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Journal articles on the topic 'Orphan nuclear receptor NURR1'

Author: Grafiati

Published: 7 June 2025

Last updated: 26 June 2025

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1

Maira, Mario, Christine Martens, Alexandre Philips, and Jacques Drouin. "Heterodimerization between Members of the Nur Subfamily of Orphan Nuclear Receptors as a Novel Mechanism for Gene Activation." Molecular and Cellular Biology 19, no. 11 (1999): 7549–57. http://dx.doi.org/10.1128/mcb.19.11.7549.

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ABSTRACT 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. Further, we have shown that the target for Nur77 dimers, the Nur response element (NurRE), is responsive to physiological stimuli in both endocrine and lymphoid cells, whereas other DNA targets of Nur77 action are not. The Nur77 subfamily also includes two related receptors, Nur-related factor 1 (Nurr1) and neuron-derived orphan receptor 1 (NOR-1). Often, more than one member of this subfamily is induced in response to extracellular signals. We now show that Nur77 and Nurr1 form heterodimers in vitro in the presence or absence of NurRE, and we have documented interactions between these proteins in vivo by using a two-hybrid system in mammalian cells. These heterodimers synergistically enhance transcription from NurRE reporters in comparison to that seen with homodimers. The naturally occurring NurRE from the pro-opiomelanocortin gene preferentially binds and activates transcription in the presence of Nur77 homo- or heterodimers, while a consensus NurRE sequence does not show this preference. Taken together, the data indicate that members of the Nur77 subfamily are most potent as heterodimers and that different dimers exhibit target sequence preference. Thus, we propose that a combinatorial code relying on specific NurRE sequences might be responsible for the activation of subsets of target genes by one of the members of the Nur77 subfamily of transcription factors.

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2

Jang, Yongwoo, Woori Kim, Pierre Leblanc, Chun-Hyung Kim, and Kwang-Soo Kim. "Potent synthetic and endogenous ligands for the adopted orphan nuclear receptor Nurr1." Experimental & Molecular Medicine 53, no. 1 (2021): 19–29. http://dx.doi.org/10.1038/s12276-021-00555-5.

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AbstractUntil recently, Nurr1 (NR4A2) was known as an orphan nuclear receptor without a canonical ligand-binding domain, featuring instead a narrow and tight cavity for small molecular ligands to bind. In-depth characterization of its ligand-binding pocket revealed that it is highly dynamic, with its structural conformation changing more than twice on the microsecond-to-millisecond timescale. This observation suggests the possibility that certain ligands are able to squeeze into this narrow space, inducing a conformational change to create an accessible cavity. The cocrystallographic structure of Nurr1 bound to endogenous ligands such as prostaglandin E1/A1 and 5,6-dihydroxyindole contributed to clarifying the crucial roles of Nurr1 and opening new avenues for therapeutic interventions for neurodegenerative and/or inflammatory diseases related to Nurr1. This review introduces novel endogenous and synthetic Nurr1 agonists and discusses their potential effects in Nurr1-related diseases.

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3

Lappas, Martha. "Effect of spontaneous term labour on the expression of the NR4A receptors nuclear receptor related 1 protein (Nurr1), neuron-derived clone 77 (Nur77) and neuron-derived orphan receptor 1 (NOR1) in human fetal membranes and myometrium." Reproduction, Fertility and Development 28, no. 7 (2016): 893. http://dx.doi.org/10.1071/rd14315.

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Inflammation has been implicated in the mechanisms responsible for human labour. Emerging evidence indicates that nuclear receptor subfamily 4A (NR4A) receptors regulate the transcription of genes involved in inflammation. The aim of the present study was to determine the effect of spontaneous term labour, Toll-like receptor (TLR) ligands and nucleotide-binding oligomerisation domain-containing (NOD) ligands on the expression of nuclear receptor related 1 protein (Nurr1), neuron-derived clone 77 (Nur77) and neuron-derived orphan receptor 1 (NOR1) in human fetal membranes and myometrium. Human fetal membranes and myometrium were collected from term non-labouring women and women after spontaneous labour onset. Tissue explants were used to determine the effect of the bacterial products lipopolysaccharide (LPS; TLR4 ligand), flagellin (TLR5 ligand), fibroblast-stimulating lipopeptide (FSL-1) (TLR2 ligand), γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP) (NOD1 ligand) or minimal peptidoglycan muramyl dipeptide (MDP; NOD2 ligand) on Nurr1, Nur77 and NOR1 expression. Term labour was associated with significantly higher Nurr1 and Nur77, but not NOR1, expression in fetal membranes and myometrium. LPS and MDP increased Nurr1, Nur77 and NOR in fetal membranes; flagellin increased Nurr1 in fetal membranes and the myometrium, as well as NOR1 in the myometrium; and FSL-1 increased Nurr1 expression in fetal membranes. In summary, human labour and bacterial products increase Nurr1, Nur77 and/or NOR1 expression in human fetal membranes and myometrium. This increase in NR4A receptors may contribute to the expression of proinflammatory and pro-labour genes associated with fetal membrane rupture and myometrial contractions.

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4

Zarei, Mehrdad, Rupesh Shrestha, Sneha Johnson, et al. "Nuclear Receptor 4A2 (NR4A2/NURR1) Regulates Autophagy and Chemoresistance in Pancreatic Ductal Adenocarcinoma." Cancer Research Communications 1, no. 2 (2021): 65–78. http://dx.doi.org/10.1158/2767-9764.crc-21-0073.

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis and chemotherapy with gemcitabine has limited effects and is associated with development of drug resistance. Treatment of Panc1 and MiaPaca2 pancreatic cancer cells with gemcitabine induced expression of the orphan nuclear receptor 4A2 (NURR1) and analysis of The Cancer Genome Atlas indicated the NURR1 is overexpressed in pancreatic tumors and is a negative prognostic factor for patient survival. Results of NURR1 knockdown or treatment with the NURR1 antagonist 1,1-bis(3΄-indolyl)-1-(p-chlorophenyl)methane (C-DIM 12) demonstrated that NURR1 was prooncogenic in pancreatic cancer cells and regulated cancer cell and tumor growth and survival. NURR1 is induced by gemcitabine and serves as a key drug resistance factor and is also required for gemcitabine-induced cytoprotective autophagy. NURR1-regulated genes were determined by RNA sequencing of mRNAs expressed in MiaPaCa2 cells expressing NURR1 and in CRISPR/Cas9 gene–edited cells for NURR1 knockdown and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of the differentially expressed genes showed that autophagy was the major pathway regulated by NURR1. Moreover, NURR1 regulated expression of two major autophagic genes, ATG7 and ATG12, which are also overexpressed in pancreatic tumors and like NURR1 are negative prognostic factors for patient survival. Thus, gemcitabine-induced cytoprotective autophagy is due to the NURR1–ATG7/ATG12 axis and this can be targeted and disrupted by NURR1 antagonist C-DIM12 demonstrating the potential clinical applications for combination therapies with gemcitabine and NURR1 antagonists. Significance: Gemcitabine induces NURR1-dependent ATG7 and ATG12 cytoprotective autophagy in PDA cells that can be reversed by NURR1 antagonists.

