1,282 results on '"Nuclear Receptor Subfamily 4, Group A, Member 2"'
Search Results
2. Timing of MeCP2 Expression Determines Midbrain Dopamine Neuron Phenotype Specification
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Xi-Biao He, Fang Guo, Kexuan Li, Jiaqing Yan, and Sang-Hun Lee
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Mice ,Phenotype ,Neural Stem Cells ,Tyrosine 3-Monooxygenase ,Mesencephalon ,Methyl-CpG-Binding Protein 2 ,Dopaminergic Neurons ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Animals ,Molecular Medicine ,Cell Differentiation ,Cell Biology ,Developmental Biology - Abstract
Midbrain dopamine (DA) neurons are associated with locomotor and psychiatric disorders. DA phenotype is specified in ancestral neural precursor cells (NPCs) and maintained throughout neuronal differentiation. Here we show that endogenous expression of MeCP2 coincides with DA phenotype specification in mouse mesencephalon, and premature expression of MeCP2 prevents in vitro cultured NPCs from acquiring DA phenotype through interfering NURR1 transactivation of DA phenotype genes. By contrast, ectopic MeCP2 expression does not disturb DA phenotype in the DA neurons. By analyzing the dynamic change of DNA methylation along DA neuronal differentiation at the promoter of DA phenotype gene tyrosine hydroxylase (Th), we show that Th expression is determined by TET1-mediated de-methylation of NURR1 binding sites within Th promoter. Chromatin immunoprecipitation assays demonstrate that premature MeCP2 dominates the DNA binding of the corresponding sites thereby blocking TET1 function in DA NPCs, whereas TET1-mediated de-methylation prevents excessive MeCP2 binding in DA neurons. The significance of temporal DNA methylation status is further confirmed by targeted methylation/demethylation experiments showing that targeted de-methylation in DA NPCs protects DA phenotype specification from ectopic MeCP2 expression, whereas targeted methylation disturbs phenotype maintenance in MeCP2-overexpressed DA neurons. These findings suggest the appropriate timing of MeCP2 expression as a novel determining factor for guiding NPCs into DA lineage.
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- 2022
3. Effects of bis (2‐butoxyethyl) phthalate on adrenocortical function in male rats in puberty partially via down‐regulating <scp>NR5A1</scp> / <scp>NR4A1</scp> / <scp>NR4A2</scp> pathways
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Miaoqing Liu, Haiqiong Chen, Haipeng Dai, Yiyan Wang, Jingjing Li, Fuhong Tian, Zhongrong Li, and Ren‐Shan Ge
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Male ,Health, Toxicology and Mutagenesis ,Phthalic Acids ,General Medicine ,Management, Monitoring, Policy and Law ,Steroidogenic Factor 1 ,Toxicology ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Rats ,Rats, Sprague-Dawley ,Sirtuin 1 ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Nuclear Receptor Subfamily 4, Group A, Member 1 ,Animals ,Steroids ,Sexual Maturation ,Corticosterone - Abstract
Phthalates may interfere with the biosynthesis of steroid hormones in the adrenal cortex. Bis (2-butoxyethyl) phthalate (BBOP) is a phthalate containing oxygen atoms in the alcohol moiety. In this study, 35-day-old male Sprague-Dawley rats were daily gavaged with BBOP (0, 10, 100, 250, and 500 mg/kg body weight) for 21 days. BBOP did not affect the weight of body and adrenal glands. BBOP significantly reduced serum corticosterone levels at 250 and 500 mg/kg, and lowered aldosterone level at 500 mg/kg without affecting adrenocorticotropic hormone. BBOP did not alter the thickness of the adrenal cortex. BBOP significantly down-regulated the expression of steroidogenesis-related genes (Scarb1, Star, Cyp11a1, Cyp21, Cyp11b1, Cyp11b2, Nr5a1, Nr4a1, and Nr4a2) and proteins, and antioxidant enzymes (Sod1, Sod2, Gpx1, and Cat) and their proteins, while up-regulating the expression of Mc2r and Agtr1a at various doses. BBOP reduced the phosphorylation of AKT1, AKT2, and ERK1/2, as well as the levels of SIRT1 and PGC1α without affecting the phosphorylation of AMPK. BBOP significantly induced the production of reactive oxygen species and apoptosis rate in H295R cells at 100 μM and higher after 24 h of treatment. In conclusion, male rats exposed to BBOP in puberty have significant reduction of steroid biosynthesis with a potential mechanism that is involved in the decrease in the phosphorylation of AKT1, AKT2, ERK1/2, as well as SIRT1 and PGC1α and increase in ROS.
