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Gene Review

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

Rattus norvegicus

Synonyms: HMR, Hmr, NGFI-B, NUR77, Nerve growth factor-induced protein I-B, ...
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Disease relevance of Nr4a1


High impact information on Nr4a1

  • NGFI-B, an early response protein and orphan member of this receptor superfamily, binds to a DNA sequence that contains only one half-site (5'-AAAGGTCA-3') [5].
  • A domain separate from the NGFI-B zinc fingers, termed the A box, was identified and is required for recognition of the two adenine-thymidine (A-T) base pairs at the 5' end of the NGFI-B DNA binding element [5].
  • Identification of the DNA binding site for NGFI-B by genetic selection in yeast [6].
  • Here we show that nerve growth factor (NGF) induces the phosphorylation of Ser 105 of NGFI-B in PC12 phaeochromocytoma cells, resulting in translocation of the NGFI-B-RXR heterodimer complex out of the nucleus using nuclear export signals within NGFI-B [7].
  • Modulation of retinoid signalling through NGF-induced nuclear export of NGFI-B [7].

Chemical compound and disease context of Nr4a1

  • In contrast, HMR 1402 had a smaller effect on pancreatic beta-cells (rat insuloma cells, RINm5F) hyperpolarized with 100 microM diazoxide (IC(50) = 3.9 microM, compared with glibenclamide IC(50) = 9 nM) [8].
  • Increase of transcriptional levels of egr-1 and nur77 genes due to both nicotine treatment and withdrawal in pheochromocytoma cells [9].
  • HMR 1098 also prevented cardiac arrest and mitochondrial uncoupling induced by P-1075, such as (a) depletion of phosphocreatine and ATP by 40%, (b) two-fold decrease in venous oxygen, and (c) reduction of cytochrome c oxidase (demonstrated by an increase in 603 nm optical absorbance) [10].

Biological context of Nr4a1


Anatomical context of Nr4a1

  • In the present study, expression of the NGFI-B gene in the rat pineal gland was found to exhibit a robust circadian rhythm, with elevated levels of NGFI-B mRNA occurring at night [12].
  • NGFI-B is a gene, identified by differential hybridization, that is rapidly, but transiently induced in PC12 cells by NGF [13].
  • In particular, the NGFI-B ligand-binding domain (LBD) exhibits only modest activity in cell lines in which the Nurr1 LBD strongly activates transcription [14].
  • In the rat ovary, the preovulatory surge of LH induces NGFI-B expression in granulosa cells of preovulatory follicles, reaching a peak within 1 h and declining to control levels at 6 h [15].
  • The products of nur77 are known to be involved in the apoptotic process, as nur77 is a transcription factor expressed in response to T-cell receptor-mediated apoptosis in immature T cells [16].

Associations of Nr4a1 with chemical compounds


Physical interactions of Nr4a1

  • Recently, it was demonstrated that NGFI-B interacts with Bcl-2 by inducing a conformational change in Bcl-2, converting it from protector to a killer [19].

Co-localisations of Nr4a1

  • Double in situ hybridization studies showed that striatal NGFI-B mRNA colocalized with a subset of preproenkephalin and prodynorphin positive spiny neurons within the dorsomedial striatum; 22--28% of all opiate-peptide positive cells co-expressed NGFI-B mRNA [20].

Regulatory relationships of Nr4a1

  • Thus, activation of ERK2 may overcome apoptosis-induced subcellular translocation of NGFI-B [19].
  • Fos kinase isolated from nerve growth factor-stimulated PC12 cells is indistinguishable from NGFI-B kinase I, based on their chromatographic behavior, substrate specificities, and relative sensitivity to BIM [21].
  • ATP also induced a slight increase in nur77 mRNA but was ineffective in inducing c-myc expression in these cells [22].
  • NGFI-B did not colocalize with striatal aspiny interneurons expressing choline acetyl transferase mRNA or those containing the calcium-binding protein parvalbumin [20].

