Disease relevance of NR4A1

• beta-Adrenergic receptor (beta-AR) agonists induce Nur77 mRNA expression in the C2C12 skeletal muscle cell culture model and elicit skeletal muscle hypertrophy [1].
• Nur77 activated by hypoxia-inducible factor-1alpha overproduces proopiomelanocortin in von Hippel-Lindau-mutated renal cell carcinoma [2].
• Here we found that 12-O-tetradecanoylphorbol-13-acetate (TPA) could induce cell apoptosis via induction of TR3 and E2F1 expression in LNCaP prostate cancer cells [3].
• TR3/Nur77 in colon cancer cell apoptosis [4].
• Moreover, the transactivation and apoptotic responses are also induced in other pancreatic, prostate, and breast cancer cells that express Nur77 [5].

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

• 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 [10].
• Modulation of retinoic acid sensitivity in lung cancer cells through dynamic balance of orphan receptors nur77 and COUP-TF and their heterodimerization [11].
• 10-ethyl-10-deaza-aminopterin (10-EDAM) is an analog of methotrexate that differs from its compound by modification of the N10 position and demonstrates greater preclinical antitumor activity and less toxicity [12].
• The MICs of HMR 3004 and HMR 3647 at which 90% of beta-lactamase-producing Haemophilus influenzae isolates were inhibited were 4 and 2 micrograms/ml, respectively [13].
• In androgen-responsive LNCaP human prostatic cancer cells, human TR3 orphan receptor, a member of the steroid receptor superfamily, can be rapidly induced by androgen [14].

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

• Moreover NOT is closely related to NAK1/TR3, a previously identified human orphan steroid receptor [21].
• Silencing mediator of retinoid and thyroid hormone receptors and activating signal cointegrator-2 as transcriptional coregulators of the orphan nuclear receptor Nur77 [22].
• Infection of cultured human adrenal cells with adenovirus-containing NGFIB increased cortisol production by 8-fold and increased expression of HSD3B2 mRNA 26-fold over that observed in mock-infected cells [23].
• The orphan nuclear receptor NGFIB regulates transcription of 3beta-hydroxysteroid dehydrogenase. implications for the control of adrenal functional zonation [23].
• VEGF increased protein expression of Nurr1 and Nur77 and decreased Nur77 phosphorylation at the negative regulatory site serine 351 [24].

Physical interactions of NR4A1

• Our study further showed that the coiled-coil domain of PML interacts with the DNA-binding domain of Nur77 (amino acids 267-332) [25].
• Finally, we showed that JNK-induced phosphorylation blocked the DNA binding property of TR3 and hence diminished its transactivation activity [26].
• TINUR binds to the same DNA sequence as NGFI-B/nur77 [27].
• We have recently shown that the orphan nuclear receptor Nur77 (NGFI-B) is most active in transcription when it is interacting with a cognate DNA sequence as a homodimer [28].
• Electrophoretic mobility shift and chromatin immunoprecipitation assays showed that Nur77 directly binds to the GIOT-1 promoter [29].

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

• Electrophoretic mobility shift assay demonstrated that PML interferes with Nur77 DNA binding in a dose-dependent manner [25].
• METHODS AND RESULTS: Nur77, Nurr1, and NOR-1 are expressed in early and advanced human atherosclerotic lesion macrophages primarily in areas of plaque activation/progression as detected by in situ-hybridization and immunohistochemistry [31].
• In an electrophoretic mobility shift assay with chromosomal immunoprecipitation assays, wild-type Nur77, but not S350A mutant Nur77, could specifically bind to TCL1-NBRE [32].
• The data for Nur77 promoter functional analysis were matched to the Northern blot analysis [33].
• Protective function of transcription factor TR3 orphan receptor in atherogenesis: decreased lesion formation in carotid artery ligation model in TR3 transgenic mice [34].

References