Disease relevance of Nr4a1

• Taken together, these results demonstrate that cadmium induces the expression of Nur77 family genes, leading to apoptosis in lung cells, which may cause pulmonary toxicity in response to cadmium exposure [1].
• CONCLUSIONS: We recognized the early induction of the NGFI-B family genes after ischemia-reperfusion injury in rat and human livers [2].
• Early induction of the NGFI-B/Nur77 family genes in nephritis induced by anti-glomerular basement membrane antibody [3].
• Renal injuries were most prominent on day 7 and persisted until day 28, indicating that NOR-1, NGFI-B and RNR-1 genes are induced during the early stage of glomerulonephritis and may be associated with the progression of glomerulonephritis [3].
• Differential expression of the immediate early genes c-fos, c-jun, junB, and NGFI-B in the rat brain following transient forebrain ischemia [4].

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

• Both RNR-1 and Nur77 strongly transactivate a reporter driven by a consensus r-NGFI-B/Nur77 binding site, and their effect together is additive [11].
• This set of observations extends the number of pineal genes that are known to be regulated by Fra-2, and also provides the first indication that a member of the NGFI-B group of nuclear receptors is involved in controlling gene expression in the pineal gland [12].
• The rhythm of NGFI-B mRNA is translated into a circadian rhythm of NGFI-B protein, which accumulates in the nucleus of pinealocytes [12].
• The nucleotide sequence of the NGFI-B gene was determined, and it encodes a 61 kd protein with strong homologies to members of the glucocorticoid receptor gene family [13].
• Similarly, mutation of Met414 in helix 3 to leucine or of Leu591 in helix 12 to isoleucine (the corresponding residues found in NGFI-B) significantly affects Nurr1 transactivation [14].

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

• NGFI-B protein levels are also elevated by dibutyryl cyclic AMP, as in other systems [12].
• In the present study, we characterized the induction of the Nur77 family genes in the lungs after cadmium exposure [1].
• On the other hand, cAMP analog induced strong increase, while Ca2+ ionophore induced weak increase in the transactivation activity of Nur77 [17].
• The LH-stimulated NGFI-B expression is abolished by alpha-amanitin, but superinduced by cycloheximide [15].
• Identification by DNA macroarray of nur77 as a gene induced by di-n-butyltin dichloride: its role in organotin-induced apoptosis [16].
• Denervation of rat muscle compromises expression of Nur77 in parallel with that of numerous genes linked to glucose metabolism, including glucose transporter 4 and genes involved in glycolysis, glycogenolysis, and the glycerophosphate shuttle [18].

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].

References