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- 2022
4. Structural, molecular hybridization and network based identification of miR-373-3p and miR-520e-3p as regulators of NR4A2 human gene involved in neurodegeneration
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Jitender Singh, Ashvinder Raina, Namrata Sangwan, Arushi Chauhan, and Pramod K Avti
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MicroRNAs ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Genetics ,Humans ,Molecular Medicine ,RNA, Messenger ,General Medicine ,5' Untranslated Regions ,3' Untranslated Regions ,Biochemistry ,Transcription Factors - Abstract
MicroRNAs (miRNAs) are short non-coding RNAs with a 22 nucleotide sequence length and docks to the 3'UTR/5'UTR of the gene to regulate their mRNA translation to play a vital role in neurodegenerative diseases. The Nuclear Receptor gene (NR4A2), a transcription factor, and a steroid-thyroid hormone retinoid receptor is involved in neural development, memory formation, dopaminergic neurotransmission, and cellular protection from inflammatory damage. Therefore, recognizing the miRNAs is essential to efficiently target the 3'UTR/5'UTR of the NR4A2 gene and regulate neurodegeneration. Highly stabilized top miRNA-mRNA hybridized structures, their homologs, and identification of the best structures based on their least free energy were evaluated using
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- 2022
5. Potential role of inducible GPR3 expression under stimulated T cell conditions
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Hiroko Shiraki, Shigeru Tanaka, Yun Guo, Kana Harada, Izumi Hide, Tomoharu Yasuda, and Norio Sakai
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Mice, Knockout ,Pharmacology ,GPR3 ,endocrine system ,T-Lymphocytes ,NR4A2 ,Gene Expression ,T cell ,RM1-950 ,Lymphocyte Activation ,Cell Line ,Receptors, G-Protein-Coupled ,cAMP ,Gαs protein ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Chromogranins ,Cyclic AMP ,GTP-Binding Protein alpha Subunits, Gs ,Animals ,Molecular Medicine ,Therapeutics. Pharmacology - Abstract
G protein-coupled receptor 3 (GPR3) constitutively activates Gαs proteins without any ligands and is predominantly expressed in neurons. Since the expression and physiological role of GPR3 in immune cells is still unknown, we examined the possible role of GPR3 in T lymphocytes. The expression of GPR3 was upregulated 2 h after phorbol 12-myristate 13-acetate (PMA)/ionomycin stimulation and was sustained in Jurkat cells, a human T lymphocyte cell line. In addition, the expression of nuclear receptor 4 group A member 2 (NR4A2) was highly modulated by GPR3 expression. Additionally, GPR3 expression was linked with the transcriptional promoter activity of NR4A in Jurkat cells. In mouse CD4+ T cells, transient GPR3 expression was induced immediately after the antigen receptor stimulation. However, the expression of NR4A2 was not modulated in CD4+ T cells from GPR3-knockout mice after stimulation, and the population of Treg cells in thymocytes and splenocytes was not affected by GPR3 knockout. By contrast, spontaneous effector activation in both CD4+ T cells and CD8+ T cells was observed in GPR3-knockout mice. In summary, GPR3 is immediately induced by T cell stimulation and play an important role in the suppression of effector T cell activation.
