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Gene Review

Nr4a1  -  nuclear receptor subfamily 4, group A,...

Mus musculus

Synonyms: GFRP1, Gfrp, Hbr-1, Hbr1, Hmr, ...
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Disease relevance of Nr4a1

  • Interestingly, catalepsy induced by raclopride, a specific dopamine D(2)/D(3) antagonist is completely abolished in NGFI-B-deficient mice whereas the cataleptic response to SCH 23390, a dopamine D(1) agonist, is preserved [1].
  • Differential expression of TIS21 and TIS1 genes in the various organs of Balb/c mice, thymic carcinoma tissues and human cancer cell lines [2].
  • In the present experiments, we demonstrated that hypercholesterolemia enhanced daily expression of the Pai-1, Tnf-alpha, and Nr4a1 genes in the mouse liver without affecting clock and clock-controlled genes [3].
  • Nur77 agonists induce proapoptotic genes and responses in colon cancer cells through nuclear receptor-dependent and nuclear receptor-independent pathways [4].
  • In Panc-28 pancreatic cancer cells, Nur77 agonists activate the nuclear receptor, and downstream responses include decreased cell survival and induction of cell death pathways, including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and poly(ADP-ribose) polymerase (PARP) cleavage [5].

Psychiatry related information on Nr4a1


High impact information on Nr4a1


Chemical compound and disease context of Nr4a1


Biological context of Nr4a1


Anatomical context of Nr4a1


Associations of Nr4a1 with chemical compounds

  • In response to increases in adrenocorticotropin, NGFI-B (-/-) and wild-type mice demonstrated equivalent increases in serum corticosterone levels [17].
  • Finally, when the administration of dexamethasone for suppression was stopped, P450c21 mRNA and serum corticosterone levels recovered at the same rate in wild-type and NGFI-B (-/-) mice [17].
  • Furthermore, the AF-1 domain physically associates with the Nur77 C-terminal LBD and synergizes with the retinoid X receptor LBD [19].
  • Consistent with this, homology modeling indicated that the Nur77 LBD coactivator binding cleft was substantially different from that of retinoic acid receptor gamma, a closely related AF-2-dependent receptor [19].
  • Using genetic and pharmacological approaches, we investigated the role of NGFI-B and retinoids in acute behavioral and biochemical responses to dopamine antagonists [1].

Physical interactions of Nr4a1


Enzymatic interactions of Nr4a1

  • The induction of Nur77 was also blocked by A-CREB, suggesting that MSKs control Nur77 transcription by phosphorylating CREB bound to the two AP-1-like elements [24].

Co-localisations of Nr4a1


Regulatory relationships of Nr4a1

  • This translocation is a type 1 IGF receptor-signaling independent event as IGFBP-3 induces Nur77 translocation in R-cells [26].
  • NGFI-B activates transcription through an NBRE of the gene encoding 21-hydroxylase (P450c21) in Y1 cells [17].
  • Analysis of changes in the expression pattern of potential Egr-1 target genes revealed that Egr-1 enhances the expression of the aminopeptidase BP-1/6C3 in pre-B and immature B cells and upregulates expression of the orphan nuclear receptor nur77 in IgM+ B cells [27].
  • We demonstrate that DAX-1 represses the Nur77 transactivation by transient transfection assays [21].
  • These data may suggest a repressed expression of TIS21 and TIS1 in the cancer tissues and cells derived from the organs that constitutively express TIS21 in mice and in human cancer cells [2].
  • Transcriptional profiling of Nur77-expressing preadipocytes led to the identification of gap-junction protein alpha1 (Gja1) and tolloid-like 1 (Tll1) as Nur77-responsive genes [28].

Other interactions of Nr4a1

  • Thymuses from nur77/N10-transgenic mice on a gld/gld background have increased cellularity and an almost normal profile of thymocyte subpopulations [29].
  • IGFBP-3 and Nur77 are additive in inducing apoptosis [26].
  • We found the two genes Nr4a1 and Herpud1 to be overexpressed in Wnt-1-transformed cells [30].
  • Both genes were also inducible by TPA while forskolin which activates the cAMP-dependent pathway induced TIS1 but not TIS8 [31].
  • Adrenocortical function and regulation of the steroid 21-hydroxylase gene in NGFI-B-deficient mice [17].

