Alternative titles; symbols
HGNC Approved Gene Symbol: NR4A1
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38): 12:52,022,832-52,059,503 (from NCBI)
Ryseck et al. (1989) characterized a growth factor-inducible gene, N10, encoding a nuclear protein of 601 amino acids with similarities to members of the steroid and thyroid hormone receptor families. The gene is rapidly but transiently induced by several mitogens.
Chang et al. (1989) isolated a member of the steroid receptor superfamily, which they called TR3, from a human prostate cDNA library by use of an oligonucleotide probe to the DNA-binding domain common to members of the steroid receptor superfamily. Sequence analysis of the TR3 cDNA revealed that it encodes a 598-amino acid protein with domains homologous to the DNA-binding and hormone-binding domains of other members of the steroid receptor superfamily. Chang et al. (1989) found that the TR3 receptor shares about 20% amino acid homology with the estrogen receptor and less than 15% homology with other known receptors. The authors noted that the TR3 gene may be the human homolog of the mouse nur77 gene, with which it shares 91% amino acid identity. Expression of the TR3 cDNA in rabbit reticulocyte lysate produced a 64-kD DNA-binding protein.
When they screened a human fetal muscle cDNA library with the human thyroid hormone receptor alpha-2 cDNA at low stringency, Nakai et al. (1990) found a weakly hybridizing cDNA highly homologous to mouse nur77 and rat NGFIB, which are early response genes induced by nerve growth factor and other serum growth factors. They designated this gene NAK1 for the first author of the paper in which discovery of the protein was reported (DeGroot, 1991). The mRNA of NAK1 was induced rapidly and transiently by growth-stimulating agents, such as adenosine diphosphate, in monkey kidney cells, by phytohemagglutinin in human lymphocytes, and by serum stimulation of arrested fibroblasts. NAK1 was expressed in human fetal muscle and adult liver, brain, and thyroid. Nakai et al. (1990) stated that NAK1 could be a nuclear receptor.
Using multiple-tissue expression arrays, Chtarbova et al. (2002) found that NR4A1 was expressed ubiquitously, with slightly higher expression in myogenic and endocrine tissues.
T-cell receptor-induced apoptosis of thymocytes is mediated by calcium-dependent expression of the steroid receptors Nur77 and Nor1 (NR4A3; 600542). MEF2 (see 600661) had been implicated as a calcium-dependent transcription factor for Nur77 expression. Youn et al. (1999) demonstrated that Cabin1 (604251), a calcineurin (see 114105) inhibitor, regulated MEF2. The interplay between Cabin1, MEF2, and calmodulin (114180) defines a distinct signaling pathway from the TCR to the Nur77 promoter during T cell apoptosis.
Li et al. (2000) demonstrated that TR3 regulates apoptosis through a mechanism that is independent of transcriptional regulation. In response to apoptotic stimuli, TR3 is translocated from the nucleus to the cytoplasm, where it targets mitochondria to induce cytochrome c release and apoptosis. Their results showed that a nuclear transcription factor can function at mitochondria to mediate an important biologic function. The observations that TR3 lacking the DNA-binding domain localized exclusively in the cytoplasm, where it associated with mitochondria and potently induced apoptosis, suggested that target gene regulation by TR3 is not required for its apoptotic effect. TR3 mediates not only apoptosis but also cell proliferation in response to growth factors. The findings of Li et al. (2000) and previous observations that TR3 acts as a transcription factor by heterodimerizing with nuclear receptors, such as retinoid X receptor (RXR, 180245) (Perlmann and Jansson, 1995; Forman et al., 1995; Wu et al., 1997) also suggested that the opposing biologic activities of TR3 are regulated by its subcellular localization, i.e., the mitogenic effect of TR3 occurs in the nucleus through target gene regulation, whereas its proapoptotic effect occurs in the cytoplasm through regulation of mitochondrial activity. Abnormal increase of TR3 transactivation may have oncogenic potential because a TR3 fusion protein that is 270 times as active as the native receptor in the activating gene expression is produced through chromosomal translocation in extraskeletal myxoid chondrosarcoma (Labelle et al., 1999).
Youn and Liu (2000) reported that CABIN1 represses MEF2 by 2 distinct mechanisms. CABIN1 recruits mSIN3 and its associated histone deacetylases 1 (601241) and 2 (605164); CABIN1 also competes with p300 (602700) for binding to MEF2. Thus, Youn and Liu (2000) concluded that activation of MEF2 and the consequent transcription of NUR77 are controlled by the association of MEF2 with the histone deacetylases via the calcium-dependent repressor CABIN1.
