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Gene Review

NR4A1  -  nuclear receptor subfamily 4, group A,...

Homo sapiens

Synonyms: Early response protein NAK1, GFRP1, HMR, N10, NAK-1, ...
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Disease relevance of NR4A1


Psychiatry related information on NR4A1

  • RESULTS: We report here that Nur77-deficient mice display enhanced spontaneous locomotor activity, greater sensitivity to a small dose of the dopamine D(2) receptor agonist quinpirole acting mainly at autoreceptor sites, and higher levels of the dopamine metabolite DOPAC relative to wild-type mice [6].

High impact information on NR4A1

  • The interaction is mediated by the N-terminal loop region of Bcl-2 and is required for Nur77 mitochondrial localization and apoptosis [7].
  • These findings establish the coupling of Nur77 nuclear receptor with the Bcl-2 apoptotic machinery and demonstrate that Bcl-2 can manifest opposing phenotypes, induced by interactions with proteins such as Nur77, suggesting novel strategies for regulating apoptosis in cancer and other diseases [7].
  • Nur77 binding induces a Bcl-2 conformational change that exposes its BH3 domain, resulting in conversion of Bcl-2 from a protector to a killer [7].
  • We review here recent studies on the glucocorticoid receptor and the orphan receptors Nur77 and RORgamma [8].
  • A Nur77 dominant negative protected T-cell hybridomas from activation-induced apoptosis [9].

Chemical compound and disease context of NR4A1


Biological context of NR4A1

  • These phenotypes were also observed in several other experimental cancer cells, suggesting the observed apoptosis suppression is a more general property of NR4A2 and NR4A1 [15].
  • Furthermore, down-regulation of NR4A2 as well as NR4A1 promoted intrinsic apoptosis [15].
  • In vitro functional studies using over-expression (gain of function) or gene inactivation (loss of function) type assays, combined with transgenic or knockout animal data in vivo, have revealed these effects and their physiological roles, including thymocyte development for NR4A1/3 and pro-survival in CNS for NR4A2 [16].
  • These phenotypes also suggest that the Nur77/NGFIB subfamily of orphan receptors exhibit certain oncogenic functionalities with regards to cell proliferation and apoptosis and could therefore be evaluated as potential cancer therapeutic targets [15].
  • Mutation of these elements inhibited LPS-dependent expression of the Nur77 promoter in transient transfection assays [17].

Anatomical context of NR4A1

  • We recently demonstrated that NGFI-B (nur77 or NR4A1) plays an important role in the regulation of HSD3B2 transcription and may play an important role in the functional zonation of the adrenal gland [18].
  • Consistent with its ability to be induced by oxidized lipids, Nur77 was expressed in macrophages within human atherosclerotic lesions [17].
  • Subsequently it was demonstrated by another group that beta-AR agonists and cold exposure-induced Nur77 expression in brown adipocytes and brown adipose tissue, respectively [1].
  • The exon-intron structure of the gene is generally conserved when compared with the steroid/thyroid receptor superfamily and is remarkably similar to that of the Nur77/NGFI-B genes [19].
  • The immediate early gene NUR77 (also called NGFI-B) is required for T cell antigen receptor-mediated cell death and is induced to very high levels in immature thymocytes and T cell hybridomas undergoing apoptosis [20].

Associations of NR4A1 with chemical compounds


Physical interactions of NR4A1


Regulatory relationships of NR4A1

  • We found that PML represses Nur77-mediated transactivation through a physical and functional interaction between the two proteins [25].
  • In this study, we provide the first molecular evidence that Nur77 activated by HIF under hypoxic conditions regulates production of the peptide hormone precursor POMC [2].
  • Mutation or deletion of the HIF binding site in the Nur77 promoter abrogates activation of a luciferase reporter gene under the control of Nur77 promoter by HIF-1alpha [2].
  • These results suggest that NGFIB plays a crucial role in adrenal zonation by regulating HSD3B2 gene transcription [23].
  • TR3 orphan nuclear receptor mediates apoptosis through up-regulating E2F1 in human prostate cancer LNCaP cells [3].

Other interactions of NR4A1

  • Nur77 drives transcription of PAI-1 through direct binding to an NGFI-B responsive element (NBRE), indicating monomeric binding and a ligand-independent mechanism [30].
  • PML/Nur77 colocalized in vivo in a double immunofluorescent staining and confocal microscopic analysis [25].
  • Moreover, NOR-1 (NR4A3) was hyperinduced by cold exposure in the nur77(-/-) animal model [1].
  • The treatment of Nur77 antisense oligonucleotide reduces POMC transcription under hypoxic conditions [2].
  • We show that HIF-1alpha, but not HIF-2alpha, binds to a putative HIF responsive element in the Nur77 promoter, activating the expression of Nur77 [2].

