The nuclear receptor subfamily 4 group A1 in human disease
Abstract
Nuclear receptor 4A1 (NR4A1), a member of the NR4A subfamily, acts as a gene regulator in a wide range of signaling pathways and responses to human diseases. Here, we provide a brief overview of the current functions of NR4A1 in human diseases and the factors involved in its function. A deeper understanding of these mechanisms can potentially improve drug development and disease therapy.
Get full access to this article
View all available purchase options and get full access to this article.
References
Alexopoulou A.N., Leao M., Caballero O.L., Da Silva L., Reid L., Lakhani S.R., et al. 2010. Dissecting the transcriptional networks underlying breast cancer: NR4A1 reduces the migration of normal and breast cancer cell lines. Breast Cancer Res. 12(4): R51.
Bai M., Liu Y., Zhou F., Zhang Y., Zhu Q., Zhang L., et al. 2018. Berberine inhibits glucose oxidation and insulin secretion in rat islets. Endocr. J. 65(4): 469–477.
Balasubramanian S., Jansen M., Valerius M.T., Humphreys B.D., Strom T.B. 2012. Orphan nuclear receptor Nur77 promotes acute kidney injury and renal epithelial apoptosis. J. Am. Soc. Nephrol. 23(4): 674–686.
Berriel Diaz M., Lemke U., Herzig S. 2006. Discovering orphans' sweet secret: NR4A receptors and hepatic glucose production. Cell Metab. 4(5): 339–340.
Cao J., Xu T., Zhou C., Wang S., Jiang B., Wu K., Ma L. 2021. NR4A1 knockdown confers hepatoprotection against ischaemia–reperfusion injury by suppressing TGFβ1 via inhibition of CYR61/NF-κB in mouse hepatocytes. J. Cell. Mol. Med. 25(11): 5099–5112.
Castro-Obregón S., Rao R.V., del Rio G., Chen S.F., Poksay K.S., Rabizadeh S., et al. 2004. Alternative, nonapoptotic programmed cell death: mediation by arrestin 2, ERK2, and Nur77. J. Biol. Chem. 279(17): 17543–17553.
Chao L.C., Wroblewski K., Zhang Z., Pei L., Vergnes L., Ilkayeva O.R., et al. 2009. Insulin resistance and altered systemic glucose metabolism in mice lacking Nur77. Diabetes, 58(12): 2788–2796.
Chen H.Z., Zhao B.X., Zhao W.X., Li L., Zhang B., Wu Q. 2008. Akt phosphorylates the TR3 orphan receptor and blocks its targeting to the mitochondria. Carcinogenesis, 29(11): 2078–2088.
Chen H.Z., Li L., Wang W.J., Du X.D., Wen Q., He J.P., et al. 2012. Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis. Oncogene, 31(23): 2876–2887.
Chen J., Jia J., Ma L., Li B., Qin Q., Qian J., Ge J. 2021. Nur77 deficiency exacerbates cardiac fibrosis after myocardial infarction by promoting endothelial-to-mesenchymal transition. J. Cell. Physiol. 236(1): 495–506.
Chen J., Huang X.R., Yang F., Yiu W.H., Yu X., Tang S.C.W., Lan H.Y. 2022. Single-cell RNA sequencing identified novel Nr4a1(+) Ear2(+) anti-inflammatory macrophage phenotype under myeloid-TLR4 dependent regulation in anti-glomerular basement membrane (GBM) crescentic glomerulonephritis (cGN). Adv. Sci. (Weinheim, Ger.), 9(18): e2200668.
Chen L., Fan F., Wu L., Zhao Y. 2020. The nuclear receptor 4A family members: mediators in human disease and autophagy. Cell. Mol. Biol. Lett. 25(1): 48.
Chen Y., Wang Y., Ertürk A., Kallop D., Jiang Z., Weimer R.M., et al. 2014. Activity-induced Nr4a1 regulates spine density and distribution pattern of excitatory synapses in pyramidal neurons. Neuron, 83(2): 431–443.
Cui L., Bao H., Zhu W., Tang Y., Luo Q., Si Y., et al. 2022. hUMSCs transplantation regulates AMPK/NR4A1 signaling axis to inhibit ovarian fibrosis in POI rats. Stem Cell Rev. Rep.
Cui P., Wu S., Xu X., Ye H., Hou J., Liu X., et al. 2019. Deficiency of the transcription factor NR4A1 enhances bacterial clearance and prevents lung injury during Escherichia coli pneumonia. Shock, 51(6): 787–794.
Dai Y., Sun Q., Zhang X., Hu Y., Zhou M., Shi J. 2014a. Cyclosporin A ameliorates early brain injury after subarachnoid hemorrhage through inhibition of a Nur77 dependent apoptosis pathway. Brain Res. 1556: 67–76.
Dai Y., Zhang W., Sun Q., Zhang X., Zhou X., Hu Y., Shi J. 2014b. Nuclear receptor nur77 promotes cerebral cell apoptosis and induces early brain injury after experimental subarachnoid hemorrhage in rats. J. Neurosci. Res. 92(9): 1110–1121.