Other interactions of Nr4a1

  • RNR-1, a nuclear receptor in the NGFI-B/Nur77 family that is rapidly induced in regenerating liver [11].
  • Among these genes, we are particularly interested in Nor-1, because this gene belongs to the Nur77 family, which plays a key role in the apoptotic processes of a variety of cells and tissues, including the lung [1].
  • When a plasmid encoding dominant-negative Nur77 was transfected into A549 cells, cadmium-induced apoptotic changes, such as chromosomal condensation and Bax expression, were significantly reduced, suggesting that the expression of Nur77 plays an important role in cadmium-induced apoptosis [1].
  • We focused our attention to expression of transcription factors and several of them were up- or down-regulated by nicotine, among these Nr4a1 (Nurr77), Egr-1 and Egr-2 [23].
  • The prominent induction of NGFI-B, NGFI-C, egr-2, and egr-3 in the anterior cingulate cortex, the ACA/MCA transition zone, and medial striatum could reflect the ischemic regions around MCA infarcts [24].

Analytical, diagnostic and therapeutic context of Nr4a1

  • We found that nur77 was rapidly transcripted in vitro following exposure of freshly isolated rat thymocytes to 3 microM DBTC. nur77 induction has also been observed in vivo after treatment of rats with apoptotic doses (60 mg/kg body wt) of DBTC [16].
  • In situ hybridization was performed to check the localization of the NGFI-B gene in rat liver [2].
  • In human specimens, the NGFI-B family genes expression was stronger than that before ischemic insult. pCREB protein was detected in the rat liver sampled 15 min after reperfusion [2].
  • Expression of phospho-Ser-133-specific cyclic adenosine-3' :5'-monophosphate response element binding (pCREB) protein was examined by Western blot analysis and gel shift assay, since the promoter region of the NGFI-B family genes contains CRE [2].
  • METH injection resulted in increased expression of members of the Jun, Egr, and Nur77 subfamilies of transcription factors (TFs), changes that were confirmed by quantitative PCR [25].


