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Nuclear receptor subfamily 4, group A, member 2 (Gene NR4A2) Homo SapiensThe NR4A2 (map locus: Ensembl: 2q24.1; Entrez/HGNC: 2q22-q23) gene product, NURR1/NOT/Nuclear receptor subfamily 4 group A member 2, is a 598 AA (66.6 kDa) protein, that contains a 76 AA (260-335) DNA-binding domain, two NR C4-type zinc finger domains, 21 AA (263-283) and 25 AA (299 to 323), and a ligand-binding domain, 51 AA (409 to 459). Nurr1 also contains a phosphorylation site, Ser181. Four distinct isoforms have been identified. The mouse and human NR4A2 genes have been cloned and characterized by Saucedo-Cardenas O, (1997) and Ichinose H, et al. (1999), respectively. Human NR4A2 contains eight exons and the potential regulatory consensus binding sites for NF-kappaB, CREB and Sp1. Nurr1 is a member of a large gene family comprised of nuclear receptors for steroids, retinoids and thyroid hormones. Nurr1 was identified in 1992 as a brain-specific transcription factor, Law SW, et al. (1992), but its expression occurs in other tissues and organs outside the brain. Nurr1 is also expressed in T-cells, B-cells, fibroblasts, and synovial inflammatory cells. It is involved in T-cell apoptosis, brain development, the hypothalamic-pituitary-adrenal axis and vascular disease. Nurr1 is selectively expressed in both the developing and the adult brain where it persists in the olfactory bulb, parts of the cortex, the hippocampal formation and especially the substantia nigra. The substantia nigra and ventral tegment are areas that regulate movement and affective behavior. Cells in these areas typically degenerate in Parkinson’s disease (PD). Consequently, Nurr1 has been studied extensively in the area of dopaminergic system development, Jankovic J, et al. (2005). NURR1 is required for the maintenance of the dopaminergic system. It is expressed in the nigrostriatal dopamine system and is required for maintenance of dopaminergic neurons, Zetterström RH, et al. (1996, 1997); Pennisi E. (1997); and Le W, et al. (1999). Nurr1 functions late in dopamine cell development to drive differentiation of ventral mesencephalic late DA precursor neurons where it is essential for specifying commitment of mesencephalic precursors to the full dopaminergic phenotype, Saucedo-Cardenas O, et al. (1998). Nurr1 supports dopaminergic neurons in the substantia nigra/ventral tegmental area, but is not essential to hypothalamic neurons, Castillo, SO, et al. (1998). Nurr1 can induce cell arrest and a highly differentiated morphology in the dopamine-synthesizing cell line MN9D, Castro DS, et al. (2001). The role of Nurr1 in differentiation of DA neurons precursors and DA neuron survival has been reviewed, Arenas E. (2005) and Alavian KN, et al. (2008). Nurr1 enhances the transcription of several genes that support the synthesis and storage of dopamine. Nurr1 enhances the transcription of human tyrosine hydroxylase (TH), Sakurada K, et al. (1999), dopamine transporter gene (hDAT), Sacchetti P, et al (2001), vesicular monoamine transporter 2 (VMAT2), and l-aromatic amino acid decarboxylase (AADC), Hermanson E, et al. (2003). In addition to its importance for the understanding of neurological diseases such as Parkinson’s disease, Nurr1 has been associated with major inflammatory diseases such as rheumatoid (RA) and psoriatic arthritis (PsA) and vascular diseases such as atherosclerosis and vein-graft disease. Nurr1 may have a role in human inflammatory arthritis, McEvoy AN, et al. (2002), Davies MR, et al. (2005). Nurr1 is induced in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) inflammatory cells by synoviocyte corticotrophin-releasing hormone (CRH), Murphy EP, et al. (2004). Glucocorticoids dramatically suppressed cytokine- and CRH-induced synovial NURR1 mRNA. The links between Nurr1 and vascular diseases such as atherosclerosis and vein-graft disease has been studied, Pei L, et al. (2005), Martínez-González J, et al (2005) and recently reviewed, Bonta PI, et al. (2007), Pols TW, et al. (2007). Sigma offers antibodies and shRNAs useful for the study of NR4A2 (NURR1) gene products. References: Alavian KN, et al. (2008) Transcriptional regulation of mesencephalic dopaminergic neurons: the full circle of life and death. Mov Disord. 23: 319-328. |
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