Analytical, diagnostic and therapeutic context of NR4A1


  1. The Orphan Nuclear Receptor, NOR-1, Is a Target of {beta}-Adrenergic Signaling in Skeletal Muscle. Pearen, M.A., Ryall, J.G., Maxwell, M.A., Ohkura, N., Lynch, G.S., Muscat, G.E. Endocrinology (2006) [Pubmed]
  2. Nur77 activated by hypoxia-inducible factor-1alpha overproduces proopiomelanocortin in von Hippel-Lindau-mutated renal cell carcinoma. Choi, J.W., Park, S.C., Kang, G.H., Liu, J.O., Youn, H.D. Cancer Res. (2004) [Pubmed]
  3. TR3 orphan nuclear receptor mediates apoptosis through up-regulating E2F1 in human prostate cancer LNCaP cells. Mu, X., Chang, C. J. Biol. Chem. (2003) [Pubmed]
  4. TR3/Nur77 in colon cancer cell apoptosis. Wilson, A.J., Arango, D., Mariadason, J.M., Heerdt, B.G., Augenlicht, L.H. Cancer Res. (2003) [Pubmed]
  5. Activation of Nur77 by selected 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes induces apoptosis through nuclear pathways. Chintharlapalli, S., Burghardt, R., Papineni, S., Ramaiah, S., Yoon, K., Safe, S. J. Biol. Chem. (2005) [Pubmed]
  6. Nur77 gene knockout alters dopamine neuron biochemical activity and dopamine turnover. Gilbert, F., Morissette, M., St-Hilaire, M., Paquet, B., Rouillard, C., Di Paolo, T., Lévesque, D. Biol. Psychiatry (2006) [Pubmed]
  7. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Lin, B., Kolluri, S.K., Lin, F., Liu, W., Han, Y.H., Cao, X., Dawson, M.I., Reed, J.C., Zhang, X.K. Cell (2004) [Pubmed]
  8. Nuclear hormone receptors in T lymphocytes. Winoto, A., Littman, D.R. Cell (2002) [Pubmed]
  9. Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Woronicz, J.D., Calnan, B., Ngo, V., Winoto, A. Nature (1994) [Pubmed]
  10. Orphan nuclear receptor Nur77 translocates to mitochondria in the early phase of apoptosis induced by synthetic chenodeoxycholic acid derivatives in human stomach cancer cell line SNU-1. Jeong, J.H., Park, J.S., Moon, B., Kim, M.C., Kim, J.K., Lee, S., Suh, H., Kim, N.D., Kim, J.M., Park, Y.C., Yoo, Y.H. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
  11. Modulation of retinoic acid sensitivity in lung cancer cells through dynamic balance of orphan receptors nur77 and COUP-TF and their heterodimerization. Wu, Q., Li, Y., Liu, R., Agadir, A., Lee, M.O., Liu, Y., Zhang, X. EMBO J. (1997) [Pubmed]
  12. Phase II study of 10-ethyl-10-deaza-aminopterin in patients with stage III and IV non-small-cell lung cancer. Shum, K.Y., Kris, M.G., Gralla, R.J., Burke, M.T., Marks, L.D., Heelan, R.T. J. Clin. Oncol. (1988) [Pubmed]
  13. Ketolide treatment of Haemophilus influenzae experimental pneumonia. Piper, K.E., Rouse, M.S., Steckelberg, J.M., Wilson, W.R., Patel, R. Antimicrob. Agents Chemother. (1999) [Pubmed]
  14. Antisense TR3 orphan receptor can increase prostate cancer cell viability with etoposide treatment. Uemura, H., Chang, C. Endocrinology (1998) [Pubmed]
  15. Nuclear hormone receptor NR4A2 is involved in cell transformation and apoptosis. Ke, N., Claassen, G., Yu, D.H., Albers, A., Fan, W., Tan, P., Grifman, M., Hu, X., Defife, K., Nguy, V., Meyhack, B., Brachat, A., Wong-Staal, F., Li, Q.X. Cancer Res. (2004) [Pubmed]
  16. NR4A1, 2, 3--an orphan nuclear hormone receptor family involved in cell apoptosis and carcinogenesis. Li, Q.X., Ke, N., Sundaram, R., Wong-Staal, F. Histol. Histopathol. (2006) [Pubmed]
  17. Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli. Pei, L., Castrillo, A., Chen, M., Hoffmann, A., Tontonoz, P. J. Biol. Chem. (2005) [Pubmed]
  18. A role for the NGFI-B family in adrenal zonation and adrenocortical disease. Bassett, M.H., White, P.C., Rainey, W.E. Endocr. Res. (2004) [Pubmed]
  19. Structure, mapping and expression of a human NOR-1 gene, the third member of the Nur77/NGFI-B family. Ohkura, N., Ito, M., Tsukada, T., Sasaki, K., Yamaguchi, K., Miki, K. Biochim. Biophys. Acta (1996) [Pubmed]