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- 2022
6. Regulation of CCR4-NOT complex deadenylase activity and cellular responses by MK2-dependent phosphorylation of CNOT2
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Toru Suzuki, Miyuki Hoshina, Saori Nishijima, Naosuke Hoshina, Chisato Kikuguchi, Takumi Tomohiro, Akira Fukao, Toshinobu Fujiwara, and Tadashi Yamamoto
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Receptors, CCR4 ,phosphorylation ,RNA Stability ,stress response ,Intracellular Signaling Peptides and Proteins ,CCR4-NOT complex ,Cell Biology ,Protein Serine-Threonine Kinases ,Cell Line ,MK2 ,Enzyme Activation ,Repressor Proteins ,mRNA decay ,Osmotic Pressure ,Stress, Physiological ,Multiprotein Complexes ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Humans ,RNA, Messenger ,Molecular Biology ,Research Article ,Research Paper - Abstract
CCR4-NOT complex-mediated mRNA deadenylation serves critical functions in multiple biological processes, yet how this activity is regulated is not fully understood. Here, we show that osmotic stress induces MAPKAPK-2 (MK2)-mediated phosphorylation of CNOT2. Programmed cell death is greatly enhanced by osmotic stress in CNOT2-depleted cells, indicating that CNOT2 is responsible for stress resistance of cells. Although wild-type (WT) and non-phosphorylatable CNOT2 mutants reverse this sensitivity, a phosphomimetic form of CNOT2, in which serine at the phosphorylation site is replaced with glutamate, does not have this function. We also show that mRNAs have elongated poly(A) tails in CNOT2-depleted cells and that introduction of CNOT2 WT or a non-phosphorylatable mutant, but not phosphomimetic CNOT2, renders their poly(A) tail lengths comparable to those in control HeLa cells. Consistent with this, the CCR4-NOT complex containing phosphomimetic CNOT2 exhibits less deadenylase activity than that containing CNOT2 WT. These data suggest that CCR4-NOT complex deadenylase activity is regulated by post-translational modification, yielding dynamic control of mRNA deadenylation.
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- 2022
7. The lncRNA LUCAT1 is elevated in inflammatory disease and restrains inflammation by regulating the splicing and stability of NR4A2
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Tim Vierbuchen, Shiuli Agarwal, John L. Johnson, Liraz Galia, Xuqiu Lei, Karina Stein, David Olagnier, Karoline I. Gaede, Christian Herzmann, Christian K. Holm, Holger Heine, Athma Pai, Aisling O’Hara Hall, Kasper Hoebe, and Katherine A. Fitzgerald
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Inflammation ,Cell Proliferation/genetics ,Multidisciplinary ,Nuclear Receptor Subfamily 4, Group A, Member 2/genetics ,Cell Movement ,Inflammation/genetics ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Cell Movement/genetics ,Humans ,Receptors, Cytoplasmic and Nuclear ,RNA, Long Noncoding ,RNA, Long Noncoding/genetics ,Cell Proliferation - Abstract
The nuclear long non-coding RNA LUCAT1 has previously been identified as a negative feedback regulator of type I interferon and inflammatory cytokine expression in human myeloid cells. Here, we define the mechanistic basis for the suppression of inflammatory gene expression by LUCAT1. Using comprehensive identification of RNA-binding proteins by mass spectrometry as well as RNA immunoprecipitation, we identified proteins important in processing and alternative splicing of mRNAs as LUCAT1-binding proteins. These included heterogeneous nuclear ribonucleoprotein C, M, and A2B1. Consistent with this finding, cells lacking LUCAT1 have altered splicing of selected immune genes. In particular, upon lipopolysaccharide stimulation, the splicing of the nuclear receptor 4A2 (NR4A2) gene was particularly affected. As a consequence, expression of NR4A2 was reduced and delayed in cells lacking LUCAT1. NR4A2-deficient cells had elevated expression of immune genes. These observations suggest that LUCAT1 is induced to control the splicing and stability of NR4A2, which is in part responsible for the anti-inflammatory effect of LUCAT1. Furthermore, we analyzed a large cohort of patients with inflammatory bowel disease as well as asthma and chronic obstructive pulmonary disease. In these patients, LUCAT1 levels were elevated and in both diseases, positively correlated with disease severity. Collectively, these studies define a key molecular mechanism of LUCAT1-dependent immune regulation through post-transcriptional regulation of mRNAs highlighting its role in the regulation of inflammatory disease.