  1. Induction of orphan nuclear receptor Nur77 gene expression and its role in cadmium-induced apoptosis in lung. Shin, H.J., Lee, B.H., Yeo, M.G., Oh, S.H., Park, J.D., Park, K.K., Chung, J.H., Moon, C.K., Lee, M.O. Carcinogenesis (2004) [Pubmed]
  2. Early induction of nerve growth factor-induced genes after liver resection-reperfusion injury. Ohkubo, T., Sugawara, Y., Sasaki, K., Maruyama, K., Ohkura, N., Makuuchi, M. J. Hepatol. (2002) [Pubmed]
  3. Early induction of the NGFI-B/Nur77 family genes in nephritis induced by anti-glomerular basement membrane antibody. Hayashi, K., Ohkura, N., Miki, K., Osada, S., Tomino, Y. Mol. Cell. Endocrinol. (1996) [Pubmed]
  4. Differential expression of the immediate early genes c-fos, c-jun, junB, and NGFI-B in the rat brain following transient forebrain ischemia. Neumann-Haefelin, T., Wiessner, C., Vogel, P., Back, T., Hossmann, K.A. J. Cereb. Blood Flow Metab. (1994) [Pubmed]
  5. Participation of non-zinc finger residues in DNA binding by two nuclear orphan receptors. Wilson, T.E., Paulsen, R.E., Padgett, K.A., Milbrandt, J. Science (1992) [Pubmed]
  6. Identification of the DNA binding site for NGFI-B by genetic selection in yeast. Wilson, T.E., Fahrner, T.J., Johnston, M., Milbrandt, J. Science (1991) [Pubmed]
  7. Modulation of retinoid signalling through NGF-induced nuclear export of NGFI-B. Katagiri, Y., Takeda, K., Yu, Z.X., Ferrans, V.J., Ozato, K., Guroff, G. Nat. Cell Biol. (2000) [Pubmed]
  8. Effects of a novel cardioselective ATP-sensitive potassium channel antagonist, 1-[[5-[2-(5-chloro-o-anisamido)ethyl]-beta-methoxyethoxyphenyl]sulfonyl]-3-methylthiourea, sodium salt (HMR 1402), on susceptibility to ventricular fibrillation induced by myocardial ischemia: in vitro and in vivo studies. Billman, G.E., Houle, M.S., Englert, H.C., Gögelein, H. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  9. Increase of transcriptional levels of egr-1 and nur77 genes due to both nicotine treatment and withdrawal in pheochromocytoma cells. Ichino, N., Yamada, K., Nishii, K., Sawada, H., Nagatsu, T., Ishiguro, H. Journal of neural transmission (Vienna, Austria : 1996) (2002) [Pubmed]
  10. Cardioselective sulfonylthiourea HMR 1098 blocks mitochondrial uncoupling induced by a KATP channel opener, P-1075, in beating rat hearts. Jilkina, O., Kuzio, B., Grover, G.J., Kupriyanov, V.V. Biochim. Biophys. Acta (2003) [Pubmed]
  11. RNR-1, a nuclear receptor in the NGFI-B/Nur77 family that is rapidly induced in regenerating liver. Scearce, L.M., Laz, T.M., Hazel, T.G., Lau, L.F., Taub, R. J. Biol. Chem. (1993) [Pubmed]
  12. NGFI-B (Nurr77/Nr4a1) orphan nuclear receptor in rat pinealocytes: circadian expression involves an adrenergic-cyclic AMP mechanism. Humphries, A., Weller, J., Klein, D., Baler, R., Carter, D.A. J. Neurochem. (2004) [Pubmed]
  13. Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Milbrandt, J. Neuron (1988) [Pubmed]
  14. Structural basis for the cell-specific activities of the NGFI-B and the Nurr1 ligand-binding domain. Flaig, R., Greschik, H., Peluso-Iltis, C., Moras, D. J. Biol. Chem. (2005) [Pubmed]
  15. Regulation of NGFI-B expression during the ovulatory process. Park, J.I., Park, H.J., Lee, Y.I., Seo, Y.M., Chun, S.Y. Mol. Cell. Endocrinol. (2003) [Pubmed]
  16. Identification by DNA macroarray of nur77 as a gene induced by di-n-butyltin dichloride: its role in organotin-induced apoptosis. Gennari, A., Bleumink, R., Viviani, B., Galli, C.L., Marinovich, M., Pieters, R., Corsini, E. Toxicol. Appl. Pharmacol. (2002) [Pubmed]
  17. Transactivation activity of Nur77 discriminates between Ca2+ and cAMP signals. Klopotowska, D., Matuszyk, J., Rapak, A., Gidzinska, B., Cebrat, M., Ziolo, E., Strzadala, L. Neurochem. Int. (2005) [Pubmed]
  18. Nur77 coordinately regulates expression of genes linked to glucose metabolism in skeletal muscle. Chao, L.C., Zhang, Z., Pei, L., Saito, T., Tontonoz, P., Pilch, P.F. Mol. Endocrinol. (2007) [Pubmed]
  19. ERK2 prohibits apoptosis-induced subcellular translocation of orphan nuclear receptor NGFI-B/TR3. Jacobs, C.M., Boldingh, K.A., Slagsvold, H.H., Thoresen, G.H., Paulsen, R.E. J. Biol. Chem. (2004) [Pubmed]
  20. Cellular mRNA expression of the transcription factor NGFI-B suggests a gene regulatory role in striatal opiate-peptide neurons. Bäckman, C., Hoffer, B.J., Misawa, H., Morales, M. Brain Res. (2001) [Pubmed]
  21. Transcription factor phosphorylation by pp90(rsk2). Identification of Fos kinase and NGFI-B kinase I as pp90(rsk2). Swanson, K.D., Taylor, L.K., Haung, L., Burlingame, A.L., Landreth, G.E. J. Biol. Chem. (1999) [Pubmed]
  22. ATP-stimulated c-fos and zif268 mRNA expression is inhibited by chemical hypoxia in a rat brain-derived type 2 astrocyte cell line, RBA-2. Hung, A.C., Huang, H.M., Tsay, H.J., Lin, T.N., Kuo, J.S., Sun, S.H. J. Cell. Biochem. (2000) [Pubmed]
  23. Transcription factor gene expression profiling after acute intermittent nicotine treatment in the rat cerebral cortex. Belluardo, N., Olsson, P.A., Mudo', G., Sommer, W.H., Amato, G., Fuxe, K. Neuroscience (2005) [Pubmed]
  24. Expression of zinc finger immediate early genes in rat brain after permanent middle cerebral artery occlusion. Honkaniemi, J., States, B.A., Weinstein, P.R., Espinoza, J., Sharp, F.R. J. Cereb. Blood Flow Metab. (1997) [Pubmed]
  25. Calcineurin/NFAT-induced up-regulation of the Fas ligand/Fas death pathway is involved in methamphetamine-induced neuronal apoptosis. Jayanthi, S., Deng, X., Ladenheim, B., McCoy, M.T., Cluster, A., Cai, N.S., Cadet, J.L. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
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