Disease relevance of NR4A3

• NOR-1 is normally involved in the balance between cell proliferation and cell death, and is implicated in oncogenesis as part of the EWS/NOR-1 fusion protein found in human extraskeletal myxoid chondrosarcoma (EMC) tumors [1].
• Functional characterization of SIX3 homeodomain mutations in holoprosencephaly: interaction with the nuclear receptor NR4A3/NOR1 [2].
• Early induction of the orphan nuclear receptor NOR-1 during cell death of the human breast cancer cell line MCF-7 [3].
• Expression of NOR-1 and its closely related members of the steroid/thyroid hormone receptor superfamily in human neuroblastoma cell lines [4].
• It was initially thought to be a low grade sarcoma of cartilage derivation and was recently found, in most cases, to contain a reciprocal t(9;22), resulting in a fusion of the EWS and CHN genes [5].

Psychiatry related information on NR4A3

• The sex-dependent multipoint linkage analysis of any Major or Minor Mood Disorders produced LOD scores that reached 6.331 and 6.866 at D2S2321 and D2S2208, respectively [6].
• OBJECTIVE: Minor depressive disorder is both common and associated with significant psychosocial impairment [7].
• METHOD: Minor physical anomalies, dermatoglyphic asymmetries, and salivary cortisol levels were measured in three groups of adolescents: 20 with schizotypal personality disorder, 20 with other personality disorders, and 26 with no disorder [8].
• To determine whether the severity of psychiatric symptoms was related to CNS activity, we divided the 27 patients with psychiatric manifestations into 2 groups: the Major Group--18 patients with major psychopathology, and the Minor Group--9 patients with mild depressive syndromes.(ABSTRACT TRUNCATED AT 250 WORDS)[9]
• BACKGROUND: Minor motor disorders (MMDs) associated with human immunodeficiency virus type 1 (HIV-1) predict HIV-1 dementia and death [10].

High impact information on NR4A3

• T cell receptor (TCR)-induced apoptosis of thymocytes is mediated by calcium-dependent expression of the steroid receptors Nur77 and Nor1 [11].
• The presence of surface IgM on the different cell lines is directly correlated to target cell killing by TEC IgM-SAP [12].
• However, full potency of TEC IgM-SAP immunotoxin is restored by adding 1 mM amantadine to the incubation medium [12].
• It was 0.6% in Asia Minor. Factor V Leiden was not found in any of 1600 chromosomes from Africa, Southeast Asia, Australasia, and the Americas [13].
• We identified 13 patients with conotruncal defects and either thoracic (TEC, n = 4) or thoracoabdominal (TAEC, n = 9) ectopia cordis [14].

Chemical compound and disease context of NR4A3

• Fusion of the NH2-terminal domain of the basic helix-loop-helix protein TCF12 to TEC in extraskeletal myxoid chondrosarcoma with translocation t(9;15)(q22;q21) [15].
• Fusion of the EWS gene to CHN, a member of the steroid/thyroid receptor gene superfamily, in a human myxoid chondrosarcoma [16].
• Here, we examined the regulation and expression of the NOR-1 gene during cell death induced by a calcium ionophore A23187 in the human breast cancer cell line MCF-7 [3].
• Dose-dense adjuvant chemotherapy in node-positive breast cancer: docetaxel followed by epirubicin/cyclophosphamide (T/EC), or the reverse sequence (EC/T), every 2 weeks, versus docetaxel, epirubicin and cyclophosphamide (TEC) every 3 weeks. AERO B03 randomized phase II study [17].
• RESULTS: Eradication was achieved in 18/26 (69.2%) of subjects treated with omeprazole and amoxycillin and 18/25 (72.0%) of those treated with omeprazole and clarithromycin (P = N.S.). Minor side effects, most commonly altered taste, were reported by 16% of patients and were more frequent in those randomized to clarithromycin (P = 0.01) [18].

Biological context of NR4A3

• We report a case of EMC with no detectable NR4A3 gene alterations, as assessed with various molecular techniques including reverse transcription-polymerase chain reaction (RT-PCR), Southern blotting, interphase fluorescence in situ hybridization, and PCR single-strand conformation polymorphism-but with coexpression of native NOR1 and SIX3 [19].
• These variant sequences share the common exon-intron boundary with NOR-1 mRNA, suggesting that they were generated from a single gene by alternative splicing, with the divergent points conserved between the rat and human [20].
• CONCLUSIONS: In VSMCs, LDL-induced mitogenesis involves NOR-1 upregulation through a CREB-dependent mechanism [21].
• The hNOR-1 gene is more than 35 kilobases long and interrupted by seven introns [22].
• In all junction types, the putative translation product contained the amino-terminal transactivation domain of EWS linked to the entire TEC protein [23].