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- 2022
8. Integrative analysis reveals structural basis for transcription activation of Nurr1 and Nurr1-RXRα heterodimer
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Mohan Zhao, Na Wang, Yaoting Guo, Jingwen Li, Yue Yin, Yan Dong, Jiabin Zhu, Chao Peng, Tingting Xu, and Jinsong Liu
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Transcriptional Activation ,Retinoid X Receptor alpha ,Multidisciplinary ,Protein Domains ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Response Elements - Abstract
Orphan nuclear receptor Nurr1 plays important roles in the progression of various diseases, including Parkinson’s disease, neuroinflammation, Alzheimer’s disease, and multiple sclerosis. It can recognize DNA as a monomer or heterodimer with retinoid X receptor α (RXRα). But the molecular mechanism of its transcriptional activity regulation is still largely unknown. Here we obtained a crystal structure of monomer Nurr1 (DNA- and ligand-binding domains, DBD and LBD) bound to NGFI-B response element. The structure exhibited two different forms with distinct DBD orientations, unveiling the conformational flexibility of nuclear receptor monomer. We then generated an integrative model of Nurr1-RXRα heterodimer. In the context of heterodimer, the structural flexibility of Nurr1 would contribute to its transcriptional activity modulation. We demonstrated that the DNA sequence may specifically modulate the transcriptional activity of Nurr1 in the absence of RXRα agonist, but the modulation can be superseded when the agonist binds to RXRα. Together, we propose a set of signaling pathways for the constitutive transcriptional activation of Nurr1 and provide molecular mechanisms for therapeutic discovery targeting Nurr1 and Nurr1-RXRα heterodimer.
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- 2022
9. α-Synuclein Induces the GSK-3-Mediated Phosphorylation and Degradation of NURR1 and Loss of Dopaminergic Hallmarks
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Isabel Lastres-Becker, Leonidas Stefanis, Ángel Juan García-Yagüe, Antonio Cuadrado, Demetrios K. Vassilatis, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Comunidad de Madrid, and UAM. Departamento de Bioquímica
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Parkinson's disease ,Medicina ,Dopamine ,Neuroscience (miscellaneous) ,Down-Regulation ,Substantia nigra ,Dopaminergic neurons ,Article ,Glycogen Synthase Kinase 3 ,Cellular and Molecular Neuroscience ,GSK-3 ,Cell Line, Tumor ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,medicine ,Humans ,Phosphorylation ,Glycogen synthase ,Dopaminergic phenotype ,Synucleinopathies ,biology ,Pars compacta ,Chemistry ,Dopaminergic ,medicine.disease ,Cell biology ,Gene Expression Regulation ,nervous system ,Neurology ,alpha-Synuclein ,Parkinson’s disease ,biology.protein ,Transcription - Abstract
© The Author(s) 2021., In Parkinson’s disease, the dysfunction of the dopaminergic nigrostriatal tract involves the loss of function of dopaminergic neurons of the substantia nigra pars compacta followed by death of these neurons. The functional recovery of these neurons requires a deep knowledge of the molecules that maintain the dopaminergic phenotype during adulthood and the mechanisms that subvert their activity. Previous studies have shown that transcription factor NURR1, involved in differentiation and maintenance of the dopaminergic phenotype, is downregulated by α-synuclein (α-SYN). In this study, we provide a mechanistic explanation to this finding by connecting α-SYN-induced activation of glycogen synthase kinase-3 (GSK-3) with NURR1 phosphorylation followed by proteasomal degradation. The use of sequential deletion mutants and single point mutants of NURR1 allowed the identification of a domain comprising amino acids 123-PSSPPTPSTPS-134 that is targeted by GSK-3 and leads to subsequent ubiquitination and proteasome degradation. This study provides a detailed analysis of the regulation of NURR1 stability by phosphorylation in synucleinopathies such as Parkinson’s disease., This study was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) (grant PID2019-110061RB-I00 for A.C and PID2019-105600RB-I00 for I.L.B.) and The Autonomous Community of Madrid (grant B2017/ BMD-3827 for A.C. and B2017/BMD-3813 for I.L.B.).