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5

Solís, Miguel Ángel, Eduardo Santana, José Ramón Muñoz, Norma Cristina Segovia, Eduardo Patiño, and Carmen Sánchez-Torres. "The pro-inflammatory phenotype of human macrophages is restricted by the activity of the orphan nuclear receptor Nurr1." Journal of Immunology 210, no. 1_Supplement (2023): 168.12. http://dx.doi.org/10.4049/jimmunol.210.supp.168.12.

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Abstract The nuclear receptor related 1 protein (Nurr1) is a member of the orphan nuclear hormone receptor family whose expression has been associated with several inflammatory diseases. Macrophages are key regulators of the inflammatory processes, yet information about the role of Nurr1 in human macrophages is limited. In the present study we examined the expression and activity of Nurr1 in steady state and activated human monocyte-derived macrophages. Pro- and anti-inflammatory macrophages were derived in vitro by culture of blood monocytes with the hematopoietic cytokines GM-CSF and M-CSF, respectively. Nurr1 expression was predominant in macrophages with a pro-inflammatory phenotype. Accordingly, its expression was induced by a variety of inflammatory stimuli such as TLR-2, -3 and -4 ligands, TNF, IFN-β, and IL-4. Pro-inflammatory macrophages exposed to the Nurr1 agonist C-DIM12 decreased their production of IL-1β, IL-6, and reactive oxygen species. Conversely, Nurr1 deficient macrophages produced enhanced levels of IL-6. Mechanistically, Nurr1 agonists partially abrogated the activation of the NF-κB signaling pathway in pro-inflammatory macrophages exposed to LPS, rendering cells with a lower rate of NF-κB p65 nuclear translocation. These results suggest that Nurr1 expression is linked with the pro-inflammatory phenotype of human macrophages where it may constitute a brake to attenuate the synthesis of inflammatory mediators. Supported by grants from Secretaria de Educación Pública-Consejo Nacional de Ciencia y Tecnología (SEP-CONACYT, #A1-S-9430)

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6

Bassett, Mary H., Takashi Suzuki, Hironobu Sasano, Perrin C. White, and William E. Rainey. "The Orphan Nuclear Receptors NURR1 and NGFIB Regulate Adrenal Aldosterone Production." Molecular Endocrinology 18, no. 2 (2004): 279–90. http://dx.doi.org/10.1210/me.2003-0005.

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Abstract Aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex is regulated by transcription of CYP11B2 (encoding aldosterone synthase). The effects of nerve growth factor-induced clone B (NGFIB) (NR4A1), Nur-related factor 1 (NURR1) (NR4A2), and steroidogenic factor-1 (SF-1) (NR5A1) on transcription of human CYP11B2 (hCYP11B2) and hCYP11B1 (11β-hydroxylase) were compared in human H295R adrenocortical cells. hCYP11B2 expression was increased by NGFIB and NURR1. Although hCYP11B1 was activated by SF-1, cotransfection with SF-1 inhibited activation of hCYP11B2 by NGFIB and NURR1. NGFIB and NURR1 transcript and protein levels were strongly induced by angiotensin (Ang) II, the major regulator of hCYP11B2 expression in vivo. Sequential deletion and mutagenesis of the hCYP11B2 promoter identified two functional NGFIB response elements (NBREs), one located at −766/−759 (NBRE-1) and the previously studied Ad5 element at −129/−114. EMSAs suggested that both elements bound NGFIB and NURR1. In human adrenals, NURR1 immunoreactivity was preferentially localized in the zona glomerulosa and to a lesser degree in the zona fasciculata, whereas NGFIB was detected in both zones. The calmodulin kinase inhibitor KN93 partially blocked K+-stimulated transcription of NGFIB and NURR1. KN93 partially inhibited the effect of Ang II on NURR1 mRNA levels but did not modify the effect on expression of NGFIB. Mutation of the NBRE-1, Ad5, and Ad1/cAMP response element (CRE) cis-elements reduced both basal and Ang II-induced levels of hCYP11B2, demonstrating that all three elements are important for maximal transcriptional activity. Our results suggest that NGFIB and NURR1 are key regulators of hCYP11B2 expression and may partially mediate the regulation of hCYP11B2 by Ang II.

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7

Martens, Christine, Steve Bilodeau, Mario Maira, Yves Gauthier, and Jacques Drouin. "Protein-Protein Interactions and Transcriptional Antagonism between the Subfamily of NGFI-B/Nur77 Orphan Nuclear Receptors and Glucocorticoid Receptor." Molecular Endocrinology 19, no. 4 (2005): 885–97. http://dx.doi.org/10.1210/me.2004-0333.

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Abstract Glucocorticoids (Gc) act through the glucocorticoid receptor (GR) to enhance or repress transcription of glucocorticoid-responsive genes depending on the promoter and cellular context. Repression of proopiomelanocortin (POMC) gene expression by Gc was proposed to use different mechanisms. We described the POMC promoter Nur response element (NurRE) as a target for Gc repression. NGFI-B (Nur77), an orphan nuclear receptor, and two related factors, Nurr1 and NOR1, bind the NurRE as homo- or heterodimers to enhance POMC gene expression in response to CRH. Gc antagonize CRH-stimulated as well as NGFI-B-dependent transcription. We now show that GR antagonizes NurRE-dependent transcription induced by all members of the Nur77 subfamily and that these nuclear receptors can all interact directly with GR. Transcriptional antagonism as well as direct protein-protein interaction between NGFI-B and GR take place primarily via their respective DNA binding domains, although DNA binding itself and the GR homodimerization interface are not involved. In vivo, GR and Nur factors can be coimmunoprecipitated whereas GR is recruited to the POMC promoter upon glucocorticoid action. Thus, our data suggest a mechanism for transrepression between two nuclear receptors, GR and NGFI-B, that is unique, although quite similar to that proposed for transrepression between GR and activator protein 1 (AP-1) or nuclear factor-κB (NFκB).

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8

Torii, T., T. Kawarai, S. Nakamura, and H. Kawakami. "Organization of the human orphan nuclear receptor Nurr1 gene." Gene 230, no. 2 (1999): 225–32. http://dx.doi.org/10.1016/s0378-1119(99)00064-5.

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9

Michiels, Paul, Karen Atkins, Christian Ludwig, Sara Whittaker, Maria van Dongen, and Ulrich Günther. "Assignment of the orphan nuclear receptor Nurr1 by NMR." Biomolecular NMR Assignments 4, no. 1 (2010): 101–5. http://dx.doi.org/10.1007/s12104-010-9210-4.