Analytical, diagnostic and therapeutic context of Nr4a1


  1. The transcription factor NGFI-B (Nur77) and retinoids play a critical role in acute neuroleptic-induced extrapyramidal effect and striatal neuropeptide gene expression. Ethier, I., Beaudry, G., St-Hilaire, M., Milbrandt, J., Rouillard, C., Lévesque, D. Neuropsychopharmacology (2004) [Pubmed]
  2. Differential expression of TIS21 and TIS1 genes in the various organs of Balb/c mice, thymic carcinoma tissues and human cancer cell lines. Lim, I.K., Lee, M.S., Lee, S.H., Kim, N.K., Jou, I., Seo, J.S., Park, S.C. J. Cancer Res. Clin. Oncol. (1995) [Pubmed]
  3. Cholesterol diet enhances daily rhythm of Pai-1 mRNA in the mouse liver. Kudo, T., Nakayama, E., Suzuki, S., Akiyama, M., Shibata, S. Am. J. Physiol. Endocrinol. Metab. (2004) [Pubmed]
  4. Nur77 agonists induce proapoptotic genes and responses in colon cancer cells through nuclear receptor-dependent and nuclear receptor-independent pathways. Cho, S.D., Yoon, K., Chintharlapalli, S., Abdelrahim, M., Lei, P., Hamilton, S., Khan, S., Ramaiah, S.K., Safe, S. Cancer Res. (2007) [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. Reduction of dopamine-related transcription factors Nurr1 and NGFI-B in the prefrontal cortex in schizophrenia and bipolar disorders. Xing, G., Zhang, L., Russell, S., Post, R. Schizophr. Res. (2006) [Pubmed]
  7. TRAP220 is modulated by the antineoplastic agent 6-Mercaptopurine, and mediates the activation of the NR4A subgroup of nuclear receptors. Wansa, K.D., Muscat, G.E. J. Mol. Endocrinol. (2005) [Pubmed]
  8. Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediate-early gene nur77. Liu, Z.G., Smith, S.W., McLaughlin, K.A., Schwartz, L.M., Osborne, B.A. Nature (1994) [Pubmed]
  9. Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Lee, S.L., Wesselschmidt, R.L., Linette, G.P., Kanagawa, O., Russell, J.H., Milbrandt, J. Science (1995) [Pubmed]
  10. Nur77 nuclear import and its NBRE-binding activity in thymic lymphoma cells are regulated by different mechanisms sensitive to FK506 or HA1004. Kochel, I., Rapak, A., Ziolo, E., Strzadala, L. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  11. RXRalpha acts as a carrier for TR3 nuclear export in a 9-cis retinoic acid-dependent manner in gastric cancer cells. Lin, X.F., Zhao, B.X., Chen, H.Z., Ye, X.F., Yang, C.Y., Zhou, H.Y., Zhang, M.Q., Lin, S.C., Wu, Q. J. Cell. Sci. (2004) [Pubmed]
  12. Docosahexaenoic acid reduces haloperidol-induced dyskinesias in mice: involvement of Nur77 and retinoid receptors. Ethier, I., Kagechika, H., Shudo, K., Rouillard, C., Lévesque, D. Biol. Psychiatry (2004) [Pubmed]
  13. Thymic lymphomas are resistant to Nur77-mediated apoptosis. Matuszyk, J., Kobzdej, M., Ziolo, E., Kalas, W., Kisielow, P., Strzadala, L. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  14. Evidence for Nr4a1 as a cold-induced effector of brown fat thermogenesis. Kanzleiter, T., Schneider, T., Walter, I., Bolze, F., Eickhorst, C., Heldmaier, G., Klaus, S., Klingenspor, M. Physiol. Genomics (2005) [Pubmed]
  15. Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis. Cheng, L.E., Chan, F.K., Cado, D., Winoto, A. EMBO J. (1997) [Pubmed]
  16. The orphan nuclear receptor NR4A1 regulates insulin-like 3 gene transcription in Leydig cells. Robert, N.M., Martin, L.J., Tremblay, J.J. Biol. Reprod. (2006) [Pubmed]
  17. Adrenocortical function and regulation of the steroid 21-hydroxylase gene in NGFI-B-deficient mice. Crawford, P.A., Sadovsky, Y., Woodson, K., Lee, S.L., Milbrandt, J. Mol. Cell. Biol. (1995) [Pubmed]
  18. Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells. Zhou, T., Cheng, J., Yang, P., Wang, Z., Liu, C., Su, X., Bluethmann, H., Mountz, J.D. J. Exp. Med. (1996) [Pubmed]