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- 2021
10. NR4A2 expression is not altered in placentas from cases of growth restriction or preeclampsia, but is reduced in hypoxic cytotrophoblast
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Natasha Pritchard, Natasha de Alwis, Susan P. Walker, Katie M. Groom, Joanne M Said, Owen Stock, Natalie J. Hannan, Scott Petersen, Stefan C. Kane, Amanda Henry, Tu'uhevaha J Kaitu'u-Lino, Natalie K Binder, Sally Beard, Sean Seeho, and Stephen Tong
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Adult ,Male ,Placental growth factor ,Placenta Diseases ,Placenta ,Science ,Biology ,Predictive markers ,Antioxidants ,Article ,Preeclampsia ,Andrology ,Pre-Eclampsia ,Pregnancy ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Genetics research ,medicine ,Humans ,Gene silencing ,RNA, Messenger ,Endothelial dysfunction ,Hypoxia ,Receptor ,Placenta Growth Factor ,Inflammation ,Fetal Growth Retardation ,Multidisciplinary ,Cytotrophoblast ,Intrauterine growth ,Hypoxia (medical) ,medicine.disease ,Trophoblasts ,Oxidative Stress ,medicine.anatomical_structure ,Medicine ,Female ,Gene expression ,medicine.symptom - Abstract
Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) transcripts are elevated in the circulation of individuals whose pregnancies are complicated by preterm fetal growth restriction (FGR). In this paper, we show that the cases with preeclampsia (PE) have increased circulating NR4A2 transcripts compared to those with normotensive FGR. We aimed to establish whether the dysfunctional placenta mirrors the increase in NR4A2 transcripts and further, to uncover the function of placental NR4A2. NR4A2 expression was detected in preterm and term placental tissue; expressed higher at term. NR4A2 mRNA expression and protein were not altered in placentas from preterm FGR or PE pregnancies. Hypoxia (1% O2 compared to 8% O2) significantly reduced cytotrophoblast NR4A2 mRNA expression, but not placental explant NR4A2 expression. Silencing cytotrophoblast NR4A2 expression under hypoxia (via short interfering (si)RNAs) did not alter angiogenic Placental Growth Factor, nor anti-angiogenic sFlt-1 mRNA expression or protein secretion, but increased expression of cellular antioxidant, oxidative stress, inflammatory, and growth genes. NR4A2 expression was also not altered in a model of tumour necrosis factor-α-induced endothelial dysfunction, or with pravastatin treatment. Further studies are required to identify the origin of the circulating transcripts in pathological pregnancies, and investigate the function of placental NR4A2.
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- 2021
11. Aberrant mTOR/autophagy/Nurr1 signaling is critical for TSC-associated tumor development
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Ying Wang, Chunjia Li, Xiaojun Zha, Hongbing Zhang, Zhongdong Hu, Yan-Zhuo Zhang, and Cheng-Ai Wu
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Genetically modified mouse ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.disease_cause ,Biochemistry ,Tuberous Sclerosis Complex 1 Protein ,Mice ,Tuberous sclerosis ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Tuberous Sclerosis Complex 2 Protein ,Autophagy ,medicine ,Animals ,Molecular Biology ,Mechanistic target of rapamycin ,Cells, Cultured ,PI3K/AKT/mTOR pathway ,Mice, Knockout ,biology ,TOR Serine-Threonine Kinases ,Cell Biology ,medicine.disease ,Kidney Neoplasms ,nervous system diseases ,medicine.anatomical_structure ,Cancer research ,biology.protein ,TSC1 ,TSC2 ,Carcinogenesis ,Signal Transduction - Abstract
Tuberous sclerosis complex (TSC), an inherited neurocutaneous disease, is caused by mutations in either the TSC1 or TSC2 gene. This genetic disorder is characterized by the growth of benign tumors in the brain, kidneys, and other organs. As a member of the orphan nuclear receptor family, nuclear receptor related 1 (Nurr1) plays a vital role in some neuropathological diseases and several types of benign or malignant tumors. Here, we explored the potential regulatory role of TSC1/2 signaling in Nurr1 and the effect of Nurr1 in TSC-related tumors. We found that Nurr1 expression was drastically decreased by the disruption of the TSC1/2 complex in Tsc2-null cells, genetically modified mouse models of TSC, cortical tubers of TSC patients, and kidney tumor tissue obtained from a TSC patient. Deficient TSC1/2 complex downregulated Nurr1 expression in an mTOR-dependent manner. Moreover, hyperactivation of mTOR reduced Nurr1 expression via suppression of autophagy. In addition, Nurr1 overexpression inhibited cell proliferation and suppressed cell cycle progression. Therefore, TSC/mTOR/autophagy/Nurr1 signaling is partially responsible for the tumorigenesis of TSC. Taken together, Nurr1 may be a novel therapeutic target for TSC-associated tumors, and Nurr1 agonists or reagents that induce Nurr1 expression may be used for the treatment of TSC.