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10

Sakurada, K., M. Ohshima-Sakurada, T. D. Palmer, and F. H. Gage. "Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain." Development 126, no. 18 (1999): 4017–26. http://dx.doi.org/10.1242/dev.126.18.4017.

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Adult rat-derived hippocampal progenitor cells express many of the molecules implicated in midbrain dopaminergic determination, including FGF receptors 1, 2 and 3, the sonic hedgehog receptor components Smo and Ptc, and the region-specific transcription factors Ptx3 and Nurr1. Here we use undifferentiated progenitors to probe the events leading to the dopaminergic phenotype and find that the influences of Nurr1 can be temporally and mechanistically uncoupled from the patterning influences of sonic hedgehog and FGF-8 or the more generic process of neuronal differentiation itself. In gain-of-function experiments, Nurr1 is able to activate transcription of the tyrosine hydroxylase gene by binding a response element within a region of the tyrosine hydroxylase promoter necessary for midbrain-specific expression. This activation is mediated through a retinoid X receptor independent mechanism and occurs in all precursors, regardless of differentiation status. Overexpression of Nurr1 does not affect proliferation or stimulate neuronal differentiation and has no influence on the expression of other dopaminergic markers. This uncoupling of tyrosine hydroxylase expression from other dopaminergic markers suggests that the midbrain dopaminergic identity is dictated by a combination of pan-dopaminergic (e.g., Shh/FGF-8) and region-specific (Nurr1) mechanisms.

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11

Volakakis, Nikolaos, Michal Malewicz, Banafsheh Kadkhodai, Thomas Perlmann, and Gerard Benoit. "Characterization of the Nurr1 ligand-binding domain co-activator interaction surface." Journal of Molecular Endocrinology 37, no. 2 (2006): 317–26. http://dx.doi.org/10.1677/jme.1.02106.

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The recently solved crystal structure of the orphan nuclear receptor (NR) Nurr1 ligand-binding domain (LBD) showed that Nurr1 lacks a cavity for ligand binding and a canonical NR co-activator-binding site. Computer modeling of the Nurr1 LBD structure identified a hydrophobic region on the surface of the Nurr1 LBD that was positioned on the opposite side from the classical co-activator-binding site. Site-directed mutagenesis demonstrated that this region is critical for the activity of the Nurr1 LBD. Most mutations introduced in this region reduced or abolished transcriptional activity of the Nurr1 LBD, but mutation at lysine (K577) resulted in a drastically increased activity. Moreover, the activity of the Nurr1 LBD was shown to correlate with a propensity for proteasome-dependent degradation revealing a close association between activity and Nurr1 protein turnover. These data provide novel insights into the mechanisms of transcription via the Nurr1 LBD and identify an alternative co-activator-binding surface that is unique to the NR4A family of NRs.

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12

Solís, Miguel Ángel, Eduardo Santana, Norma Cristina Segovia та Carmen Sánchez-Torres. "The nuclear receptor Nurr1 regulates the expression and activity of PPARγ in human pro-inflammatory macrophages". Journal of Immunology 210, № 1_Supplement (2023): 168.13. http://dx.doi.org/10.4049/jimmunol.210.supp.168.13.

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Abstract Nurr1 is a member of the orphan nuclear receptor family NR4A that modulates inflammation in several cell lineages through inhibition of the NF-κB signaling pathway. Nurr1 was found to be able to interact with the peroxisome proliferator-activated receptor (PPAR)γ, as well as to be recruited to the PPARG promoter in LPS-activated microglial cells; however, the functional relationship between Nurr1 and PPARγ is not clearly established. Here, we aimed to investigate the role of Nurr1 on PPARγ activity in human macrophages. Blood monocytes were cultured with GM-CSF or M-CSF to generate pro- (GM-MDMs) and anti-inflammatory (M-MDMs) macrophages, respectively. GM-MDMs showed enhanced expression of both Nurr1 and PPARγ compared to M-MDMs, and they were preferentially located at the cytoplasmic (Nurr1) and nuclear (PPARγ) compartments. PPARγ activation in GM-MDMs with the agonist rosiglitazone did not modify Nurr1 expression. Conversely, Nurr1 activation with the agonist C-DIM12 increased PPARγ expression. This was concomitant with enhanced expression of two PPARγ target genes, CD36 and PLIN2, while silencing Nurr1 expression led to a decrease in the amounts of CD36 transcripts. Co-treatment of GM-MDMs with C-DIM12 and rosiglitazone synergistically enhanced the transcriptional activity of PPARγ, whereas C-DIM12 alone had no effect. PPARγ and Nurr1 agonists alone exerted anti-inflammatory effects on GM-MDMs, and also showed synergistic activity in combined form. In sum, our data suggests that Nurr1 positively regulates PPARγ activity at least partially through induction of PPARγ expression, which may represent a novel mechanism of Nurr1 targeting metabolic pathways and inflammation. Supported by grants from the Secretaría de Educación Pública-Consejo Nacional de Ciencia y Tecnología (SEP-CONACYT, #A1-S-9430)

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13

Safe, Stephen, Un-Ho Jin, Erik Hedrick, Alexandra Reeder, and Syng-Ook Lee. "Minireview: Role Of Orphan Nuclear Receptors in Cancer and Potential as Drug Targets." Molecular Endocrinology 28, no. 2 (2014): 157–72. http://dx.doi.org/10.1210/me.2013-1291.

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Abstract The nuclear orphan receptors for which endogenous ligands have not been identified include nuclear receptor (NR)0B1 (adrenal hypoplasia congenita critical region on chromosome X gene), NR0B2 (small heterodimer partner), NR1D1/2 (Rev-Erbα/β), NR2C1 (testicular receptor 2), NR2C2 (testicular receptor 4), NR2E1 (tailless), NR2E3 (photoreceptor-specific NR [PNR]), NR2F1 chicken ovalbumin upstream promoter transcription factor 1 (COUP-TFI), NR2F2 (COUP-TFII), NR2F6 (v-erbA-related protein), NR4A1 (Nur77), NR4A2 (Nurr1), NR4A3 (Nor1), and NR6A1 (GCNF). These receptors play essential roles in development, cellular homeostasis, and disease including cancer where over- or underexpression of some receptors has prognostic significance for patient survival. Results of receptor knockdown or overexpression in vivo and in cancer cell lines demonstrate that orphan receptors exhibit tumor-specific pro-oncogenic or tumor suppressor-like activity. For example, COUP-TFII expression is both a positive (ovarian) and negative (prostate and breast) prognostic factor for cancer patients; in contrast, the prognostic activity of adrenal hypoplasia congenita critical region on chromosome X gene for the same tumors is the inverse of COUP-TFII. Functional studies show that Nur77 is tumor suppressor like in acute leukemia, whereas silencing Nur77 in pancreatic, colon, lung, lymphoma, melanoma, cervical, ovarian, gastric, and some breast cancer cell lines induces one or more of several responses including growth inhibition and decreased survival, migration, and invasion. Although endogenous ligands for the orphan receptors have not been identified, there is increasing evidence that different structural classes of compounds activate, inactivate, and directly bind several orphan receptors. Thus, the screening and development of selective orphan receptor modulators will have important clinical applications as novel mechanism-based agents for treating cancer patients overexpressing one or more orphan receptors and also for combined drug therapies.

