Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: NR4A3
Cytogenetic location: 9q31.1 Genomic coordinates (GRCh38) : 9:99,821,885-99,866,891 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q31.1 | Chondrosarcoma, extraskeletal myxoid | 612237 | 3 |
Ohkura et al. (1994) identified a novel member of the steroid/thyroid receptor superfamily, which they designated neuron-derived orphan receptor-1 (NOR1), in primary cultured rat forebrain cells undergoing apoptosis. Ohkura et al. (1996) cloned the human NOR1 gene (NR4A3) from a fetal brain cDNA library. Human NOR1 encodes a deduced 626-amino acid protein with a calculated molecular mass of 68 kD. The NOR1 protein shows high homology with human TR3 (NR4A1; 139139) and NOT (NR4A2; 601828), suggesting that they form a distinct subfamily. Northern blot analysis detected high expression of NOR1 in brain and lung and low expression in kidney and liver in fetal tissues, In adult tissues, NOR1 was detected at a high level in heart, abundantly in skeletal muscle, and marginally in the brain and kidney. Two bands of 4.0 and 5.5 kb were found in fetal lung and adult heart and skeletal muscle, whereas only the 5.5 kb band was found in fetal and adult brain. Ohkura et al. (1998) determined that the 2 NOR1 transcripts result from alternative splicing. One of the transcripts has a different 5-prime UTR and the other lacks C-terminal amino acid sequences corresponding to the putative ligand-binding domain.
Ohkura et al. (1996) determined that the human NR4A3 gene contains 8 exons and spans over 35 kb of genomic DNA.
By fluorescence in situ hybridization, Ohkura et al. (1996) mapped the NR4A3 gene to chromosome 9q.
Using an antisense oligonucleotide to NR4A3 in primary cultured rat forebrain cells, Ohkura et al. (1996) found that suppression of NR4A3 induced the migration and neurite extension of neuronal cells without any supplementation by neurotrophic agents, indicating that NR4A3 is associated with the neural development processes in the fetal brain.
In primary mouse hepatocytes, Pei et al. (2006) demonstrated that cAMP rapidly and potently induces expression of Nr4a1, Nr4a2, and Nr4a3. In vivo, hepatic expression of all 3 Nr4a receptors was induced by the cAMP axis in response to glucagon and fasting, and was increased in diabetic mice. Pei et al. (2006) concluded that members of the NR4A family of ligand-independent orphan nuclear receptors are downstream mediators of cAMP action in the hormonal control of gluconeogenesis.
Mullican et al. (2007) found that leukemic blast cells from 46 acute myeloid leukemia (AML; 601626) patients with a variety of cytogenetic abnormalities all showed downregulation of NR4A1 and NR4A3 compared with CD34+ cells from normal controls, suggesting that epigenetic silencing of these receptors may be an obligate event in human AML development.
Pielberg et al. (2008) found that NR4A3 and the neighboring STX17 gene (604204) are overexpressed in melanomas from Gray horses, which undergo a loss of hair pigmentation caused by mutation in the STX17 gene. Gray horses carrying a loss-of-function mutation in the ASIP (600201) gene had a higher incidence of melanoma, implying that increased melanocortin-1 receptor signaling promotes melanoma development in Gray horses.
NR4A3/EWS Fusion Gene
Extraskeletal myxoid chondrosarcomas (EMC; 612237) are soft tissue tumors of chondroblastic origin that occur primarily in adults. A recurrent translocation t(9;22)(q22-31;q11-12) was observed in EMCs by Hinrichs et al. (1985), Turc-Carel et al. (1988), Orndal et al. (1991), and Stenman et al. (1995).
Tarkkanen et al. (1994) observed this translocation in a dedifferentiated chondrosarcoma (215300) with no evidence of myxoid component.
In a patient with skeletal myxoid chondrosarcoma and a t(9;22)(q22-31;q11-12), Gill et al. (1995) demonstrated that a segment on chromosome 9 was fused to the N-terminal region of the EWS gene (133450) as a result of the reciprocal translocation.