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- 2021
12. Analogs of the Dopamine Metabolite 5,6-Dihydroxyindole Bind Directly to and Activate the Nuclear Receptor Nurr1
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Yoshie Iizuka, Geoffrey Lang, Pamela M. England, Matthew P. Jacobson, Svetlana A. Kholodar, Harman S. Brah, and Wilian A. Cortopassi
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Nuclear Receptor Subfamily 4 ,Member 2 ,0301 basic medicine ,Indoles ,Metabolite ,Population ,Enzyme Activators ,Substantia nigra ,01 natural sciences ,Biochemistry ,Article ,Cell Line ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Protein Domains ,Transcription (biology) ,Dopamine ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Genetics ,medicine ,2.1 Biological and endogenous factors ,Animals ,Aetiology ,education ,Transcription factor ,Group A ,education.field_of_study ,010405 organic chemistry ,Pars compacta ,Chemistry ,Organic Chemistry ,Neurosciences ,General Medicine ,Biological Sciences ,humanities ,0104 chemical sciences ,Cell biology ,030104 developmental biology ,Nuclear receptor ,Neurological ,Chemical Sciences ,Mutation ,Molecular Medicine ,Generic health relevance ,Protein Binding ,medicine.drug - Abstract
The nuclear receptor-related 1 protein, Nurr1, is a transcription factor critical for the development and maintenance of dopamine-producing neurons in the substantia nigra pars compacta, a cell population that progressively loses the ability to make dopamine and degenerates in Parkinson's disease. Recently, we demonstrated that Nurr1 binds directly to and is regulated by the endogenous dopamine metabolite 5,6-dihydroxyindole (DHI). Unfortunately, DHI is an unstable compound, and thus a poor tool for studying Nurr1 function. Here, we report that 5-chloroindole, an unreactive analog of DHI, binds directly to the Nurr1 ligand binding domain with micromolar affinity and stimulates the activity of Nurr1, including the transcription of genes governing the synthesis and packaging of dopamine.