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14

Amoasii, Leonela, Efrain Sanchez-Ortiz, Teppei Fujikawa, Joel K. Elmquist, Rhonda Bassel-Duby, and Eric N. Olson. "NURR1 activation in skeletal muscle controls systemic energy homeostasis." Proceedings of the National Academy of Sciences 116, no. 23 (2019): 11299–308. http://dx.doi.org/10.1073/pnas.1902490116.

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Skeletal muscle plays a central role in the control of metabolism and exercise tolerance. Analysis of muscle enhancers activated after exercise in mice revealed the orphan nuclear receptor NURR1/NR4A2 as a prominent component of exercise-responsive enhancers. We show that exercise enhances the expression of NURR1, and transgenic overexpression of NURR1 in skeletal muscle enhances physical performance in mice. NURR1 expression in skeletal muscle is also sufficient to prevent hyperglycemia and hepatic steatosis, by enhancing muscle glucose uptake and storage as glycogen. Furthermore, treatment of obese mice with putative NURR1 agonists increases energy expenditure, improves glucose tolerance, and confers a lean phenotype, mimicking the effects of exercise. These findings identify a key role for NURR1 in governance of skeletal muscle glucose metabolism, and reveal a transcriptional link between exercise and metabolism. Our findings also identify NURR1 agonists as possible exercise mimetics with the potential to ameliorate obesity and other metabolic abnormalities.

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15

Pei, Liming, Antonio Castrillo, and Peter Tontonoz. "Regulation of Macrophage Inflammatory Gene Expression by the Orphan Nuclear Receptor Nur77." Molecular Endocrinology 20, no. 4 (2006): 786–94. http://dx.doi.org/10.1210/me.2005-0331.

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Abstract Members of the nuclear hormone receptor superfamily have emerged as important regulators of macrophage gene expression in inflammation and disease. Previous studies have shown that the lipid-activated receptors peroxisomal proliferator-activated receptor and liver X receptor inhibit nuclear factor-κB (NF-κB) signaling and inflammatory gene expression. We recently identified the NR4A subfamily of orphan nuclear receptors (Nur77/NR4A1, Nurr1/NR4A2, and NOR1/NR4A3) as lipopolysaccharide- and NF-κB-responsive genes in macrophages. However, the role of these transcription factors in macrophage gene expression is unknown. We demonstrate here that, in contrast to peroxisomal proliferator-activated receptor and liver X receptor, the role of NR4A receptors in macrophages is proinflammatory. Retroviral expression of Nur77 in macrophages leads to the transcriptional activation of multiple genes involved in inflammation, apoptosis, and cell cycle control. One particularly interesting Nur77-responsive gene is the inducible kinase IKKi/IKKε, an important component of the NF-κB signaling pathway. The IKKi promoter contains a functional NR4A binding site and is activated by all three NR4A receptors in transient transfection assays. Consistent with the activation of IKKi, expression of Nur77 in macrophages potentiates the induction of inflammatory gene expression in response to lipopolysaccharide. These results identify a new role for NR4A orphan nuclear receptors in the control of macrophage gene expression during inflammation.

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16

Sacchetti, Paola, Hélène Dwornik, Pierre Formstecher, Christophe Rachez, and Philippe Lefebvre. "Requirements for Heterodimerization between the Orphan Nuclear Receptor Nurr1 and Retinoid X Receptors." Journal of Biological Chemistry 277, no. 38 (2002): 35088–96. http://dx.doi.org/10.1074/jbc.m205816200.

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17

Achermann, J. C., and J. L. Jameson. "Human disorders caused by nuclear receptor gene mutations." Pure and Applied Chemistry 75, no. 11-12 (2003): 1785–96. http://dx.doi.org/10.1351/pac200375111785.

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The identification of naturally occurring nuclear receptor mutations highlights the critical role that many of these transcription factors play in human endocrine development and function. Inactivating mutations in the ligand-dependent nuclear receptors (TRβ, VDR, ERα, GR, MR, AR) are well characterized in patients with conditions such as androgen insensitivity syndrome (AIS) and vitamin D resistance. On the other hand, mutations in TRβ act in a dominant negative manner to cause hormone resistance. Inactivating mutations in orphan nuclear receptors have also been identified (PPARγ2, HNF4α, PNR, NURR1, SF1, DAX1, SHP) and reveal important developmental and metabolic functions for this group of receptors with previously elusive physiologic roles. In addition to loss of function mutations, receptor activation can result from mutations that confer constitutive activity or altered ligand responsiveness to the receptor (MR, AR), or from genetic duplication (DAX1) or the expression of fusion proteins (RARA, PPARγ1). Together, these naturally occurring mutations provide fascinating insight into key structural and functional receptor domains to reveal the diverse role nuclear receptors play in human biology.

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18

Pirih, Flavia Q., Alan Tang, Ibrahim C. Ozkurt, Jeanne M. Nervina, and Sotirios Tetradis. "Nuclear Orphan Receptor Nurr1 Directly Transactivates the Osteocalcin Gene in Osteoblasts." Journal of Biological Chemistry 279, no. 51 (2004): 53167–74. http://dx.doi.org/10.1074/jbc.m405677200.

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19

Guo, J., G. Zu, T. Zhou, J. Xing, and Z. Wang. "Clinicopathological significance of orphan nuclear receptor Nurr1 expression in gastric cancer." Clinical and Translational Oncology 17, no. 10 (2015): 788–94. http://dx.doi.org/10.1007/s12094-015-1305-z.

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20

Munoz-Tello, Paola, Sarah Mosure, Patrick Griffin, Venkatasubramanian Dharmarajan, Ian de Vera, and Douglas Kojetin. "Defining a Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1." Biophysical Journal 114, no. 3 (2018): 66a. http://dx.doi.org/10.1016/j.bpj.2017.11.411.

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21

Dubois, Celine, Bastian Hengerer, and Henri Mattes. "Identification of a Potent Agonist of the Orphan Nuclear Receptor Nurr1." ChemMedChem 1, no. 9 (2006): 955–58. http://dx.doi.org/10.1002/cmdc.200600078.

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22

Maijenburg, Marijke, Christian Gilissen, Joris Veltman, et al. "Nur77 and Nurr1, Two Novel Players In MSC Migration and Immune Function." Blood 116, no. 21 (2010): 3854. http://dx.doi.org/10.1182/blood.v116.21.3854.3854.