  19. The activation function-1 domain of Nur77/NR4A1 mediates trans-activation, cell specificity, and coactivator recruitment. Wansa, K.D., Harris, J.M., Muscat, G.E. J. Biol. Chem. (2002) [Pubmed]
  20. Dimer-specific potentiation of NGFI-B (Nur77) transcriptional activity by the protein kinase A pathway and AF-1-dependent coactivator recruitment. Maira, M., Martens, C., Batsché, E., Gauthier, Y., Drouin, J. Mol. Cell. Biol. (2003) [Pubmed]
  21. The atypical orphan nuclear receptor DAX-1 interacts with orphan nuclear receptor Nur77 and represses its transactivation. Song, K.H., Park, Y.Y., Park, K.C., Hong, C.Y., Park, J.H., Shong, M., Lee, K., Choi, H.S. Mol. Endocrinol. (2004) [Pubmed]
  22. The orphan nuclear receptor NGFI-B regulates expression of the gene encoding steroid 21-hydroxylase. Wilson, T.E., Mouw, A.R., Weaver, C.A., Milbrandt, J., Parker, K.L. Mol. Cell. Biol. (1993) [Pubmed]
  23. Ligation of retinoic acid receptor alpha regulates negative selection of thymocytes by inhibiting both DNA binding of nur77 and synthesis of bim. Szegezdi, E., Kiss, I., Simon, A., Blaskó, B., Reichert, U., Michel, S., Sándor, M., Fésüs, L., Szondy, Z. J. Immunol. (2003) [Pubmed]
  24. MSKs are required for the transcription of the nuclear orphan receptors Nur77, Nurr1 and Nor1 downstream of MAPK signalling. Darragh, J., Soloaga, A., Beardmore, V.A., Wingate, A.D., Wiggin, G.R., Peggie, M., Arthur, J.S. Biochem. J. (2005) [Pubmed]
  25. Retinoid X receptor heterodimerization and developmental expression distinguish the orphan nuclear receptors NGFI-B, Nurr1, and Nor1. Zetterström, R.H., Solomin, L., Mitsiadis, T., Olson, L., Perlmann, T. Mol. Endocrinol. (1996) [Pubmed]
  26. Rapid apoptosis induction by IGFBP-3 involves an insulin-like growth factor-independent nucleomitochondrial translocation of RXRalpha/Nur77. Lee, K.W., Ma, L., Yan, X., Liu, B., Zhang, X.K., Cohen, P. J. Biol. Chem. (2005) [Pubmed]
  27. The transcription factor early growth response 1 (Egr-1) advances differentiation of pre-B and immature B cells. Dinkel, A., Warnatz, K., Ledermann, B., Rolink, A., Zipfel, P.F., Bürki, K., Eibel, H. J. Exp. Med. (1998) [Pubmed]
  28. Inhibition of adipocyte differentiation by Nur77, Nurr1, and Nor1. Chao, L.C., Bensinger, S.J., Villanueva, C.J., Wroblewski, K., Tontonoz, P. Mol. Endocrinol. (2008) [Pubmed]
  29. Apoptosis of nur77/N10-transgenic thymocytes involves the Fas/Fas ligand pathway. Weih, F., Ryseck, R.P., Chen, L., Bravo, R. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  30. Murine Nr4a1 and Herpud1 are up-regulated by Wnt-1, but the homologous human genes are independent from beta-catenin activation. Chtarbova, S., Nimmrich, I., Erdmann, S., Herter, P., Renner, M., Kitajewski, J., Müller, O. Biochem. J. (2002) [Pubmed]
  31. Differential regulation of primary response gene expression in skeletal muscle cells through multiple signal transduction pathways. Lim, R.W., Zhu, C.Y., Stringer, B. Biochim. Biophys. Acta (1995) [Pubmed]
  32. Structure, mapping and expression of a growth factor inducible gene encoding a putative nuclear hormonal binding receptor. Ryseck, R.P., Macdonald-Bravo, H., Mattéi, M.G., Ruppert, S., Bravo, R. EMBO J. (1989) [Pubmed]
  33. Transcriptional activation of known and novel apoptotic pathways by Nur77 orphan steroid receptor. Rajpal, A., Cho, Y.A., Yelent, B., Koza-Taylor, P.H., Li, D., Chen, E., Whang, M., Kang, C., Turi, T.G., Winoto, A. EMBO J. (2003) [Pubmed]
  34. Endocrine disrupter bisphenol a induces orphan nuclear receptor Nur77 gene expression and steroidogenesis in mouse testicular Leydig cells. Song, K.H., Lee, K., Choi, H.S. Endocrinology (2002) [Pubmed]
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