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- 2021
13. Controlling for activity‐dependent genes and behavioral states is critical for determining brain relationships within and across species
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Erich D. Jarvis, Matthew T. Biegler, Lindsey J. Cantin, and Danielle L. Scarano
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Male ,0301 basic medicine ,Arcopallium ,nuclear receptor subfamily 4 group a member 2 ,neuroanatomy ,immediate‐early genes ,Population ,Hippocampus ,Biology ,Amygdala ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Species Specificity ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,medicine ,Animals ,education ,Zebra finch ,Research Articles ,Brain Chemistry ,education.field_of_study ,General Neuroscience ,songbirds ,Brain ,Claustrum ,030104 developmental biology ,medicine.anatomical_structure ,comparative anatomy ,Finches ,Vocalization, Animal ,Chickens ,Insula ,Neuroscience ,030217 neurology & neurosurgery ,Research Article ,Neuroanatomy - Abstract
The genetic profile of vertebrate pallia has long driven debate on homology across distantly related clades. Based on an expression profile of the orphan nuclear receptor NR4A2 in mouse and chicken brains, Puelles et al. (The Journal of Comparative Neurology, 2016, 524, 665–703) concluded that the avian lateral mesopallium is homologous to the mammalian claustrum, and the medial mesopallium homologous to the insula cortex. They argued that their findings contradict conclusions by Jarvis et al. (The Journal of Comparative Neurology, 2013, 521, 3614–3665) and Chen et al. (The Journal of Comparative Neurology, 2013, 521, 3666–3701) that the hyperpallium densocellare is instead a mesopallium cell population, and by Suzuki and Hirata (Frontiers in Neuroanatomy, 2014, 8, 783) that the avian mesopallium is homologous to mammalian cortical layers 2/3. Here, we find that NR4A2 is an activity‐dependent gene and cannot be used to determine brain organization or species relationships without considering behavioral state. Activity‐dependent NR4A2 expression has been previously demonstrated in the rodent brain, with the highest induction occurring within the claustrum, amygdala, deep and superficial cortical layers, and hippocampus. In the zebra finch, we find that NR4A2 is constitutively expressed in the arcopallium, but induced in parts of the mesopallium, and in sparse cells within the hyperpallium, depending on animal stimulus or behavioral state. Basal and induced NR4A2 expression patterns do not discount the previously named avian hyperpallium densocellare as dorsal mesopallium and conflict with proposed homology between the avian mesopallium and mammalian claustrum/insula at the exclusion of other brain regions. Broadly, these findings highlight the importance of controlling for behavioral state and neural activity to genetically define brain cell population relationships within and across species., In 2016, Puelles et al. sought to determine the relationship of avian and mammalian pallial regions using the expression profile of the NR4A2 nuclear orphan receptor, concluding that the lateral avian mesopallium was most like the mammalian claustrum, not layer 2 of the cortex as found by Suzuki and Hirata (Frontiers in Neuroanatomy, 2014, 8, 783). However, we found that the NR4A2 expression patterns were characteristic of an activity‐dependent gene. Looking at different behavioral contexts in the zebra finch, we found induced expression of NR4A2 in regions across the pallium associated with visual, somatosensory, and motor activity, confounding and contradicting previous findings. Accordingly, we do not believe NR4A2 is a suitable gene for assessing homologous brain anatomy without understanding the animal's behavioral state.
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- 2021
14. Medicinal Chemistry and Chemical Biology of Nurr1 Modulators: An Emerging Strategy in Neurodegeneration
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Sabine Willems and Daniel Merk
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Chemistry, Pharmaceutical ,Drug Discovery ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Molecular Medicine ,Humans ,Receptors, Cytoplasmic and Nuclear ,Ligands ,Transcription Factors - Abstract
Nuclear receptor related 1 (Nurr1) is a transcription factor with neuroprotective and antineuroinflammatory properties. Observations from genetic studies and human patients support potential of Nurr1 as a therapeutic target in neurodegeneration, but due to a lack of high-quality chemical tools for pharmacological control of Nurr1, its target validation is pending. Nevertheless, considerable progress has recently been made in elucidating structural and functional characteristics of Nurr1, and several ligand scaffolds have been discovered. Here, we analyze Nurr1's structure and mechanisms compared to other nuclear receptors, summarize the known small molecule Nurr1 ligands, and discuss the available evidence for the therapeutic potential of Nurr1 in neurodegeneration.
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- 2022
15. The role of NURR1 in metabolic abnormalities of Parkinson’s disease
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Murad Al-Nusaif, Yuting Yang, Song Li, Cheng Cheng, and Weidong Le
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Cellular and Molecular Neuroscience ,Dopamine ,Dopaminergic Neurons ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Humans ,Parkinson Disease ,Neurology (clinical) ,Molecular Biology ,Transcription Factors - Abstract
A constant metabolism and energy supply are crucial to all organs, particularly the brain. Age-dependent neurodegenerative diseases, such as Parkinson’s disease (PD), are associated with alterations in cellular metabolism. These changes have been recognized as a novel hot topic that may provide new insights to help identify risk in the pre-symptomatic phase of the disease, understand disease pathogenesis, track disease progression, and determine critical endpoints. Nuclear receptor-related factor 1 (NURR1), an orphan member of the nuclear receptor superfamily of transcription factors, is a major risk factor in the pathogenesis of PD, and changes in NURR1 expression can have a detrimental effect on cellular metabolism. In this review, we discuss recent evidence that suggests a vital role of NURR1 in dopaminergic (DAergic) neuron development and the pathogenesis of PD. The association between NURR1 and cellular metabolic abnormalities and its implications for PD therapy have been further highlighted.