Dai Y., Zhang W., Zhou X., Shi J. 2015. Activation of the protein kinase B (Akt) reduces Nur77-induced apoptosis during early brain injury after experimental subarachnoid hemorrhage in rat. Ann. Clin. Lab. Sci. 45(6): 615–622.
Deng J.W., Yang Q., Cai X.P., Zhou J.M., E W.G., An Y.D., et al. 2020. Early use of dexamethasone increases Nr4a1 in Kupffer cells ameliorating acute liver failure in mice in a glucocorticoid receptor-dependent manner. J. Zhejiang Univ. Sci. B, 21(9): 727–739.
Deng S., Chen B., Huo J., Liu X. 2022. Therapeutic potential of NR4A1 in cancer: focus on metabolism. Front. Oncol. 12: 972984.
Dodat F., Cotnoir-White D., Dianati E., Vallet A., Mader S., Lévesque D. 2021. Complex regulation of orphan nuclear receptor Nur77 (Nr4a1) transcriptional activity by SUMO2 and PIASγ. Biochim. Biophys. Acta Mol. Cell Res. 1868(2): 118908.
Dong W., Yang H., Cheng M., Zhang X., Yin J., Zeng Z., Huang G. 2020. Dexmedetomidine alleviates pulmonary ischemia–reperfusion injury through modulating the miR-21-5p/Nr4a1 signaling pathway. Acta Biochim. Pol. 67(4): 521–529.
Drouin J., Maira M., Philips A. 1998. Novel mechanism of action for Nur77 and antagonism by glucocorticoids: a convergent mechanism for CRH activation and glucocorticoid repression of POMC gene transcription. J. Steroid Biochem. Mol. Biol. 65(1–6): 59–63.
Hamers A.A., Argmann C., Moerland P.D., Koenis D.S., Marinković G., Sokolović M., et al. 2016. Nur77-deficiency in bone marrow-derived macrophages modulates inflammatory responses, extracellular matrix homeostasis, phagocytosis and tolerance. BMC Genomics, 17: 162.
Han Y.H., Cao X., Lin B., Lin F., Kolluri S.K., Stebbins J., et al. 2006. Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt. Oncogene, 25(21): 2974–2986.
Hanna R.N., Carlin L.M., Hubbeling H.G., Nackiewicz D., Green A.M., Punt J.A., et al. 2011. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C-monocytes. Nat. Immunol. 12(8): 778–785.
Hanna R.N., Shaked I., Hubbeling H.G., Punt J.A., Wu R., Herrley E., et al. 2012. NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis. Circ. Res. 110(3): 416–427.
Harant H., Lindley I.J. 2004. Negative cross-talk between the human orphan nuclear receptor Nur77/NAK-1/TR3 and nuclear factor-kappaB. Nucleic Acids Res. 32(17): 5280–5290.
He Z., Zhang M., Xu H., Zhou W., Xu C., Wang Z., et al. 2022. Yiqi Huoxue Tongluo recipe regulates NR4A1 to improve renal mitochondrial function in unilateral ureteral obstruction (UUO) rats. Pharm. Biol. 60(1): 2308–2318.
Hedrick E., Li X., Cheng Y., Lacey A., Mohankumar K., Zarei M., Safe S. 2019. Potent inhibition of breast cancer by bis-indole-derived nuclear receptor 4A1 (NR4A1) antagonists. Breast Cancer Res. Treat. 177(1): 29–40.
Herring J.A., Elison W.S., Tessem J.S. 2019. Function of Nr4a orphan nuclear receptors in proliferation, apoptosis and fuel utilization across tissues. Cells, 8(11): 1373.
Hirata Y., Kiuchi K., Chen H.C., Milbrandt J., Guroff G. 1993. The phosphorylation and DNA binding of the DNA-binding domain of the orphan nuclear receptor NGFI-B. J. Biol. Chem. 268(33): 24808–24812.
Hiwatashi N., Mukudai S., Bing R., Branski R.C. 2018. The effects of cytosporone-B, a novel antifibrotic agent, on vocal fold fibroblasts. Laryngoscope, 128(12): e425–e428.
Hong C.Y., Park J.H., Ahn R.S., Im S.Y., Choi H.S., Soh J., et al. 2004. Molecular mechanism of suppression of testicular steroidogenesis by proinflammatory cytokine tumor necrosis factor alpha. Mol. Cell. Biol. 24(7): 2593–2604.
Huang B., Pei H.Z., Chang H.W., Baek S.H. 2018. The E3 ubiquitin ligase Trim13 regulates Nur77 stability via casein kinase 2α. Sci. Rep. 8(1): 13895.
Huang Q., Xu J., Ge Y., Shi Y., Wang F., Zhu M. 2022. NR4A1 inhibits the epithelial-mesenchymal transition of hepatic stellate cells: involvement of TGF-β-Smad2/3/4-ZEB signaling. Open Life Sci. 17(1): 447–454.
Jacobs C.M., Boldingh K.A., Slagsvold H.H., Thoresen G.H., Paulsen R.E. 2004. ERK2 prohibits apoptosis-induced subcellular translocation of orphan nuclear receptor NGFI-B/TR3. J. Biol. Chem. 279(48): 50097–50101.