Anatomical context of NR4A3

• SIX3 expression is normally confined specifically to the developing eye and fetal forebrain, although the expression of NR4A3 is largely ubiquitous [19].
• These studies underscored the importance of understanding the role of NOR-1 in skeletal muscle [24].
• Recently, we have shown that the transcription factor neuron-derived orphan receptor-1 (NOR-1) is involved in vascular smooth muscle cell (VSMC) proliferation [21].
• 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 [22].
• Nuclear Receptors Nur77, Nurr1, and NOR-1 Expressed in Atherosclerotic Lesion Macrophages Reduce Lipid Loading and Inflammatory Responses [25].

Associations of NR4A3 with chemical compounds

• Moreover, in agreement with these observations, isoprenaline also significantly increased the activity of the NOR-1 promoter [24].
• The Orphan Nuclear Receptor, NOR-1, Is a Target of {beta}-Adrenergic Signaling in Skeletal Muscle [24].
• Using glutathione S-transferase fusion protein pull-down assays and transient cotransfections of Neuro-2a cells with expression and reporter vectors, we found that one mutation, c.676C>G (p.L226V), does not alter the properties of SIX3 toward NOR1 [2].
• The chimeric transcript encodes a protein in which the first 108 amino acids of the NH2-terminus of the basic helix-loop-helix (bHLH) protein TCF12 is linked to the entire TEC protein [15].
• The NR4A Orphan Nuclear Receptor NOR1 Is Induced by Platelet-derived Growth Factor and Mediates Vascular Smooth Muscle Cell Proliferation [26].

Physical interactions of NR4A3

• The third mutation, c.770G>C (p.R257P), results in a mutant SIX3 protein that no longer interacts with NOR1 in vivo [2].
• Gel shift assay suggested that CREB bound to neuron-derived orphan receptor gene in rat liver cells [27].

Regulatory relationships of NR4A3

• In this study, we investigated the functional consequences of these SIX3 mutations with respect to the ability of the protein to interact with and stimulate the transcriptional activity of the nuclear receptor NOR1 (NR4A3) [2].
• Antisense oligonucleotides against NOR-1 inhibit DNA synthesis induced by LDL in VSMCs as efficiently as antisense against the protooncogene c-fos [21].
• Antisense oligonucleotides against NOR-1 inhibited VEGF-induced endothelial cell growth (reduced DNA synthesis, and inhibited cell cycle progression and endothelial cell wound repair after mechanical injury) [28].
• A differential display analysis has identified the PLAGL1 gene as being down-regulated in the CFK2(EWS/NOR1) cell line compared to native CFK2 cells [29].

Other interactions of NR4A3

• Moreover, NOR-1 (NR4A3) was hyperinduced by cold exposure in the nur77(-/-) animal model [24].
• NOR-1 is involved in VEGF-induced endothelial cell growth [28].
• Fusion of the RBP56 and CHN genes in extraskeletal myxoid chondrosarcomas with translocation t(9;17)(q22;q11) [30].
• TFG is a novel fusion partner of NOR1 in extraskeletal myxoid chondrosarcoma [31].
• In this study, we investigated whether the NO donors, S-nitrosoglutathione (GS-NO) and NOR-1, could regulate chemokine production by human keratinocytes activated with interferon-gamma and tumor necrosis factor-alpha [32].

Analytical, diagnostic and therapeutic context of NR4A3

• METHODS AND RESULTS: Nur77, Nurr1, and NOR-1 are expressed in early and advanced human atherosclerotic lesion macrophages primarily in areas of plaque activation/progression as detected by in situ-hybridization and immunohistochemistry [25].
• Sequence analysis suggests that CHN encodes a novel orphan nuclear receptor with a zinc finger DNA-binding domain [33].
• By PCR amplification, with primers designed from conserved sequences among nuclear receptors, a novel member of the thyroid/steroid receptor superfamily was identified from forebrain neuronal cells undergoing apoptosis and designated as NOR-1 (neuron derived orphan receptor) [34].
• A23187 caused a transient increase in NOR-1 mRNA levels within 6 h after treatment [3].
• Using mobility shift assay, we showed that the NOR-1 protein binds to the B1a response-element which has been identified as the target sequence of the Nur77 family, suggesting that three members of the Nur77 family may transactivate common target gene(s) at different situations [34].

References