Labelle et al. (1995) noted that in all known EWS fusion proteins, the RNA-recognition motif of EWS is replaced by the DNA-binding domain of the corresponding transcription factor. They demonstrated by fluorescence in situ hybridization that in 1 EMC tumor the chromosome 22 breakpoint occurred in the EWS gene. Northern blot analysis revealed an aberrant transcript that was cloned by a modified RT-PCR procedure. This transcript consisted of an in-frame fusion of the 5-prime end of EWS to the NR4A3 gene, which Labelle et al. (1995) called TEC and which has also been called CSMF. This fusion transcript was detected in 6 of 8 EMCs studied, and 3 different junction types between the 2 genes were found. EWS linked to the entire NR4A3 protein. Homology analysis showed that the predicted NR4A3 protein contains a DNA-binding domain characteristic of nuclear receptors. The highest identity scores were observed with the NURR1 family of orphan nuclear receptors (NR4A2; 601828). (This situation is reminiscent of the FUS/CHOP fusion protein in which the entire CHOP (126337) protein is linked to the amino-terminal domain of FUS (137070) by an additional 26 amino acid sequence.) Labelle et al. (1995) stated that the EWS/NR4A3 gene fusion is the second example of the oncogenic conversion of a nuclear receptor in human tumorigenesis, the first being the PML/RARA gene fusion generated by the t(15;17) translocation in acute promyelocytic leukemia.
Clark et al. (1996), who symbolized the NR4A3 gene as CHN, found that the chimeric EWS/CHN gene encodes an EWS/CHN fusion protein in which the C-terminal RNA-binding domain of EWS is replaced by the entire CHN protein, comprising a long N-terminal domain, a central DNA binding domain, and a C-terminal ligand-binding/dimerization domain.
By cotransfection experiments of COS cells and human chondrocytes, Labelle et al. (1999) demonstrated that whereas NR4A3 moderately activates transcription from an NGFIB response element (NBRE)-containing promoter, a corresponding EWS (133450)/NR4A3 fusion protein, generated by the t(9;22) chromosomal translocation, is a highly potent transcriptional activator of the same promoter, being approximately 270-fold more active than the native receptor. EWS/NR4A3 may thus exert its oncogenic potential in chondrosarcomas by activating the transcription of target genes involved in cell proliferation.
Using a yeast functional complementation assay to identify possible functions of the EWS/NOR1 fusion gene, Ohkura et al. (2002) determined that the EWS/NOR1 fusion gene gained a novel activity affecting RNA. EWS/NOR1 partially functioned as an snRNP in yeast and affected pre-mRNA splicing in mammalian cells. Mammalian cell studies showed that the EWS/NOR1 fusion gene localized within the nucleus and showed characteristics similar to that of an RNA-binding protein. Overexpression of EWS/NOR1 in mammalian cells resulted in increased usage of the distal 5-prime splice site of pre-mRNA splicing and that EWS/NOR1 interacted with the U1C splicing protein. The findings suggested an oncogenic mechanism alternative to that of transcriptional control, and indicated that changes in pre-mRNA splicing may contribute to oncogenesis.
NR4A3/RBP56 Fusion Gene
Panagopoulos et al. (1999) demonstrated that RBP56 (601574) can combine with the NR4A3 gene to generate a chimeric RBP56/NR4A3 gene; the fusion gene was identified in a subset of extraskeletal myxoid chondrosarcomas with the translocation t(9;17)(q22;q11).
NR4A3/TCF12 Fusion Gene
By spectral karyotyping, Sjogren et al. (2000) identified a reciprocal t(9;15)(q22;q21) translocation in cells obtained from a tumor with characteristics of EMC. The translocation produced a chimeric transcript encoding a protein in which the first 108 amino acids of the N terminus of TCF12 (600480) were fused in-frame upstream of the entire NR4A3 sequence. The N-terminal TCF12 sequence included in the fusion product contains potential phosphorylation and N-glycosylation sites.
NR4A3/TFG Fusion Gene
Hisaoka et al. (2004) identified an NOR1/TFG (602498) fusion gene in an EMC derived from a Japanese patient. The fusion occurred between exon 6 of the TFG gene and exon 3 of the NOR1 gene.
Note that 2 literature designations for this gene, TEC and CHN, have been used by the HUGO Nomenclature Committee for other genes described in entries 600583 and 118423, respectively.
Ponnio and Conneely (2004) found that Nor1-null mice showed increased limbic seizure activity in response to the excitotoxic glutamate receptor agonist kainic acid compared to wildtype mice. Pathologic examination of the mutant mice showed defective postnatal hippocampal development, including abnormal axonal guidance of dentate gyrus granule and mossy cells, disorganization of the pyramidal cell layer, and early postnatal death of CA1 pyramidal neurons. The authors concluded that Nor1 plays a role in neuronal survival and axonal guidance in the developing murine hippocampus.