Jennings E., Elliot T.A.E., Thawait N., Kanabar S., Yam-Puc J.C., Ono M., et al. 2020. Nr4a1 and Nr4a3 reporter mice are differentially sensitive to T cell receptor signal strength and duration. Cell Rep. 33(5): 108328.
Ji J.J., Qian L.L., Zhu Y., Jiang Y., Guo J.Q., Wu Y., et al. 2022. Kallistatin/Serpina3c inhibits cardiac fibrosis after myocardial infarction by regulating glycolysis via Nr4a1 activation. Biochim. Biophys. Acta Mol. Basis Dis. 1868(9): 166441.
Jiang C., He J., Xu S., Wang Q., Cheng J. 2022. NR4A1 promotes LEF1 expression in the pathogenesis of papillary thyroid cancer. Cell Death Discov. 8(1): 46.
Jiang Y., Zeng Y., Huang X., Qin Y., Luo W., Xiang S., et al. 2016. Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model. Am. J. Physiol. Lung Cell Mol. Physiol. 311(6): L1023–l1035.
Jin Y., Liu Z., Li Z., Li H., Zhu C., Li R., et al. 2022. Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1. Int. J. Oral Sci. 14(1): 34.
Kang S.A., Na H., Kang H.J., Kim S.H., Lee M.H., Lee M.O. 2010. Regulation of Nur77 protein turnover through acetylation and deacetylation induced by p300 and HDAC1. Biochem. Pharmacol. 80(6): 867–873.
Karki K., Wright G.A., Mohankumar K., Jin U.H., Zhang X.H., Safe S. 2020. A bis-indole-derived NR4A1 antagonist induces PD-L1 degradation and enhances antitumor immunity. Cancer Res. 80(5): 1011–1023.
Karki K., Mohankumar K., Schoeller A., Martin G., Shrestha R., Safe S. 2021. NR4A1 ligands as potent inhibitors of breast cancer cell and tumor growth. Cancers (Basel), 13(11): 2682.
Katagiri Y., Takeda K., Yu Z.X., Ferrans V.J., Ozato K., Guroff G. 2000. Modulation of retinoid signalling through NGF-induced nuclear export of NGFI-B. Nat. Cell Biol. 2(7): 435–440.
Kim H., Kim B.Y., Soh J.W., Cho E.J., Liu J.O., Youn H.D. 2006. A novel function of Nur77: physical and functional association with protein kinase C. Biochem. Biophys. Res. Commun. 348(3): 950–956.
Kim Y.C., Song S.B., Lee S.K., Park S.M., Kim Y.S. 2014. The nuclear orphan receptor NR4A1 is involved in the apoptotic pathway induced by LPS and Simvastatin in RAW 264.7 macrophages. Immune Netw. 14(2): 116–122.
Koenis D.S., Medzikovic L., van Loenen P.B., van Weeghel M., Huveneers S., Vos M., et al. 2018. Nuclear receptor Nur77 limits the macrophage inflammatory response through transcriptional reprogramming of mitochondrial metabolism. Cell Rep. 24(8): 2127–2140.e2127.
Kolluri S.K., Bruey-Sedano N., Cao X., Lin B., Lin F., Han Y.H., et al. 2003. Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in lung cancer cells. Mol. Cell. Biol. 23(23): 8651–8667.
Lee H.S., Kim S.H., Kim B.M., Safe S., Lee S.O. 2021. Broussochalcone A is a novel inhibitor of the orphan nuclear receptor NR4A1 and induces apoptosis in pancreatic cancer cells. Molecules, 26(8): 2316.
Lee H.S., Kim D.H., Lee I.S., Park J.H., Martin G., Safe S., et al. 2022. Plant alkaloid tetrandrine is a nuclear receptor 4A1 antagonist and inhibits Panc-1 cell growth in vitro and in vivo. Int. J. Mol. Sci. 23(9): 5280.
Lee S.O., Li X., Khan S., Safe S. 2011. Targeting NR4A1 (TR3) in cancer cells and tumors. Expert Opin. Ther. Targets, 15(2): 195–206.
Li J., Zhou H., Fu X., Zhang M., Sun F., Fan H. 2021. Dynamic role of macrophage CX3CR1 expression in inflammatory bowel disease. Immunol. Lett. 232: 39–44.
Li Q., Li Y., Huang W., Wang X., Liu Z., Chen J., et al. 2022. Loss of Lipocalin 10 exacerbates diabetes-induced cardiomyopathy via disruption of Nr4a1-mediated anti-inflammatory response in macrophages. Front. Immunol. 13: 930397.
Li S., Dong S., Xu Q., Shi B., Li L., Zhang W., et al. 2022. Sleeve gastrectomy-induced AMPK activation attenuates diabetic cardiomyopathy by maintaining mitochondrial homeostasis via NR4A1 suppression in rats. Front. Physiol. 13: 837798.
Li W., Shi Y., Guo Y., Tian S. 2022. Nur77 promotes invasion and migration of gastric cancer cells through the NF-κB/IL-6 pathway. Nan Fang Yi Ke Da Xue Xue Bao, 42(9): 1410–1417.
