Disease relevance of Nr4a3

• The NR4A1-3 (Nur77, NURR1 and NOR-1) subfamily of nuclear hormone receptors (NRs) has been implicated in Parkinson's disease, schizophrenia, manic depression, atherogenesis, Alzheimer's disease, rheumatoid arthritis, cancer and apoptosis [1].
• Translocated in extraskeletal chondrosarcoma (TEC) is an orphan nuclear receptor involved in the control of cell proliferation and apoptosis and is expressed mainly in the mammalian central nervous system [2].
• IFN-gamma promotes the development of lymphocytic spontaneous autoimmune thyroiditis (L-SAT) in NOD.H-2h4 mice and inhibits the development of thyrocyte hyperplasia and proliferation (TEC H/P) [3].
• These tumors involved three mammary carcinomas (dbrB, DBAH, MT2), a spindle-cell sarcoma (TEC) and a lymphoblastic type of lymphoma (DBA/3) [4].
• Approximately half of the TEC tumors responded to prolonged treatment by hyperthermia alone, yielding total regressions; the MT2 tumor proved to be resistant to this modality [5].

High impact information on Nr4a3

• Tec kinases in T cell development: a clue behind the mask [6]?
• Antigen-presenting activity of each TEC was determined by using ovalbumin-specific, I-Ab-restricted helper T cell lines [7].
• In thymocytes, Nor-1 protein is induced to a very high level upon TCR stimulation and has similar kinetics to Nur77 [8].
• As in the case of our Nur77-FL mice, FasL is not detectable in the thymocytes of Nor-1 transgenic mice [8].
• Thus, Nor-1 and Nur77 demonstrate functional redundancy in an apparently Fas-independent apoptosis [8].

Biological context of Nr4a3

• Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis [8].
• Here, we report the generation of Nor-1-deficient mice with a block in early embryonic development [9].
• We observed that NOR-1 trans-activates gene expression in a cell- and target-specific manner; moreover, it operates in an activation function (AF)-1-dependent manner [10].
• The Nur77/NURR1/NOR1 nuclear receptors are classified as immediate early response genes which are induced through multiple signal transduction pathways [11].
• Nur77-deficient mice, however, exhibit no phenotype, and a line of Nor-1 mutant mice was reported to exhibit a mild ear development phenotype but no other gross abnormalities [9].

Anatomical context of Nr4a3

• Furthermore, Nor1 colocalizes with NGFI-B in the adrenal glands and thymus, two tissues in which NGFI-B has been suggested to be functionally important [12].
• During early otic development, Nor-1 is expressed exclusively in the semicircular canal forming fusion plates [13].
• Disruption of the Nor-1 gene results in inner ear defects and partial bidirectional circling behavior [13].
• BACKGROUND: Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan nuclear receptors closely associated with dopamine neurotransmission in the central nervous system [14].
• We demonstrate here that Nor1 is expressed in the pituitary gland and adrenal cortex, and that ACTH and angiotensin II (AngII) treatment of adrenal fasciculata cells induces Nor1 expression [15].

Associations of Nr4a3 with chemical compounds

• Additional 6-mercaptopurine analogs all efficiently activated NOR-1, suggesting that the signaling pathways that modulate proliferation via inhibition of de novo purine and/or nucleic acid biosynthesis are involved in the regulation NR4A activity [10].
• The AF-1 domain of the orphan nuclear receptor NOR-1 mediates trans-activation, coactivator recruitment, and activation by the purine anti-metabolite 6-mercaptopurine [10].
• Nur77 and its family members, Nor-1 and Nurr1, are orphan steroid receptors implicated in a wide variety of biological processes, including apoptosis and dopamine neuron agenesis [9].
• Retinoid X receptor heterodimerization and developmental expression distinguish the orphan nuclear receptors NGFI-B, Nurr1, and Nor1 [12].
• Prostaglandin A2 acts as a transactivator for NOR1 (NR4A3) within the nuclear receptor superfamily [16].

Regulatory relationships of Nr4a3

• Parathyroid hormone induces the nuclear orphan receptor NOR-1 in osteoblasts [17].

Other interactions of Nr4a3

• Nur77 demonstrated the highest expression, followed, in order, by Nurr1 and NOR-1 [18].
• Using an anti-E-cadherin antibody specific for its extracellular domain, we detected a 50kDa degradation fragment of E-cadherin (120 kDa) from the culture medium conditioned by YAMC cells exposed to the NO-releasing drug, NOR-1, for 4 and 24 h [19].
• Moreover, we demonstrate that TRAP220 potentiates NOR-1-mediated transactivation, and interacts with the NR4A1-3 subgroup in an AF-1-dependent manner in a cellular context [1].
• 5. No receptor-stimulated activation of phosphoinositase C was detected in 'germ cell' populations, but the non-specific G protein activator A1F4-provoked inositol phosphate accumulation in these cells, so demonstrating their potential to respond through yet to be identified G protein-coupled receptors with phosphoinositidase C activation [20].

Analytical, diagnostic and therapeutic context of Nr4a3

• To begin to understand the physiological implications of these functional differences we used in situ hybridization to compare the distribution of Nor1, NGFI-B, and Nurr1 messenger RNAs during different developmental stages [12].
• To elucidate the relationships between NOR-1 and these closely related proteins, we analyzed the human NOR-1 gene and its transcripts by molecular cloning [21].
• Using electrophoretic mobility shift assays, we found that both NOR-1 and SNAP caused beta-catenin/LEF-1 DNA complex formation [22].
• To determine whether responsiveness of lymphocytes or thyrocytes to IFN-gamma is important for the development of these lesions, IFN-gammaR-/- mice, which develop TEC H/P similar to IFN-gamma-/- mice, were used as recipients for adoptive cell transfer [3].
• To investigate the cause of the distinct migration profiles of class II heterodimers in both TEC types, class II heterodimer-associated peptides were analyzed by matrix-assisted laser desorption ionization mass spectrometry [23].

References