2 is involved in cell transformation and apoptosis. Ke, N., Claassen, G., Yu, D.H., Albers, A., Fan, W., Tan, P., Grifman, M., Hu, X., Defife, K., Nguy, V., Meyhack, B., Brachat, A., Wong-Staal, F., Li, Q.X. Cancer Res. (2004) [Pubmed]
  10. 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. Ishiguro, H., Okubo, Y., Ohtsuki, T., Yamakawa-Kobayashi, K., Arinami, T. Am. J. Med. Genet. (2002) [Pubmed]
  11. NR4A1, 2, 3--an orphan nuclear hormone receptor family involved in cell apoptosis and carcinogenesis. Li, Q.X., Ke, N., Sundaram, R., Wong-Staal, F. Histol. Histopathol. (2006) [Pubmed]
  12. Mutation analysis of the human NR4A2 gene, an essential gene for midbrain dopaminergic neurogenesis, in schizophrenic patients. Chen, Y.H., Tsai, M.T., Shaw, C.K., Chen, C.H. Am. J. Med. Genet. (2001) [Pubmed]
  13. Structure, mapping and expression of a human NOR-1 gene, the third member of the Nur77/NGFI-B family. Ohkura, N., Ito, M., Tsukada, T., Sasaki, K., Yamaguchi, K., Miki, K. Biochim. Biophys. Acta (1996) [Pubmed]
  14. Identification and characterization of human NR4A2 polymorphisms in attention deficit hyperactivity disorder. Smith, K.M., Bauer, L., Fischer, M., Barkley, R., Navia, B.A. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2005) [Pubmed]
  15. Distribution of haplotypes derived from three common variants of the NR4A2 gene in Japanese patients with schizophrenia. 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. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2003) [Pubmed]
  16. NR4A2 and schizophrenia: lack of association in a Portuguese/Brazilian study. Ruano, D., Macedo, A., Dourado, A., Soares, M.J., Valente, J., Coelho, I., Santos, V., Azevedo, M.H., Goodman, A., Hutz, M.H., Gama, C., Lobato, M.I., Belmonte-de-Abreu, P., Palha, J.A. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2004) [Pubmed]
  17. Decreased expression of the transcription factor NURR1 in dopamine neurons of cocaine abusers. Bannon, M.J., Pruetz, B., Manning-Bog, A.B., Whitty, C.J., Michelhaugh, S.K., Sacchetti, P., Granneman, J.G., Mash, D.C., Schmidt, C.J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  18. Transcriptional Repression of Matrix Metalloproteinase Gene Expression by the Orphan Nuclear Receptor NURR1 in Cartilage. Mix, K.S., Attur, M.G., Al-Mussawir, H., Abramson, S.B., Brinckerhoff, C.E., Murphy, E.P. J. Biol. Chem. (2007) [Pubmed]
  19. Involvement of the nuclear orphan receptor NURR1 in the regulation of corticotropin-releasing hormone expression and actions in human inflammatory arthritis. Murphy, E.P., McEvoy, A., Conneely, O.M., Bresnihan, B., FitzGerald, O. Arthritis Rheum. (2001) [Pubmed]
  20. cDNA cloning of a NGFI-B/nur77-related transcription factor from an apoptotic human T cell line. Okabe, T., Takayanagi, R., Imasaki, K., Haji, M., Nawata, H., Watanabe, T. J. Immunol. (1995) [Pubmed]
  21. Orphan nuclear receptor Nurr1 directly transactivates the promoter activity of the tyrosine hydroxylase gene in a cell-specific manner. Kim, K.S., Kim, C.H., Hwang, D.Y., Seo, H., Chung, S., Hong, S.J., Lim, J.K., Anderson, T., Isacson, O. J. Neurochem. (2003) [Pubmed]
  22. Familial Parkinson's disease: a hint to elucidate the mechanisms of nigral degeneration. Hattori, N., Kobayashi, H., Sasaki-Hatano, Y., Sato, K., Mizuno, Y. J. Neurol. (2003) [Pubmed]
  23. A role for the NGFI-B family in adrenal zonation and adrenocortical disease. Bassett, M.H., White, P.C., Rainey, W.E. Endocr. Res. (2004) [Pubmed]
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