Li X., Xu M., Wang F., Ji Y., Davidso N.W., Li Z., Tso P. 2015. Interaction of ApoA-IV with NR4A1 and NR1D1 represses G6Pase and PEPCK transcription: nuclear receptor-mediated downregulation of hepatic gluconeogenesis in mice and a human hepatocyte cell line. PloS ONE, 10(11): e0142098.
Li Y., Wang S.M., Li X., Lv C.J., Peng L.Y., Yu X.F., et al. 2022. Pterostilbene pre-treatment reduces LPS-induced acute lung injury through activating NR4A1. Pharm. Biol. 60(1): 394–403.
Liang H., Xie X., Song X., Huang M., Su T., Chang X., et al. 2019. Orphan nuclear receptor NR4A1 suppresses hyperhomocysteinemia-induced hepatic steatosis in vitro and in vivo. FEBS Lett. 593(10): 1061–1071.
Lin B., Kolluri S.K., Lin F., Liu W., Han Y.H., Cao X., et al. 2004. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell, 116(4): 527–540.
Liu B., Wu J.F., Zhan Y.Y., Chen H.Z., Zhang X.Y., Wu Q. 2007. Regulation of the orphan receptor TR3 nuclear functions by c-Jun N terminal kinase phosphorylation. Endocrinology, 148(1): 34–44.
Liu B., Liu N., Zhu X., Yang L., Ye B., Li H., et al. 2021. Circular RNA circZbtb20 maintains ILC3 homeostasis and function via Alkbh5-dependent m(6)A demethylation of Nr4a1 mRNA. Cell. Mol. Immunol. 18(6): 1412–1424.
Liu N., Wu Z., Chen A., Chai D., Li L., Zhang L., Zheng J. 2019. ISG12a and its interaction partner NR4A1 are involved in TRAIL-induced apoptosis in hepatoma cells. J. Cell. Mol. Med. 23(5): 3520–3529.
Liu X., Wang Y., Lu H., Li J., Yan X., Xiao M., et al. 2019. Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction. Nature, 567(7749): 525–529.
Liu Y., Liu N., Yu Y., Wang D. 2021. Nr4a1 promotes cell adhesion and fusion by regulating Zeb1 transcript levels in myoblasts. Biochem. Biophys. Res. Commun. 556: 127–133.
Luo Q., Tang Y., Jiang Z., Bao H., Fu Q., Zhang H. 2022. hUCMSCs reduce theca interstitial cells apoptosis and restore ovarian function in premature ovarian insufficiency rats through regulating NR4A1-mediated mitochondrial mechanisms. Reprod. Biol. Endocrinol. 20(1): 125.
Ma G., Chen F., Liu Y., Zheng L., Jiang X., Tian H., et al. 2022. Nur77 ameliorates age-related renal tubulointerstitial fibrosis by suppressing the TGF-β/Smads signaling pathway. FASEB J. 36(2): e22124.
Maira M., Martens C., Batsché E., Gauthier Y., Drouin J. 2003. Dimer-specific potentiation of NGFI-B (Nur77) transcriptional activity by the protein kinase A pathway and AF-1-dependent coactivator recruitment. Mol. Cell. Biol. 23(3): 763–776.
Malewicz M., Kadkhodaei B., Kee N., Volakakis N., Hellman U., Viktorsson K., et al. 2011. Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair. Genes Dev. 25(19): 2031–2040.
Masuyama N., Oishi K., Mori Y., Ueno T., Takahama Y., Gotoh Y. 2001. Akt inhibits the orphan nuclear receptor Nur77 and T-cell apoptosis. J. Biol. Chem. 276(35): 32799–32805.
McMorrow J.P., Murphy E.P. 2011. Inflammation: a role for NR4A orphan nuclear receptors? Biochem. Soc. Trans. 39(2): 688–693.
Miao L., Yang Y., Liu Y., Lai L., Wang L., Zhan Y., et al. 2019. Glycerol kinase interacts with nuclear receptor NR4A1 and regulates glucose metabolism in the liver. FASEB J. 33(6): 6736–6747.
Miao L., Su F., Yang Y., Liu Y., Wang L., Zhan Y., et al. 2020. Glycerol kinase enhances hepatic lipid metabolism by repressing nuclear receptor subfamily 4 group A1 in the nucleus. Biochem. Cell Biol. 98(3): 370–377.
Mohan H.M., Aherne C.M., Rogers A.C., Baird A.W., Winter D.C., Murphy E.P. 2012. Molecular pathways: the role of NR4A orphan nuclear receptors in cancer. Clin. Cancer Res. 18(12): 3223–3228.
Mohankumar K., Lee J., Wu C.S., Sun Y., Safe S. 2018. Bis-indole-derived NR4A1 ligands and metformin exhibit NR4A1-dependent glucose metabolism and uptake in C2C12 cells. Endocrinology, 159(5): 1950–1963.
Mohankumar K., Li X., Sridharan S., Karki K., Safe S. 2019. Nuclear receptor 4A1 (NR4A1) antagonists induce ROS-dependent inhibition of mTOR signaling in endometrial cancer. Gynecol. Oncol. 154(1): 218–227.