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Abstract Abstract 3854 Mesenchymal stromal cells (MSC) have a promising potential for cellular therapies, based on their immunomodulatory functions and their differentiation capacity. However, it remains unclear how MSC exert their functions and especially homing towards effector sites is poorly understood. An imperative for future therapies is to understand the process of MSC migration. We have previously shown that only 10–20% of culture-expanded MSC is capable to migrate in vitro, but these migratory cells can not be discriminated by markers. To identify genes specific for migratory MSC, we performed a gene expression study. Using a Transwell system (12mm pore size), migrating and non-migrating fetal bone marrow MSC (FBMSC) were physically separated and RNA was extracted. MSC that were exposed to a SDF-1 gradient (0.4mm pore size) and cultured FBMSC were included as controls. Only 9 genes were differentially expressed between migratory and non-migratory MSC. This set did not include cell surface markers that enable selection for a migratory subset. The nuclear orphan receptor family members Nurr1 and Nur77 were 2-fold upregulated in migratory MSC. These results were confirmed by RQ-PCR. Nurr1 and Nur77 are members of the NR4A nuclear orphan receptor family and were first described as early response transcription factors upon growth factor stimulation. We observed that the chemokine SDF-1 and the growth factor PDGF-BB increased the expression of Nur77 and Nurr1 in MSC. To investigate the role of Nur77 and Nurr1 in migration, FBMSC were transduced with lentivirus to achieve overexpression. Both overexpression of Nur77 and Nurr1 increased specific migration towards SDF-1 compared to Mock transduced FBMSC (n=4) (Nur77 mean 297% ± 186 relative to Mock, p≤ 0.014; Nurr1 mean 227% ± 79, p≤ 0.014). We previously described that cell cycle influences MSC migration, with S- and G2/M-phase of the cell cycle negatively influencing migration. In MSC cultures overexpressing Nur77 or Nurr1, the percentage of cells in S-phase of the cell cyle was significantly reduced (Nur77 15.2±7.8%, p≤0.007; Nurr1 16.4±9.1%, p≤0.039) compared to Mock-transduced cells (24.0±8.9%). Possibly, part of the Nur77 and Nurr1 effect is regulated by an effect on cell cycle. Together these data suggest that Nur77 and Nurr1 are involved in migration of MSC, which offers perspectives to modulate migration of MSC. Because these nuclear orphan receptors were not implied in MSC biology to date, we study their immunomodulatory effect. NR4A genes modulate immune responses in a variety of cells by influencing cytokine production. The immunomodulatory effect of MSC also seems to be based on secretion of a wide variety of cytokines, chemokines and growth factors. We therefore investigated whether Nur77 and Nurr1 play a role in cytokine and growth factor production in MSC. Compared to Mock transduced MSC, overexpression of Nur77 and Nurr1 in MSC resulted in increased basal levels of IL-6 protein (Nur77 3.4±2.4 fold, p≤0.007; Nurr1 3.8±3.1 ns) and IL-8 protein (Nur77 5.9±3.3 fold, p≤0.046; Nurr1 4.7±2.2, p≤0.031) and HGF mRNA expression (Nur77 5.4±0.8 fold, p≤0.021; Nurr1 3.4±1.18, p≤0.026). This was further enhanced upon stimulation with TNFα for 24hrs relative to the unstimulated Mock (IL-6 Mock 22.9±19.5 fold; Nur77 35.1±21.9 fold; Nurr1 35.8±24.1 fold; IL-8 Mock 58±37 fold; Nur77 160±141 fold; Nurr1 262±181 fold). HGF mRNA levels were slightly elevated by stimulation with IFNγ for 24hrs (Mock 1.8±1.6 fold; Nur77 7.0±3.8 fold; Nurr1 7.1±1.7 fold; ns). Expression levels of IDO1 and TGF-ß, also involved in immune modulation by MSC, were not influenced by Nur77 or Nurr1. In conclusion, we identified two novel genes involved in MSC migration. Intriguingly these genes are also involved in cytokine production, suggesting that the fraction with the best migratory capacity is able to modulate the immune response at its effector site distinct from the bulk of culture expanded MSC that lack migratory capacity. Modulation of Nur77 and Nurr1 expression in MSC could therefore offer perspectives to ameliorate cellular therapy. Disclosures: No relevant conflicts of interest to declare.

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Kim, Chun-Hyung, Baek-Soo Han, Jisook Moon, et al. "Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson’s disease." Proceedings of the National Academy of Sciences 112, no. 28 (2015): 8756–61. http://dx.doi.org/10.1073/pnas.1509742112.

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Parkinson’s disease (PD), primarily caused by selective degeneration of midbrain dopamine (mDA) neurons, is the most prevalent movement disorder, affecting 1–2% of the global population over the age of 65. Currently available pharmacological treatments are largely symptomatic and lose their efficacy over time with accompanying severe side effects such as dyskinesia. Thus, there is an unmet clinical need to develop mechanism-based and/or disease-modifying treatments. Based on the unique dual role of the nuclear orphan receptor Nurr1 for development and maintenance of mDA neurons and their protection from inflammation-induced death, we hypothesize that Nurr1 can be a molecular target for neuroprotective therapeutic development for PD. Here we show successful identification of Nurr1 agonists sharing an identical chemical scaffold, 4-amino-7-chloroquinoline, suggesting a critical structure–activity relationship. In particular, we found that two antimalarial drugs, amodiaquine and chloroquine stimulate the transcriptional function of Nurr1 through physical interaction with its ligand binding domain (LBD). Remarkably, these compounds were able to enhance the contrasting dual functions of Nurr1 by further increasing transcriptional activation of mDA-specific genes and further enhancing transrepression of neurotoxic proinflammatory gene expression in microglia. Importantly, these compounds significantly improved behavioral deficits in 6-hydroxydopamine lesioned rat model of PD without any detectable signs of dyskinesia-like behavior. These findings offer proof of principle that small molecules targeting the Nurr1 LBD can be used as a mechanism-based and neuroprotective strategy for PD.

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Wang, Tianhong, Qiong Jiang, Camie Chan, et al. "Inhibition of activation-induced death of dendritic cells and enhancement of vaccine efficacy via blockade of MINOR." Blood 113, no. 13 (2009): 2906–13. http://dx.doi.org/10.1182/blood-2008-08-176354.

