Disease relevance of NR4A2

• Modulation of the NURR subfamily of nuclear receptors may be an important mechanism regulating pathways associated with inflammatory joint disease [1].
• Mutations in NR4A2 associated with familial Parkinson disease [2].
• Prostaglandin E2 regulates the nuclear receptor NR4A2 in colorectal cancer [3].
• A common NURR1 polymorphism associated with Parkinson disease and diffuse Lewy body disease [4].
• In the present study, we examined the gene expression of NOR-1 as well as NGFI-B and NURR1 in human neuroblastoma cell lines by reverse transcription-polymerase chain reaction and nucleotide sequencing [5].

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

• In summary, these findings establish the nuclear orphan receptor NURR1 as a molecular target of MTX action in human inflammatory joint disease and demonstrate that the immunomodulatory actions of MTX on NURR1 expression are mediated through adenosine release [7].
• Modulation of orphan nuclear receptor NURR1 expression by methotrexate in human inflammatory joint disease involves adenosine A2A receptor-mediated responses [7].
• There is a highly homologous NURR1 gene in humans (formerly known as NOT) which therefore constitutes a good candidate gene for neurologic and psychiatric disorders with an involvement of the dopamine neuron system, such as Parkinson's disease, schizophrenia, and manic-depression [8].

Biological context of NR4A2

• Furthermore, down-regulation of NR4A2 as well as NR4A1 promoted intrinsic apoptosis [9].
• Small interfering RNA-mediated down-regulation of NR4A2 in HeLa cells, either transiently or stably, resulted in reduced anchorage-independent growth that was largely attributable to increased anoikis [9].
• However, they revealed a significant association between the NR4A2 gene haplotype and alcohol dependence, indicating that 2q22-q23 including the NR4A2 gene locus is a possible genomic region contributing to genetic susceptibility to alcohol dependence [10].
• In vitro functional studies using over-expression (gain of function) or gene inactivation (loss of function) type assays, combined with transgenic or knockout animal data in vivo, have revealed these effects and their physiological roles, including thymocyte development for NR4A1/3 and pro-survival in CNS for NR4A2 [11].
• We have established that transcriptional activation of the NURR1 gene by IL-1beta and TNF-alpha requires a proximal promoter region that contains a consensus NF-kappaB DNA-binding motif [1].

Anatomical context of NR4A2

• Retinoid X receptors (RXRs) form heterodimer complexes with nuclear-related receptor 1 (NURR1) or with peroxisome proliferator-activated receptors (PPARs) [10].
• Human colorectal cancers relative to matched normal mucosa showed increased NR4A2 expression [3].
• Mutation analysis of the human NR4A2 gene, an essential gene for midbrain dopaminergic neurogenesis, in schizophrenic patients [12].
• The high homology between hNOR-1, mNur77/rNGFI-B/hTR3, and mNurr1/rRNR-1/hNOT indicated that these three orphan receptors form a distinct subfamily within the steroid/thyroid receptor superfamily [13].
• NR4A2, or Nurr1, is an orphan nuclear receptor implicated in the development of dopaminergic cells of the ventral tegmental area (VTA) and the substantia nigra (SN) [14].

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

• In summary, enhanced NF-kappaB- and CREB-1-binding activity on the NURR1 promoter by inflammatory mediators delineates novel mechanisms in the regulation of NURR1 transcription [1].
• To explore the molecular mechanisms of NURR1 transrepression, we reveal that this receptor targets a critical region of the MMP-1 promoter (-1772 to -1546 bp) and that repression does not require consensus binding sites for NURR1 [18].
• Nuclear extracts were analyzed by electrophoretic mobility shift assay to determine NURR1 binding to the CRH promoter/enhancer [19].
• TINUR binds to the same DNA sequence as NGFI-B/nur77 [20].

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].

References