Chtarbova et al. (2002) found that Nr4a1 was overexpressed in Wnt1 (164820)-transformed mouse mammary cells. Nr4a1 was also induced by lithium, a Wnt1 mimic, and the Nr4a1 promoter was activated by lithium and beta-catenin (see 116806), a Wnt1 downstream effector. In contrast, human NR4A1 was not upregulated by beta-catenin, indicating that this gene is regulated differently in human and mouse cells. In addition, the nuclear localization of mouse Nr4a1 was independent of Wnt1 transformation or tumor progression.
Caspases play a key role in apoptosis, but pan-caspase inhibitors do not always prevent cell death. Kim et al. (2003) showed that Nur77 expression was upregulated after exposure to lipopolysaccharide (LPS) and correlated with LPS-induced cell death in the presence of caspase inhibitor in a mouse macrophage cell line. Expression of a Nur77 mutant lacking the DNA-binding domain induced macrophage cell death, and cell death was decreased in macrophages from Nur77 -/- mice. Nur77 induction required activation of the ERK (see MAPK3; 601795) pathway and increased activity of MEF2 transcription factors. Kim et al. (2003) concluded that Nur77 has a role in caspase-independent cell death.
Lin et al. (2004) showed that BCL2 (151430) interacts with nuclear receptor NUR77, which is required for cancer cell apoptosis induced by many antineoplastic agents. The interaction was mediated by the N-terminal loop region of BCL2 and was required for NUR77 mitochondrial localization and apoptosis. NUR77 binding induced a BCL2 conformational change that exposed its BH3 domain, resulting in conversion of BCL2 from a protector to a killer. These findings coupled NUR77 with the BCL2 apoptotic machinery and demonstrated that BCL2 can manifest opposing phenotypes, induced by interactions with proteins such as NUR77.
Using Northern and Western blot analyses, Dequiedt et al. (2003) found that treatment of a mouse T-cell hybridoma line with an HDAC inhibitor led to increased expression of Nur77. Chromatin immunoprecipitation and immunofluorescence microscopy showed that Nur77 was regulated by acetylation and inhibited by human HDAC7 (606542). Western blot and coimmunoprecipitation analysis showed that the N terminus of HDAC7 interacted with the transcription factor MEF2D (600663), and HDAC7-MEF2D interaction was essential for repression of Nur77. Mutations of ser155, ser318, and ser448 to alanine in HDAC7 abolished Nur77 induction in response to T-cell receptor activation and diminished thymocyte apoptosis. Dequiedt et al. (2003) concluded that HDAC7 regulates NUR77 and apoptosis in developing thymocytes.
Using immunohistochemistry, Goto et al. (2006) analyzed sections of adrenal cortex from 121 human fetuses and demonstrated synthesis of cortisol much earlier than previously documented, associated with transient expression of NR4A1 and its regulatory target, HSD3B2 (613890). Cortisol synthesis was maximal at 8 to 9 weeks postconception under the regulation of ACTH; negative feedback was apparent at the anterior pituitary corticotrophs. ACTH also stimulated the adrenal gland to secrete androstenedione and testosterone. Goto et al. (2006) concluded that this represents a distinctive mechanism for normal human development in which cortisol production, determined by transient NR4A1 and HSD3B2 expression, provides feedback at the anterior pituitary to modulate androgen biosynthesis and safeguard normal female sexual differentiation.
In primary mouse hepatocytes, Pei et al. (2006) demonstrated that cAMP rapidly and potently induced expression of Nr4a1, Nr4a2 (601828), 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. Adenoviral expression of Nr4a1 induced genes involved in gluconeogenesis, stimulated glucose production both in vitro and in vivo, and raised blood glucose levels. Conversely, expression of an inhibitory mutant Nr4a3 receptor antagonized gluconeogenic gene expression and lowered blood glucose levels in db/db 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 to CD34+ cells from normal controls, suggesting that epigenetic silencing of these receptors may be an obligate event in human AML development.
Ryseck et al. (1989) determined that the N10 transcription unit is 8 kb long and split into 7 exons. The exon-intron distribution is similar to that of other members of the nuclear receptor superfamily.
Ryseck et al. (1989) mapped the N10 gene to mouse chromosome 15 and human chromosome 12q13 by in situ hybridization. These localizations are close to that of the gene encoding gamma retinoic acid receptor (180190).
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.