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Abstract Activation of dendritic cells (DCs) leads to cell maturation, which is accompanied by a regulated pattern of gene expression changes. Two significant and contradictory consequences of DC activation are that, although activation is necessary for maximal T-cell stimulation, it also leads to the initiation of gene expression that results ultimately in cell death. We have identified a gene, MINOR (mitogen-inducible nuclear orphan receptor), that becomes highly up-regulated on activation and whose expression leads to apoptosis in mature DCs. MINOR is a member of the Nur77 family of nuclear orphan receptors, which includes Nur77 and Nurr1. Although Nur77 and Nurr1 are expressed in macrophages and DCs, their expression levels do not change on DC activation. We thus tested the hypothesis that induction of MINOR would lead to an activation-induced cell death in DCs and that its inhibition would increase the lifespan of DCs and improve their vaccine efficacy. To block natural expression of MINOR by DCs, we generated a lentiviral vector that expresses a small interfering RNA. Our results indicate that blockade of MINOR expression dramatically decreases apoptosis in DCs and suggest that this approach may be a novel means to improve the potency of ex vivo–generated DC vaccines.

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Park, Tae-Yoon, and Kwang-Soo Kim. "Chloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseases." Journal of Immunology 204, no. 1_Supplement (2020): 238.9. http://dx.doi.org/10.4049/jimmunol.204.supp.238.9.

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Abstract For over a half-century the anti-malarial drug chloroquine (CQ) has been used as a therapeutic agent, alone or in combination, to treat autoimmune diseases. However, neither the underlying mechanism(s) of action nor their molecular target(s) are well defined. The orphan nuclear receptor Nurr1 (also known as NR4A2) is an essential transcription factor affecting the development and maintenance of midbrain dopaminergic neurons. In this study, using in vitro T cell differentiation models, we demonstrate that CQ activates TREG cell differentiation and induces Foxp3 gene expression in a Nurr1-dependent manner. Remarkably, CQ appears to induce Nurr1 function by two distinct mechanisms: firstly, by direct binding to Nurr1’s ligand-binding domain and promoting its transcriptional activity and secondly by upregulation of Nurr1 expression through the CREB signaling pathway. In contrast, CQ suppressed gene expression and differentiation of pathogenic TH17 cells. Importantly, using a valid animal model of inflammatory bowel disease (IBD), we demonstrated that CQ promotes Foxp3 expression and differentiation of TREG cells in a Nurr1-dependent manner, leading to significant improvement of IBD-related symptoms. Taken together, these data suggest that CQ ameliorates autoimmune diseases via regulating Nurr1 function/expression and that Nurr1 is a promising target for developing effective therapeutics of human inflammatory autoimmune diseases.

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Wang, Zhu, Dinglan Wu, Chi-Fai Ng, et al. "Nuclear receptor profiling in prostatospheroids and castration-resistant prostate cancer." Endocrine-Related Cancer 25, no. 1 (2018): 35–50. http://dx.doi.org/10.1530/erc-17-0280.

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Nuclear receptors (NRs), which belong to a superfamily of transcription factors and consist of a total of 48 members in humans, govern the expression of genes involved in a board range of developmental, reproductive, metabolic and immunological programs. Given the significant importance of androgen receptor and a few known NRs in the progression of prostate cancer, we surveyed the expression profiles of the entire NR superfamily in three-dimensional cultured prostatospheroids derived from different prostate cancer cell lines and a tumor xenograft model of castration-resistant prostate cancer VCaP-CRPC by quantitative real-time RT-PCR. Our results revealed that prostatospheroids and castration-relapse VCaP-CRPC xenografts, both contained enriched populations of prostate cancer stem/progenitor-like cells (PCSCs), displayed distinct expression patterns of NRs. Intriguingly, most of these differentially expressed NRs were orphan NRs and showed upregulation. Pairwise analysis identified five orphan NRs (including RORβ, TLX, COUP-TFII, NURR1 and LRH-1) that showed common upregulation in both mRNA and protein levels in the prostatospheroids and castration-relapse VCaP-CRPC xenografts, and overexpression of these orphan NRs could increase cancer stem cell marker expressions and enhance spheroid formation capacity in prostate cancer cells, suggesting that these orphan NRs might perform positive roles in the growth regulation of PCSCs and castration-resistant prostate cancer. Together, our NR expression dataset not only revealed the distinct physiologic status and regulatory roles governed by the networks of specific NRs but also some of these identified orphan NRs could be the potential therapeutic targets for PCSCs or castration-resistant prostate cancer.

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Kitagawa, Hirochika, William J. Ray, Helmut Glantschnig, et al. "A Regulatory Circuit Mediating Convergence between Nurr1 Transcriptional Regulation and Wnt Signaling." Molecular and Cellular Biology 27, no. 21 (2007): 7486–96. http://dx.doi.org/10.1128/mcb.00409-07.

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ABSTRACT The orphan nuclear receptor Nurr1 is essential for the development and maintenance of midbrain dopaminergic neurons, the cells that degenerate during Parkinson's disease, by promoting the transcription of genes involved in dopaminergic neurotransmission. Since Nurr1 lacks a classical ligand-binding pocket, it is not clear which factors regulate its activity and how these factors are affected during disease pathogenesis. Since Wnt signaling via β-catenin promotes the differentiation of Nurr1+ dopaminergic precursors in vitro, we tested for functional interactions between these systems. We found that β-catenin and Nurr1 functionally interact at multiple levels. In the absence of β-catenin, Nurr1 is associated with Lef-1 in corepressor complexes. β-Catenin binds Nurr1 and disrupts these corepressor complexes, leading to coactivator recruitment and induction of Wnt- and Nurr1-responsive genes. We then identified KCNIP4/calsenilin-like protein as being responsive to concurrent activation by Nurr1 and β-catenin. Since KCNIP4 interacts with presenilins, the Alzheimer's disease-associated proteins that promote β-catenin degradation, we tested the possibility that KCNIP4 induction regulates β-catenin signaling. KCNIP4 induction limited β-catenin activity in a presenilin-dependent manner, thereby serving as a negative feedback loop; furthermore, Nurr1 inhibition of β-catenin activity was absent in PS1−/− cells or in the presence of small interfering RNAs specific to KCNIP4. These data describe regulatory convergence between Nurr1 and β-catenin, providing a mechanism by which Nurr1 could be regulated by Wnt signaling.

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Ariës, Ingrid M., Rosanna van den Dungen, Rob Pieters, and Monique L. Den Boer. "The NR4A Orphan Nuclear Receptors Do Not Confer Prednisolone resistance In Pediatric Acute Lymphoblastic Leukemia." Blood 122, no. 21 (2013): 3870. http://dx.doi.org/10.1182/blood.v122.21.3870.3870.