  20. Akt phosphorylates and regulates the orphan nuclear receptor Nur77. Pekarsky, Y., Hallas, C., Palamarchuk, A., Koval, A., Bullrich, F., Hirata, Y., Bichi, R., Letofsky, J., Croce, C.M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  21. NOT, a human immediate-early response gene closely related to the steroid/thyroid hormone receptor NAK1/TR3. Mages, H.W., Rilke, O., Bravo, R., Senger, G., Kroczek, R.A. Mol. Endocrinol. (1994) [Pubmed]
  22. Silencing mediator of retinoid and thyroid hormone receptors and activating signal cointegrator-2 as transcriptional coregulators of the orphan nuclear receptor Nur77. Sohn, Y.C., Kwak, E., Na, Y., Lee, J.W., Lee, S.K. J. Biol. Chem. (2001) [Pubmed]
  23. The orphan nuclear receptor NGFIB regulates transcription of 3beta-hydroxysteroid dehydrogenase. implications for the control of adrenal functional zonation. Bassett, M.H., Suzuki, T., Sasano, H., De Vries, C.J., Jimenez, P.T., Carr, B.R., Rainey, W.E. J. Biol. Chem. (2004) [Pubmed]
  24. Vascular endothelial growth factor-regulated gene expression in endothelial cells: KDR-mediated induction of Egr3 and the related nuclear receptors Nur77, Nurr1, and Nor1. Liu, D., Jia, H., Holmes, D.I., Stannard, A., Zachary, I. Arterioscler. Thromb. Vasc. Biol. (2003) [Pubmed]
  25. Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions. Wu, W.S., Xu, Z.X., Ran, R., Meng, F., Chang, K.S. Oncogene (2002) [Pubmed]
  26. Regulation of the Orphan Receptor TR3 Nuclear Functions by c-Jun N Terminal Kinase Phosphorylation. Liu, B., Wu, J.F., Zhan, Y.Y., Chen, H.Z., Zhang, X.Y., Wu, Q. Endocrinology (2007) [Pubmed]
  27. cDNA cloning of a NGFI-B/nur77-related transcription factor from an apoptotic human T cell line. Okabe, T., Takayanagi, R., Imasaki, K., Haji, M., Nawata, H., Watanabe, T. J. Immunol. (1995) [Pubmed]
  28. Heterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activation. Maira, M., Martens, C., Philips, A., Drouin, J. Mol. Cell. Biol. (1999) [Pubmed]
  29. Orphan nuclear receptor Nur77 induces zinc finger protein GIOT-1 gene expression, and GIOT-1 acts as a novel corepressor of orphan nuclear receptor SF-1 via recruitment of HDAC2. Song, K.H., Park, Y.Y., Kee, H.J., Hong, C.Y., Lee, Y.S., Ahn, S.W., Kim, H.J., Lee, K., Kook, H., Lee, I.K., Choi, H.S. J. Biol. Chem. (2006) [Pubmed]
  30. Direct binding of Nur77/NAK-1 to the plasminogen activator inhibitor 1 (PAI-1) promoter regulates TNF alpha -induced PAI-1 expression. Gruber, F., Hufnagl, P., Hofer-Warbinek, R., Schmid, J.A., Breuss, J.M., Huber-Beckmann, R., Lucerna, M., Papac, N., Harant, H., Lindley, I., de Martin, R., Binder, B.R. Blood (2003) [Pubmed]
  31. Nuclear Receptors Nur77, Nurr1, and NOR-1 Expressed in Atherosclerotic Lesion Macrophages Reduce Lipid Loading and Inflammatory Responses. Bonta, P.I., van Tiel, C.M., Vos, M., Pols, T.W., van Thienen, J.V., Ferreira, V., Arkenbout, E.K., Seppen, J., Spek, C.A., van der Poll, T., Pannekoek, H., de Vries, C.J. Arterioscler. Thromb. Vasc. Biol. (2006) [Pubmed]
  32. Identification of Nerve Growth Factor-responsive Element of the TCL1 Promoter as a Novel Negative Regulatory Element. Hiromura, M., Suizu, F., Narita, M., Kinowaki, K., Noguchi, M. J. Biol. Chem. (2006) [Pubmed]
  33. Upregulation of orphan nuclear receptor Nur77 following PGF(2alpha), Bimatoprost, and Butaprost treatments. Essential role of a protein kinase C pathway involved in EP(2) receptor activated Nur77 gene transcription. Liang, Y., Li, C., Guzman, V.M., Chang, W.W., Evinger, A.J., Pablo, J.V., Woodward, D.F. Br. J. Pharmacol. (2004) [Pubmed]
  34. Protective function of transcription factor TR3 orphan receptor in atherogenesis: decreased lesion formation in carotid artery ligation model in TR3 transgenic mice. Arkenbout, E.K., de Waard, V., van Bragt, M., van Achterberg, T.A., Grimbergen, J.M., Pichon, B., Pannekoek, H., de Vries, C.J. Circulation (2002) [Pubmed]
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