Mullican et al. (2007) generated Nr4a1/Nr4a3 double-null mice and observed the development of rapidly lethal AML involving abnormal expansion of hematopoietic stem cells and myeloid progenitors, decreased expression of Junb (165161) and Jun (165160), and defective extrinsic apoptotic signaling (FASL, 134638; TRAIL, 603598).
Ramirez-Herrick et al. (2011) found that reduced gene dosage of Nr4a1 and Nr4a3 in hypoallelic (Nr4a1 +/- Nr4a3 -/- or Nr4a1 -/- Nrfa3 +/-) mice below a critical threshold led to chronic myeloid malignancy with features of mixed myelodysplastic/myeloproliferative neoplasms, with progression to AML in rare cases.
Clark, J., Benjamin, H., Gill, S., Sidhar, S., Goodwin, G., Crew, J., Gusterson, B. A., Shipley, J., Cooper, C. S. Fusion of the EWS gene to CHN, a member of the steroid/thyroid receptor gene superfamily, in a human myxoid chondrosarcoma. Oncogene 12: 229-235, 1996. [PubMed: 8570200]
Gill, S., McManus, A. P., Crew, A. J., Benjamin, H., Sheer, D., Gusterson, B. A., Pinkerton, C. R., Patel, K., Cooper, C. S., Shipley, J. M. Fusion of the EWS gene to a DNA segment from 9q22-31 in a human myxoid chondrosarcoma. Genes Chromosomes Cancer 12: 307-310, 1995. [PubMed: 7539287] [Full Text: https://doi.org/10.1002/gcc.2870120412]
Hinrichs, S. H., Jaramillo, M. A., Gumerlock, P. H., Gardner, M. B., Lewis, J. P., Freeman, A. E. Myxoid chondrosarcoma with a translocation involving chromosomes 9 and 22. Cancer Genet. Cytogenet. 14: 219-226, 1985. [PubMed: 3967207] [Full Text: https://doi.org/10.1016/0165-4608(85)90187-6]
Hisaoka, M., Ishida, T., Imamura, T., Hashimoto, H. RFG is a novel fusion partner of NOR1 in extraskeletal myxoid chondrosarcoma. Genes Chromosomes Cancer 40: 325-328, 2004. [PubMed: 15188455] [Full Text: https://doi.org/10.1002/gcc.20044]
Labelle, Y., Bussieres, J., Courjal, F., Goldring, M. B. The EWS/TEC fusion protein encoded by the t(9;22) chromosomal translocation in human chondrosarcomas is a highly potent transcriptional activator. Oncogene 18: 3303-3308, 1999. [PubMed: 10359536] [Full Text: https://doi.org/10.1038/sj.onc.1202675]
Labelle, Y., Zucman, J., Stenman, G., Kindblom, L.-G., Knight, J., Turc-Carel, C., Dockhorn-Dworniczak, B., Mandahl, N., Desmaze, C., Peter, M., Aurias, A., Delattre, O., Thomas, G. Oncogenic conversion of a novel orphan nuclear receptor by chromosome translocation. Hum. Molec. Genet. 4: 2219-2226, 1995. [PubMed: 8634690] [Full Text: https://doi.org/10.1093/hmg/4.12.2219]
Mullican, S. E., Zhang, S., Konopleva, M., Ruvolo, V., Andreeff, M., Milbrandt, J., Conneely, O. M. Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nature Med. 13: 730-735, 2007. [PubMed: 17515897] [Full Text: https://doi.org/10.1038/nm1579]
Ohkura, N., Hijikuro, M., Miki, K. Antisense oligonucleotide to NOR-1, a novel orphan nuclear receptor, induces migration and neurite extension of cultured forebrain cells. Molec. Brain Res. 35: 309-313, 1996. [PubMed: 8717368] [Full Text: https://doi.org/10.1016/0169-328x(95)00210-j]
Ohkura, N., Hijikuro, M., Yamanoto, A., Miki, K. Molecular cloning of a novel thyroid/steroid receptor superfamily gene from cultured rat neuronal cells. Biochem. Biophys. Res. Commun. 205: 1959-1965, 1994. [PubMed: 7811288] [Full Text: https://doi.org/10.1006/bbrc.1994.2900]
Ohkura, N., Ito, M., Tsukada, T., Sasaki, K., Yamaguchi, K., Miki, K. Structure, mapping and expression of a human NOR-1 gene, the third member of the Nur77/NGFI-B family. Biochim. Biophys. Acta 1308: 205-214, 1996. [PubMed: 8809112] [Full Text: https://doi.org/10.1016/0167-4781(96)00101-7]