Mohankumar K., Li X., Sung N., Cho Y.J., Han S.J., Safe S. 2020. Bis-indole-derived nuclear receptor 4A1 (NR4A1, Nur77) ligands as inhibitors of endometriosis. Endocrinology, 161(4): bqaa027.
Nasiri-Ansari N., Dimitriadis G.K., Agrogiannis G., Perrea D., Kostakis I.D., Kaltsas G., et al. 2018. Canagliflozin attenuates the progression of atherosclerosis and inflammation process in APOE knockout mice. Cardiovasc. Diabetol. 17(1): 106.
Niu G., Lu L., Gan J., Zhang D., Liu J., Huang G. 2014. Dual roles of orphan nuclear receptor TR3/Nur77/NGFI-B in mediating cell survival and apoptosis. Int. Rev. Cell Mol. Biol. 313: 219–258.
Nowyhed H.N., Huynh T.R., Thomas G.D., Blatchley A., Hedrick C.C. 2015. Cutting edge: the orphan nuclear receptor Nr4a1 regulates CD8+ T cell expansion and effector function through direct repression of Irf4. J. Immunol. 195(8): 3515–3519.
Nus M., Basatemur G., Galan M., Cros-Brunsó L., Zhao T.X., Masters L., et al. 2020. NR4A1 deletion in marginal zone B cells exacerbates atherosclerosis in mice-brief report. Arterioscler. Thromb. Vasc. Biol. 40(11): 2598–2604.
Pawlak A., Strzadala L., Kalas W. 2015. Non-genomic effects of the NR4A1/Nur77/TR3/NGFIB orphan nuclear receptor. Steroids, 95: 1–6.
Pearen M.A., Muscat G.E. 2010. Minireview: nuclear hormone receptor 4A signaling: implications for metabolic disease. Mol. Endocrinol. 24(10): 1891–1903.
Pei L., Waki H., Vaitheesvaran B., Wilpitz D.C., Kurland I.J., Tontonoz P. 2006. NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism. Nat. Med. 12(9): 1048–1055.
Pekarsky Y., Hallas C., Palamarchuk A., Koval A., Bullrich F., Hirata Y., et al. 2001. Akt phosphorylates and regulates the orphan nuclear receptor Nur77. Proc. Natl. Acad. Sci. U. S. A. 98(7): 3690–3694.
Peng J., Zhao S., Li Y., Niu G., Chen C., Ye T., et al. 2019. DLL4 and Jagged1 are angiogenic targets of orphan nuclear receptor TR3/Nur77. Microvasc. Res. 124: 67–75.
Peng X., Wang W., Wang W., Qi J. 2022. NR4A1 promotes oxidative stresses after myocardial ischemia reperfusion injury in aged mice. Exp. Gerontol. 162: 111742.
Ping F., Zhang C., Wang X., Wang Y., Zhou D., Hu J., et al. 2021. Cx32 inhibits the autophagic effect of Nur77 in SH-SY5Y cells and rat brain with ischemic stroke. Aging (Albany NY), 13(18): 22188–22207.
Pu Z.Q., Liu D., Lobo Mouguegue H.P.P., Jin C.W., Sadiq E., Qin D.D., et al. 2020. NR4A1 counteracts JNK activation incurred by ER stress or ROS in pancreatic β-cells for protection. J. Cell. Mol. Med. 24(24): 14171–14183.
Pu Z.Q., Yu T.F., Liu D., Jin C.W., Sadiq E., Qiao X., et al. 2021. NR4A1 enhances MKP7 expression to diminish JNK activation induced by ROS or ER-stress in pancreatic β cells for surviving. Cell Death Discov. 7(1): 133.
Qin D.D., Yang Y.F., Pu Z.Q., Liu D., Yu C., Gao P., et al. 2018. NR4A1 retards adipocyte differentiation or maturation via enhancing GATA2 and p53 expression. J. Cell. Mol. Med. 22(10): 4709–4720.
Ramaswamy S., Ross K.N., Lander E.S., Golub T.R. 2003. A molecular signature of metastasis in primary solid tumors. Nat. Genet. 33(1): 49–54.
Reynolds M.S., Hancock C.R., Ray J.D., Kener K.B., Draney C., Garland K., et al. 2016. β-Cell deletion of Nr4a1 and Nr4a3 nuclear receptors impedes mitochondrial respiration and insulin secretion. Am. J. Physiol. Endocrinol. Metab. 311(1): E186–E201.
Safe S., Jin U.H., Morpurgo B., Abudayyeh A., Singh M., Tjalkens R.B. 2016. Nuclear receptor 4A (NR4A) family- orphans no more. J. Steroid Biochem. Mol. Biol. 157: 48–60.
Safe S., Shrestha R., Mohankumar K. 2021. Orphan nuclear receptor 4A1 (NR4A1) and novel ligands. Essays Biochem. 65(6): 877–886.
Sheng J., Li H., Dai Q., Lu C., Xu M., Zhang J., Feng J. 2018. NR4A1 promotes diabetic nephropathy by activating Mff-mediated mitochondrial fission and suppressing Parkin-mediated mitophagy. Cell Physiol. Biochem. 48(4): 1675–1693.