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Abstract Background Resistance against the glucocorticoid prednisolone still remains an obstacle for treatment of pediatric precursor B acute lymphoblastic leukemia (BCP-ALL) at initial diagnosis and even more after relapse. The molecular mechanisms behind prednisolone resistance in pediatric BCP-ALL is poorly defined. The NR4A family, consisting of NR4A1 (Nur77), NR4A2 (Nurr1) and NR4A3 (Nor1), are orphan nuclear receptors, which antagonize the glucocorticoid receptor. We hypothesized that upregulated NR4A family expression is responsible for prednisolone resistance in BCP-ALL. Methods Newly diagnosed pediatric acute lymphoblastic leukemia patients’ cells were isolated from bone marrow aspirates and only samples with ≥ 90% leukemic blasts were used in the present study. Gene expression microarrays of 178 BCP-ALL patients tested for in vitro prednisolone resistance were analyzed with Limma R Package in the statistical environment R, version 2.15.0. Microarray expression levels were confirmed using qRT-PCR. Nur77, Nurr1 and Nor1 protein expression in primary BCP-ALL patients’ were assessed with reverse phase protein array. Leukemic patients’ cells were transfected with labeled siRNA against NR4A1, NR4A2, and NR4A3, simultaneously, or with labeled siScrl, using the transfection reagent Dharmafect 4. Hereafter, cytotoxicity to prednisolone was determined by the in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) drug-resistance assay. Furthermore, viability of transfected cells was counted by trypan blue exclusion assay and cells were harvested after 72 hours of culture for RNA and protein isolation. Knockdown was confirmed with qRT-PCR and Western blot. Results In this study of 178 precursor BCP-ALL patients we discovered a 3.0-fold (p=0.007) raise in NR4A1, NR4A2, and NR4A3 microarray mRNA expression in in vitro prednisolone resistant compared to sensitive BCP-ALL patients’ cells, which was confirmed by qRT-PCR. In addition, reverse phase protein array identified a 2.7-fold (p<0.001) increased Nurr1 (NR4A1) and Nur77 (NR4A2) protein expression in in vitro prednisolone resistant compared to sensitive BCP-ALL patients’ cells. Nurr1 and Nur77 protein levels were overall 5-fold (p<0.001) higher in BCP-ALL patients compared to normal bone marrow cells. Simultaneous siRNA mediated knockdown of Nur77, Nurr1 and Nor1 in pediatric leukemic patients’ ALL cells decreased leukemic cell survival by 25.4±11.1% (p=0.029), but did not sensitize these cells to prednisolone (n=4). Conclusion The NR4A family members are higher expressed in prednisolone resistant ALL patients’ cells. Although literature describes an antagonizing effect of the NR4A family members on the glucocorticoid receptor, we could not find a functional contribution of the NR4A family to prednisolone resistance in BCP-ALL. We furthermore discovered an increased NR4A family expression in leukemic cells of BCP-ALL patients compared to normal bone marrow cells. Targeting of NR4A genes impaired cell survival. However, compensatory mechanisms exist and consequently all three NR4A members need to be targeted simultaneously to diminish cell survival. These data therefore suggest that the NR4A genes are not suitable to reverse prednisolone resistance nor to kill leukemic cells by targeted drugs. Disclosures: No relevant conflicts of interest to declare.

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Perlmann, Thomas, and �sa Wall�n-Mackenzie. "Nurr1, an orphan nuclear receptor with essential functions in developing dopamine cells." Cell and Tissue Research 318, no. 1 (2004): 45–52. http://dx.doi.org/10.1007/s00441-004-0974-7.

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de Vera, Ian Mitchelle S., Paola Munoz-Tello, Jie Zheng, et al. "Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1." Structure 27, no. 1 (2019): 66–77. http://dx.doi.org/10.1016/j.str.2018.10.002.

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Meir, Tomer, Karina Durlacher, Zheng Pan, et al. "Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription." Kidney International 86, no. 6 (2014): 1106–15. http://dx.doi.org/10.1038/ki.2014.215.

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Sirin, Olga, Georgi L. Lukov, Rui Mao, Orla M. Conneely, and Margaret A. Goodell. "The orphan nuclear receptor Nurr1 restricts the proliferation of haematopoietic stem cells." Nature Cell Biology 12, no. 12 (2010): 1213–19. http://dx.doi.org/10.1038/ncb2125.

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Nordzell, Mariette, Piia Aarnisalo, Gérard Benoit, Diogo S. Castro, and Thomas Perlmann. "Defining an N-terminal activation domain of the orphan nuclear receptor Nurr1." Biochemical and Biophysical Research Communications 313, no. 1 (2004): 205–11. http://dx.doi.org/10.1016/j.bbrc.2003.11.079.

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Wu, Yimin, Sagar Ghosh, Yoshihiro Nishi, Toshihiko Yanase, Hajime Nawata, and Yanfen Hu. "The Orphan Nuclear Receptors NURR1 and NGFI-B Modulate Aromatase Gene Expression in Ovarian Granulosa Cells: A Possible Mechanism for Repression of Aromatase Expression upon Luteinizing Hormone Surge." Endocrinology 146, no. 1 (2005): 237–46. http://dx.doi.org/10.1210/en.2004-0889.

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Ovarian granulosa cells play pivotal roles in many aspects of ovary functions including folliculogenesis and steroidogenesis. In response to FSH and LH, the elevation of intracellular cAMP level in granulosa cells leads to activation of multiple ovarian genes. Here, we report findings from a genome-wide study of the cAMP-responsive gene expression profiles in a human granulosa-like tumor cell line, KGN. The study identified 140 genes that are either activated or repressed by 2-fold or greater after stimulation by the adenylyl cyclase activator forskolin. The induction patterns of some cAMP-responsive genes were further analyzed by quantitative real-time PCR. Consistent with previous observations, the LH-responsive genes, such as the nuclear receptor 4A subfamily (NURR1, NGFI-B, and NOR-1), were rapidly but transiently induced, whereas the FSH-responsive gene CYP19 encoding aromatase was induced in a delayed fashion. Interestingly, ectopic expression of NURR1 or NGFI-B severely attenuated the cAMP-responsive activation of the ovary-specific aromatase promoter. Reduction of the endogenous NURR1 or NGFI-B by small interfering RNA significantly elevated aromatase gene expression. The cis-elements responsible for NURR1/NGFI-B-mediated repression were mapped to the minimal aromatase promoter sequence that confers camp responsiveness. Furthermore, the DNA-binding domain of NURR1 was required for the repression. Taken together, these results strongly suggest a causal relationship between the rapid decline of aromatase mRNA and induction of nuclear receptor subfamily 4A expression, which concomitantly occur upon LH surge at the later stages of ovarian follicular development.

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Shaik, Shahensha, Ha’reanna Campbell, and Christopher Williams. "NURR1 Is Differentially Expressed in Breast Cancer According to Patient Racial Identity and Tumor Subtype." BioMedInformatics 2, no. 4 (2022): 680–91. http://dx.doi.org/10.3390/biomedinformatics2040045.