Chang, C., Kokontis, J., Liao, S. S., Chang, Y. Isolation and characterization of human TR3 receptor: a member of steroid receptor superfamily. J. Steroid Biochem. 34: 391-395, 1989. [PubMed: 2626032] [Full Text: https://doi.org/10.1016/0022-4731(89)90114-3]
Chtarbova, S., Nimmrich, I., Erdmann, S., Herter, P., Renner, M., Kitajewski, J., Muller, O. Murine Nr4a1 and Herpud1 are up-regulated by Wnt-1, but the homologous human genes are independent from beta-catenin activation. Biochem. J. 367: 723-728, 2002. [PubMed: 12153396] [Full Text: https://doi.org/10.1042/BJ20020699]
DeGroot, L. J. Personal Communication. Chicago, Ill. 12/19/1991.
Dequiedt, F., Kasler, H., Fischle, W., Kiermer, V., Weinstein, M., Herndier, B. G., Verdin, E. HDAC7, a thymus-specific class II histone deacetylase, regulates Nur77 transcription and TCR-mediated apoptosis. Immunity 18: 687-698, 2003. [PubMed: 12753745] [Full Text: https://doi.org/10.1016/s1074-7613(03)00109-2]
Forman, B. M., Umesono, K., Chen, J., Evans, R. M. Unique response pathways are established by allosteric interactions among nuclear hormone receptors. Cell 81: 541-550, 1995. [PubMed: 7758108] [Full Text: https://doi.org/10.1016/0092-8674(95)90075-6]
Goto, M., Hanley, K. P., Marcos, J., Wood, P. J., Wright, S., Postle, A. D., Cameron, I. T., Mason, J. I., Wilson, D. I., Hanley, N. A. In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development. J. Clin. Invest. 116: 953-960, 2006. [PubMed: 16585961] [Full Text: https://doi.org/10.1172/JCI25091]
Kim, S. O., Ono, K., Tobias, P. S., Han, J. Orphan nuclear receptor Nur77 is involved in caspase-independent macrophage cell death. J. Exp. Med. 197: 1441-1452, 2003. [PubMed: 12782711] [Full Text: https://doi.org/10.1084/jem.20021842]
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]
Li, H., Kolluri, S. K., Gu, J., Dawson, M. I., Cao, X., Hobbs, P. D, Lin, B., Chen, G., Lu, J., Lin, F., Xie, Z., Fontana, J. A., Reed, J. C., Zhang, X. Cytochrome c release and apoptosis induced by mitochondrial targeting of orphan receptor TR3 nuclear. Science 289: 1159-1164, 2000. [PubMed: 10947977] [Full Text: https://doi.org/10.1126/science.289.5482.1159]
Lin, B., Kolluri, S. K., Lin, F., Liu, W., Han, Y.-H., Cao, X., Dawson, M. I., Reed, J. C., Zhang, X. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 116: 527-540, 2004. [PubMed: 14980220] [Full Text: https://doi.org/10.1016/s0092-8674(04)00162-x]
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]
Nakai, A., Kartha, S., Sakurai, A., Toback, F. G., DeGroot, L. J. A human early response gene homologous to murine nur77 and rat NGFI-B, and related to the nuclear receptor superfamily. Molec. Endocr. 4: 1438-1443, 1990. [PubMed: 2283997] [Full Text: https://doi.org/10.1210/mend-4-10-1438]
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]
Perlmann, T., Jansson, L. A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes Dev. 9: 769-782, 1995. [PubMed: 7705655] [Full Text: https://doi.org/10.1101/gad.9.7.769]
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]
Ryseck, R.-P., Macdonald-Bravo, H., Mattei, M. G., Siegfried, R. L., Bravo, R. Structure, mapping and expression of a growth factor inducible gene encoding a putative nuclear hormonal binding receptor. EMBO J. 8: 3327-3335, 1989. [PubMed: 2555161] [Full Text: https://doi.org/10.1002/j.1460-2075.1989.tb08494.x]
Wu, Q., Dawson, M. I., Zheng, Y., Hobbs, P. D., Agadir, A., Jong, L., Li, Y., Liu, R., Lin, B., Zhang, X. K. Inhibition of trans-retinoic acid-resistant human breast cancer cell growth by retinoid X receptor-selective retinoids. Molec. Cell. Biol. 17: 6598-6608, 1997. [PubMed: 9343423] [Full Text: https://doi.org/10.1128/MCB.17.11.6598]
Youn, H.-D., Liu, J. O. Cabin1 represses MEF2-dependent Nur77 expression and T cell apoptosis by controlling association of histone deacetylases and acetylases with MEF2. Immunity 13: 85-94, 2000. [PubMed: 10933397] [Full Text: https://doi.org/10.1016/s1074-7613(00)00010-8]
Youn, H.-D., Sun, L., Prywes, R., Liu, J. O. Apoptosis of T cells mediated by Ca(2+)-induced release of the transcription factor MEF2. Science 286: 790-793, 1999. [PubMed: 10531067] [Full Text: https://doi.org/10.1126/science.286.5440.790]