Shi W., Dong J., Liang Y., Liu K., Peng Y. 2019. NR4A1 silencing protects against renal ischemia–reperfusion injury through activation of the β-catenin signaling pathway in old mice. Exp. Mol. Pathol. 111: 104303.
Slagsvold H.H., Østvold A.C., Fallgren A.B., Paulsen R.E. 2002. Nuclear receptor and apoptosis initiator NGFI-B is a substrate for kinase ERK2. Biochem. Biophys. Res. Commun. 291(5): 1146–1150.
Smith C.J., Kener K.B., Tessem J.S. 2018. Nr4a1 and Nr4a3 knock out mice have impaired glucose clearance and beta-cell function under high-fat feeding. Diabetes, 67.
Stasik I., Rapak A., Kalas W., Ziolo E., Strzadala L. 2007. Ionomycin-induced apoptosis of thymocytes is independent of Nur77 NBRE or NurRE binding, but is accompanied by Nur77 mitochondrial targeting. Biochim. Biophys. Acta, 1773(9): 1483–1490.
Szczepanski H.E., Flannigan K.L., Mainoli B., Alston L., Baruta G.M., Lee J.W., et al. 2022. NR4A1 modulates intestinal smooth muscle cell phenotype and dampens inflammation-associated intestinal remodeling. FASEB J. 36(11): e22609.
Tacke R., Hilgendorf I., Garner H., Waterborg C., Park K., Nowyhed H., et al. 2015. The transcription factor NR4A1 is essential for the development of a novel macrophage subset in the thymus. Sci. Rep. 5: 10055.
Tang X., Zheng H., Xu H., Wang M., Kang X., Wu Z. 2022. NR4A1 affects endometrial receptivity by participating in mesenchymal–epithelial transition of endometrial stromal cells. Reprod. Sci. 29(1): 133–142.
Tessem J.S., Herring J., Smith C.J., Austin M.C., Wynn A.G. 2019. 2190-P: sex-based differences in Nr4a1 beta-cell activity. Diabetes, 68.
Tessem J.S., Herring J. 2022. 1446-P: sex-specific effects of Nr4a1 in the pancreatic beta cell. Diabetes, 71.
Thompson J., Burger M.L., Whang H., Winoto A. 2010. Protein kinase C regulates mitochondrial targeting of Nur77 and its family member Nor-1 in thymocytes undergoing apoptosis. Eur. J. Immunol. 40(7): 2041–2049.
Venu P.K.V., Alston L., Iftinca M., Tsai Y.C., Stephens M., Warriyar K.V.V., et al. 2021. Nr4A1 modulates inflammation-associated intestinal fibrosis and dampens fibrogenic signaling in myofibroblasts. Am. J. Physiol. Gastrointest. Liver Physiol. 321(3): G280–g297.
Wang L.M., Zhang Y., Li X., Zhang M.L., Zhu L., Zhang G.X., Xu Y.M. 2018. Nr4a1 plays a crucial modulatory role in Th1/Th17 cell responses and CNS autoimmunity. Brain Behav. Immun. 68: 44–55.
Wang S., Zuo A., Jiang W., Xie J., Lin H., Sun W., et al. 2021. JMJD1A/NR4A1 signaling regulates the procession of renal tubular epithelial interstitial fibrosis induced by AGEs in HK-2. Front. Med. (Lausanne), 8: 807694.
Wang S.C., Muscat G.E. 2013. Nuclear receptors and epigenetic signaling: novel regulators of glycogen metabolism in skeletal muscle. IUBMB Life, 65(8): 657–664.
Wang W., Wang J., Tang Q., Zhu X., Zhu R., Cui D., et al. 2021. CX3CR1 deficiency aggravates brain white matter injury and affects expression of the CD36 /15LO/NR4A1 signal. Biochem. Biophys. Res. Commun. 549: 47–53.
Wang X., Liu L., Zhang L., Guo J., Yu L., Li T. 2022. Circ_0057583 facilitates brain microvascular endothelial cell injury through modulating miR-204-5p/NR4A1 axis. Metab. Brain Dis. 37(2): 501–511.
Wenzl K., Troppan K., Neumeister P., Deutsch A.J. 2015. The nuclear orphan receptor NR4A1 and NR4A3 as tumor suppressors in hematologic neoplasms. Curr. Drug Targets, 16(1): 38–46.
Westbrook L., Johnson A.C., Regner K.R., Williams J.M., Mattson D.L., Kyle P.B., et al. 2014. Genetic susceptibility and loss of Nr4a1 enhances macrophage-mediated renal injury in CKD. J. Am. Soc. Nephrol. 25(11): 2499–2510.
Wette S.G., Lamb G.D., Murphy R.M. 2021. Nuclei isolation methods fail to accurately assess the subcellular localization and behaviour of proteins in skeletal muscle. Acta Physiol. (Oxf.), 233(3): e13730.
Wilson T.E., Fahrner T.J., Milbrandt J. 1993. The orphan receptors NGFI-B and steroidogenic factor 1 establish monomer binding as a third paradigm of nuclear receptor–DNA interaction. Mol. Cell. Biol. 13(9): 5794–5804.