Ohkura, N., Ito, M., Tsukada, T., Sasaki, K., Yamaguchi, K., Miki, K. Alternative splicing generates isoforms of human neuron-derived orphan receptor-1 (NOR-1) mRNA. Gene 211: 79-85, 1998. [PubMed: 9573341] [Full Text: https://doi.org/10.1016/s0378-1119(98)00095-x]
Ohkura, N., Yaguchi, H., Tsukada, T., Yamaguchi, K. The EWS/NOR1 fusion gene product gains a novel activity affecting pre-mRNA splicing. J. Biol. Chem. 277: 535-543, 2002. [PubMed: 11673470] [Full Text: https://doi.org/10.1074/jbc.M109018200]
Orndal, C., Carlen, B., Akerman, M., Willen, H., Mandahl, N., Heim, S., Rydholm, A., Mitelman, F. Chromosomal abnormality t(9;22)(q22;q12) in an extraskeletal myxoid chondrosarcoma characterized by fine needle aspiration cytology, electron microscopy, immunohistochemistry and DNA flow cytometry. Cytopathology 2: 261-270, 1991. [PubMed: 1782363] [Full Text: https://doi.org/10.1111/j.1365-2303.1991.tb00497.x]
Panagopoulos, I., Mencinger, M., Dietrich, C. U., Bjerkehagan, B., Saeter, G., Mertens, F., Mandahl, N., Heim, S. Fusion of the RBP56 and CHN genes in extraskeletal myxoid chondrosarcomas with translocation t(9;17)(q22;q11). Oncogene 18: 7594-7598, 1999. [PubMed: 10602519] [Full Text: https://doi.org/10.1038/sj.onc.1203155]
Pei, L., Waki, H., Vaitheesvaran, B., Wilpitz, D. C., Kurland, I. J., Tontonoz, P. NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism. Nature Med. 12: 1048-1055, 2006. [PubMed: 16906154] [Full Text: https://doi.org/10.1038/nm1471]
Pielberg, G. R., Golovko, A., Sundstrom, E., Curik, I., Lennartsson, J., Seltenhammer, M. H., Druml, T., Binns, M., Fitzsimmons, C., Lindgren, G., Sandberg, K., Baumung, R., and 9 others. A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse. Nature Genet. 40: 1004-1009, 2008. [PubMed: 18641652] [Full Text: https://doi.org/10.1038/ng.185]
Ponnio, T., Conneely, O. M. Nor-1 regulates hippocampal axon guidance, pyramidal cell survival, and seizure susceptibility. Molec. Cell. Biol. 24: 9070-9078, 2004. [PubMed: 15456880] [Full Text: https://doi.org/10.1128/MCB.24.20.9070-9078.2004]
Ramirez-Herrick, A. M., Mullican, S. E., Sheehan, A. M., Conneely, O. M. Reduced NR4A gene dosage leads to mixed myelodysplastic/myeloproliferative neoplasms in mice. Blood 117: 2681-2690, 2011. [PubMed: 21205929] [Full Text: https://doi.org/10.1182/blood-2010-02-267906]
Sjogren, H., Wedell, B., Meis-Kindblom, J. M., Kindblom, L.-G., Stenman, G. 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). Cancer Res. 60: 6832-6835, 2000. Note: Erratum: Cancer Res. 61: 2339 only, 2001. [PubMed: 11156374]
Stenman, G., Andersson, H., Mandahl, N., Meis-Kindblom, J. M., Kindblom, L.-G. Translocation t(9;22)(q22;q12) is a primary cytogenetic abnormality in extraskeletal myxoid chondrosarcoma. Int. J. Cancer 62: 398-402, 1995. [PubMed: 7635565] [Full Text: https://doi.org/10.1002/ijc.2910620407]
Tarkkanen, M., Wiklund, T., Virolainen, M., Elomaa, I., Knuutila, S. Dedifferentiated chondrosarcoma with t(9;22)(q34;q11-12). Genes Chromosomes Cancer 9: 136-140, 1994. [PubMed: 7513544] [Full Text: https://doi.org/10.1002/gcc.2870090210]
Turc-Carel, C., Dal Cin, P., Rao, U., Karakousis, C., Sandberg, A. A. Recurrent breakpoints at 9q31 and 22q12.2 in extraskeletal myxoid chondrosarcoma. Cancer Genet. Cytogenet. 30: 145-150, 1988. [PubMed: 3422040] [Full Text: https://doi.org/10.1016/0165-4608(88)90103-3]