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Breast carcinoma (BCa) remains the second most common cause of cancer-related death among American women. Whereas estrogen receptor (ER) expression is typically regarded as a favorable prognostic indicator, a significant proportion of ER(+) patients still experience either de novo or acquired endocrine resistance. Previously, we have shown that the loss of orphan nuclear receptor NURR1 expression is associated with neoplastic transformation of the breast epithelium and shorter relapse-free survival (RFS) among systemically treated breast cancer (BCa) patients. Here, we further ascertain the prognostic value of NURR1 in BCa, and its differential expression among Black and White female BCa patients. We assessed the expression of NURR1 mRNA in BCa patients using the Cancer Genome Atlas (TGCA) and compared the occurrence of basal-like cancer and luminal A breast cancer subtypes. Expression levels were further stratified according to racial identity of the patient. We next assessed the correlation of NURR1 expression with Oncotype DX prognostic markers, and the association of NURR1 expression with relapse free survival in patients treated with endocrine therapy. Our study shows that NURR1 mRNA expression is differentially correlated with luminal A vs. basal-like cancer BCa and is predictive of poor relapse-free survival, confirming a similar trend observed in our previous studies using microarray data. NURR1 expression was positively correlated with expression of Oncotype DX biomarkers associated with estrogen responsiveness, while being inversely correlated with biomarkers associated with cell proliferation. Furthermore, we observed that NURR1 expression was positively associated with greater relapse-free survival at 5 years among patients treated with endocrine therapy. Interestingly, we found that among Black women with luminal A BCa, NURR1 expression was repressed in comparison to White women with the same subtype.

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Aarnisalo, Piia, Chae-Hee Kim, Jae Woon Lee, and Thomas Perlmann. "Defining Requirements for Heterodimerization between the Retinoid X Receptor and the Orphan Nuclear Receptor Nurr1." Journal of Biological Chemistry 277, no. 38 (2002): 35118–23. http://dx.doi.org/10.1074/jbc.m201707200.

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Willems, Sabine, Julia Ohrndorf, Whitney Kilu, Jan Heering, and Daniel Merk. "Fragment-like Chloroquinolineamines Activate the Orphan Nuclear Receptor Nurr1 and Elucidate Activation Mechanisms." Journal of Medicinal Chemistry 64, no. 5 (2021): 2659–68. http://dx.doi.org/10.1021/acs.jmedchem.0c01779.

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Jiang, H., and M. Xiang. "Subtype Specification of GABAergic Amacrine Cells by the Orphan Nuclear Receptor Nr4a2/Nurr1." Journal of Neuroscience 29, no. 33 (2009): 10449–59. http://dx.doi.org/10.1523/jneurosci.3048-09.2009.

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Inamoto, Teruo, Sabitha Papineni, Sudhakar Chintharlapalli, et al. "A NOVEL ACTIVATOR OF THE ORPHAN NUCLEAR RECEPTOR Nurr1 INHIBITS BLADDER TUMOR GROWTH." Journal of Urology 179, no. 4S (2008): 369. http://dx.doi.org/10.1016/s0022-5347(08)61081-2.

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Sacchetti, Paola, Rodolphe Carpentier, Pascaline Ségard, Cécile Olivé-Cren, and Philippe Lefebvre. "Multiple signaling pathways regulate the transcriptional activity of the orphan nuclear receptor NURR1." Nucleic Acids Research 34, no. 19 (2006): 5515–27. http://dx.doi.org/10.1093/nar/gkl712.

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Lammi, Johanna, Johanna Huppunen, and Piia Aarnisalo. "Regulation of the Osteopontin Gene by the Orphan Nuclear Receptor NURR1 in Osteoblasts." Molecular Endocrinology 18, no. 6 (2004): 1546–57. http://dx.doi.org/10.1210/me.2003-0247.

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Arimatsu, Yasuyoshi, Mami Ishida, Takeshi Kaneko, Sachiyo Ichinose, and Akira Omori. "Organization and development of corticocortical associative neurons expressing the orphan nuclear receptor Nurr1." Journal of Comparative Neurology 466, no. 2 (2003): 180–96. http://dx.doi.org/10.1002/cne.10875.

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Munoz-Tello, Paola, Hua Lin, Pasha Khan, Ian Mitchelle S. de Vera, Theodore M. Kamenecka, and Douglas J. Kojetin. "Assessment of NR4A Ligands That Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1." Journal of Medicinal Chemistry 63, no. 24 (2020): 15639–54. http://dx.doi.org/10.1021/acs.jmedchem.0c00894.

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Zhang, Tao, Pingping Wang, Haigang Ren, Jun Fan, and Guanghui Wang. "NGFI-B Nuclear Orphan Receptor Nurr1 Interacts with p53 and Suppresses Its Transcriptional Activity." Molecular Cancer Research 7, no. 8 (2009): 1408–15. http://dx.doi.org/10.1158/1541-7786.mcr-08-0533.

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Zetterström, R. H., L. Solomin, T. Mitsiadis, L. Olson, and T. Perlmann. "Retinoid X receptor heterodimerization and developmental expression distinguish the orphan nuclear receptors NGFI-B, Nurr1, and Nor1." Molecular Endocrinology 10, no. 12 (1996): 1656–66. http://dx.doi.org/10.1210/mend.10.12.8961274.

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Zetterstrom, R. H. "Retinoid X receptor heterodimerization and developmental expression distinguish the orphan nuclear receptors NGFI-B, Nurr1, and Nor1." Molecular Endocrinology 10, no. 12 (1996): 1656–66. http://dx.doi.org/10.1210/me.10.12.1656.

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Wang, Jian, Jing Yang, Ying Zou, Guo-Liang Huang, and Zhi-Wei He. "Orphan Nuclear Receptor Nurr1 as a Potential Novel Marker for Progression in Human Prostate Cancer." Asian Pacific Journal of Cancer Prevention 14, no. 3 (2013): 2023–28. http://dx.doi.org/10.7314/apjcp.2013.14.3.2023.

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Mix, Kimberlee S., Mukundan G. Attur, Hayf Al-Mussawir, Steven B. Abramson, Constance E. Brinckerhoff, and Evelyn P. Murphy. "Transcriptional Repression of Matrix Metalloproteinase Gene Expression by the Orphan Nuclear Receptor NURR1 in Cartilage." Journal of Biological Chemistry 282, no. 13 (2007): 9492–504. http://dx.doi.org/10.1074/jbc.m608327200.

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de Vera, Ian Mitchelle S., Pankaj K. Giri, Paola Munoz-Tello, et al. "Identification of a Binding Site for Unsaturated Fatty Acids in the Orphan Nuclear Receptor Nurr1." ACS Chemical Biology 11, no. 7 (2016): 1795–99. http://dx.doi.org/10.1021/acschembio.6b00037.

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Shang, Wenjing, Xiuming Liang, Shuyan Li, et al. "Orphan nuclear receptor Nurr1 promotes Helicobacter pylori-associated gastric carcinogenesis by directly enhancing CDK4 expression." EBioMedicine 53 (March 2020): 102672. http://dx.doi.org/10.1016/j.ebiom.2020.102672.

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