Wingate A.D., Campbell D.G., Peggie M., Arthur J.S. 2006. Nur77 is phosphorylated in cells by RSK in response to mitogenic stimulation. Biochem. J. 393(Pt 3): 715–724.
Woronicz J.D., Lina A., Calnan B.J., Szychowski S., Cheng L., Winoto A. 1995. Regulation of the Nur77 orphan steroid receptor in activation-induced apoptosis. Mol. Cell. Biol. 15(11): 6364–6376.
Wu H., Lin Y., Li W., Sun Z., Gao W., Zhang H., et al. 2011. Regulation of Nur77 expression by β-catenin and its mitogenic effect in colon cancer cells. FASEB J. 25(1): 192–205.
Wu H., Bi J., Peng Y., Huo L., Yu X., Yang Z., et al. 2017. Nuclear receptor NR4A1 is a tumor suppressor down-regulated in triple-negative breast cancer. Oncotarget, 8(33): 54364–54377.
Wu L., Chen L. 2018. Characteristics of Nur77 and its ligands as potential anticancer compounds (Review). Mol. Med. Rep. 18(6): 4793–4801.
Wu X., Fu S., Liu Y., Luo H., Li F., Wang Y., et al. 2019. NDP-MSH binding melanocortin-1 receptor ameliorates neuroinflammation and BBB disruption through CREB/Nr4a1/NF-κB pathway after intracerebral hemorrhage in mice. J. Neuroinflammation, 16(1): 192.
Xiong J., Kuang X., Lu T., Liu X., Cheng B., Wang W., et al. 2019. Fenretinide-induced apoptosis of acute myeloid leukemia cells via NR4A1 translocation into mitochondria and Bcl-2 transformation. J. Cancer, 10(27): 6767–6778.
Xiong Y., Ran J., Xu L., Tong Z., Abdo A., M. S., Ma C., et al. 2020. Reactivation of NR4A1 restrains chondrocyte inflammation and ameliorates osteoarthritis in rats. Front. Cell Dev. Biol. 8: 158.
Xu Y., Tian J., Kang Q., Yuan H., Liu C., Li Z., et al. 2022. Knockout of Nur77 leads to amino acid, lipid, and glucose metabolism disorders in zebrafish Front. Endocrinol. (Lausanne), 13: 864631.
Yan H., Xiao F., Zou J., Qiu C., Sun W., Gu M., Zhang L. 2018. NR4A1-induced increase in the sensitivity of a human gastric cancer line to TNFα-mediated apoptosis is associated with the inhibition of JNK/Parkin-dependent mitophagy. Int. J. Oncol. 52(2): 367–378.
Yang H.X., Sun J.H., Yao T.T., Li Y., Xu G.R., Zhang C., et al. 2021. Bellidifolin ameliorates isoprenaline-induced myocardial fibrosis by regulating TGF-β1/Smads and p38 signaling and preventing NR4A1 cytoplasmic localization. Front. Pharmacol. 12: 644886.
Yao L.M., He J.P., Chen H.Z., Wang Y., Wang W.J., Wu R., et al. 2012. Orphan receptor TR3 participates in cisplatin-induced apoptosis via Chk2 phosphorylation to repress intestinal tumorigenesis. Carcinogenesis, 33(2): 301–311.
Yousefi H., Fong J., Alahari S.K. 2022. NR4A family genes: a review of comprehensive prognostic and gene expression profile analysis in breast cancer. Front. Oncol. 12: 777824.
Yu H.Z., Zhu B.Q., Zhu L., Li S., Wang L.M. 2022. NR4A1 agonist cytosporone B attenuates neuroinflammation in a mouse model of multiple sclerosis. Neural Regen. Res. 17(12): 2765–2770.
Zárraga-Granados G., Muciño-Hernández G., Sánchez-Carbente M.R., Villamizar-Gálvez W., Peñas-Rincón A., Arredondo C., et al. 2020. The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death. PloS ONE, 15(3): e0222072.
Zeng X., Yue Z., Gao Y., Jiang G., Zeng F., Shao Y., et al. 2018. NR4A1 is involved in fibrogenesis in ovarian endometriosis. Cell. Physiol. Biochem. 46(3): 1078–1090.
Zhan Y., Du X., Chen H., Liu J., Zhao B., Huang D., et al. 2008. Cytosporone B is an agonist for nuclear orphan receptor Nur77. Nat. Chem. Biol. 4(9): 548–556.
Zhang L., Xie F., Zhang J., Dijke P.T., Zhou F. 2017. SUMO-triggered ubiquitination of NR4A1 controls macrophage cell death. Cell Death Differ. 24(9): 1530–1539.
Zhang L., Wang Q., Liu W., Liu F., Ji A., Li Y. 2018. The orphan nuclear receptor 4A1: a potential new therapeutic target for metabolic diseases. J. Diabetes Res. 2018: 9363461.
Zhang Y., Chen G., Gao B., Li Y., Liang S., Wang X., et al. 2016. NR4A1 Knockdown Suppresses Seizure Activity by Regulating Surface Expression of NR2B. Sci. Rep. 6: 37713.
Zhang Y.J., Song J.R., Zhao M.J. 2019. NR4A1 regulates cerebral ischemia-induced brain injury by regulating neuroinflammation through interaction with NF-κB/p65. Biochem. Biophys. Res. Commun. 518(1): 59–65.
Zhang Z., Yu J. 2018. NR4A1 promotes cerebral ischemia reperfusion injury by repressing Mfn2-mediated mitophagy and inactivating the MAPK–ERK–CREB signaling pathway. Neurochem. Res. 43(10): 1963–1977.
Zhao B.X., Chen H.Z., Du X.D., Luo J., He J.P., Wang R.H., et al. 2011. Orphan receptor TR3 enhances p53 transactivation and represses DNA double-strand break repair in hepatoma cells under ionizing radiation. Mol. Endocrinol. 25(8): 1337–1350.
Zheng Y., Tao Y., Zhan X., Wu Q. 2022. Nuclear receptor 4A1 (NR4A1) silencing protects hepatocyte against hypoxia-reperfusion injury in vitro by activating liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling. Bioengineered, 13(4): 8349–8359.
Zhong D., Wan Z., Cai J., Quan L., Zhang R., Teng T., et al. 2022. mPGES-2 blockade antagonizes β-cell senescence to ameliorate diabetes by acting on NR4A1. Nat. Metab. 4(2): 269–283.
Zhou F., Bai M., Zhang Y., Zhu Q., Zhang L., Zhang Q., et al. 2018. Berberine-induced activation of AMPK increases hepatic FGF21 expression via NUR77. Biochem. Biophys. Res. Commun. 495(2): 1936–1941.
Zhou H., Wang J., Zhu P., Zhu H., Toan S., Hu S., et al. 2018. NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α. Basic Res. Cardiol. 113(4): 23.
Zhou H., Zhu P., Wang J., Toan S., Ren J. 2019. DNA-PKcs promotes alcohol-related liver disease by activating Drp1-related mitochondrial fission and repressing FUNDC1-required mitophagy. Signal Transduct. Target Ther. 4: 56.
Zhu B., Yang J.R., Jia Y., Zhang P., Shen L., Li X.L., et al. 2017. Overexpression of NR4A1 is associated with tumor recurrence and poor survival in non-small-cell lung carcinoma. Oncotarget, 8(69): 113977–113986.
Zhu P., Wang J., Du W., Ren J., Zhang Y., Xie F., Xu G. 2022. NR4A1 promotes LPS-induced acute lung injury through inhibition of Opa1-mediated mitochondrial fusion and activation of PGAM5-related necroptosis. Oxid. Med. Cell. Longev. 2022: 6638244.
Zong C., Qin D., Yu C., Gao P., Chen J., Lu S., et al. 2017. The stress-response molecule NR4A1 resists ROS-induced pancreatic β-cells apoptosis via WT1. Cell Signal. 35: 129–139.
Information & Authors
Information
Published In
Biochemistry and Cell Biology
Volume 101 • Number 2 • April 2023
Pages: 148 - 159
History
Received: 1 November 2022
Accepted: 9 January 2023
Accepted manuscript online: 2 March 2023
Version of record online: 2 March 2023
Copyright
© 2023 The Author(s). Permission for reuse (free in most cases) can be obtained from copyright.com.
Data Availability Statement
The datasets generated or analyzed during this study are available from the corresponding author on reasonable request.
Key Words
Authors
Author Contributions
Conceptualization: HW, YZ, XW
Data curation: MZ
Formal analysis: HW
Funding acquisition: XW
Resources: HW, MZ, FF, CX, JL, LG, CZ
Supervision: YZ, XW
Visualization: HW
Writing – original draft: HW, MZ
Writing – review & editing: ZW
Competing Interests
The authors declare that they have no conflict of interest.
Funding Information
This study was funded by Key Program of Hebei Natural Science Foundation of Traditional Chinese Medicine, H2022423351, and Science and Technology Planning Project of Hebei Provincial Science and Technology Department, 20277714D.
Metrics & Citations
Metrics
Other Metrics
Citations
Cite As
Hongshuang Wang, Mengjuan Zhang, Fang Fang, Chang Xu, Jiazhi Liu, Lanjun Gao, Chenchen Zhao, Zheng Wang, Yan Zhong, and Xiangting Wang. 2023. The nuclear receptor subfamily 4 group A1 in human disease. Biochemistry and Cell Biology.
101(2): 148-159. https://doi.org/10.1139/bcb-2022-0331
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
Cited by
1. Nuclear receptor 4A1 ameliorates UUO-induced renal fibrosis by inhibiting the PI3K/AKT pathway
2. Roles of distinct nuclear receptors in diabetic cardiomyopathy
3. RNA
‐sequencing reveals differential fibroblast responses to bleomycin and pneumonectomy
4. Zhi Zi Chi decoction (Gardeniae fructus and semen Sojae Praeparatum) attenuates anxious depression via modulating microbiota–gut–brain axis in
corticosterone combined with chronic restraint stress
‐induced mice
5. Developing novel therapy for drug-induced gingival overgrowth by targeting NR4A1
View Options
Login options
Check if you access through your login credentials or your institution to get full access on this article.