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- 2022
16. Lmx1a-Dependent Activation of miR-204/211 Controls the Timing of Nurr1-Mediated Dopaminergic Differentiation
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Pulcrano, Salvatore, De Gregorio, Roberto, De Sanctis, Claudia, Lahti, Laura, Perrone-Capano, Carla, Ponti, Donatella, Di Porzio, Umberto, Perlmann, Thomas, Caiazzo, Massimiliano, Volpicelli, Floriana, Bellenchi, Gian Carlo, Afd Pharmaceutics, Pharmaceutics, Afd Pharmaceutics, Pharmaceutics, Pulcrano, Salvatore, De Gregorio, Roberto, De Sanctis, Claudia, Lahti, Laura, Perrone-Capano, Carla, Ponti, Donatella, di Porzio, Umberto, Perlmann, Thoma, Caiazzo, Massimiliano, Volpicelli, Floriana, and Bellenchi, Gian Carlo
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Nuclear Receptor Subfamily 4 ,Member 2 ,Transcription Factor ,LIM-Homeodomain Proteins ,LIM-Homeodomain Protein ,Lmx1a ,Catalysis ,Inorganic Chemistry ,Mice ,Mesencephalon ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Animals ,Nurr1 ,dopamine ,microRNA ,Cell Differentiation ,Dopamine ,Transcription Factors ,Dopaminergic Neurons ,MicroRNAs ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Group A ,Animal ,Organic Chemistry ,General Medicine ,Computer Science Applications ,Dopaminergic Neuron - Abstract
The development of midbrain dopaminergic (DA) neurons requires a fine temporal and spatial regulation of a very specific gene expression program. Here, we report that during mouse brain development, the microRNA (miR-) 204/211 is present at a high level in a subset of DA precursors expressing the transcription factor Lmx1a, an early determinant for DA-commitment, but not in more mature neurons expressing Th or Pitx3. By combining different in vitro model systems of DA differentiation, we show that the levels of Lmx1a influence the expression of miR-204/211. Using published transcriptomic data, we found a significant enrichment of miR-204/211 target genes in midbrain dopaminergic neurons where Lmx1a was selectively deleted at embryonic stages. We further demonstrated that miR-204/211 controls the timing of the DA differentiation by directly downregulating the expression of Nurr1, a late DA differentiation master gene. Thus, our data indicate the Lmx1a-miR-204/211-Nurr1 axis as a key component in the cascade of events that ultimately lead to mature midbrain dopaminergic neurons differentiation and point to miR-204/211 as the molecular switch regulating the timing of Nurr1 expression.
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- 2022
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17. Nurr1 Is Not an Essential Regulator of BDNF in Mouse Cortical Neurons
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Mona Abdollahi and Margaret Fahnestock
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Neurons ,Brain-Derived Neurotrophic Factor ,Organic Chemistry ,Brain ,General Medicine ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,Mice ,NR4A2/Nurr1 ,BDNF ,membrane depolarization ,amodiaquine ,Nurr1 siRNA ,nervous system ,Mesencephalon ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Animals ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy - Abstract
Nurr1 and brain-derived neurotrophic factor (BDNF) play major roles in cognition. Nurr1 regulates BDNF in midbrain dopaminergic neurons and cerebellar granule cells. Nurr1 and BDNF are also highly expressed in the cerebral cortex, a brain area important in cognition. Due to Nurr1 and BDNF tissue specificity, the regulatory effect of Nurr1 on BDNF in different brain areas cannot be generalized. The relationship between Nurr1 and BDNF in the cortex has not been investigated previously. Therefore, we examined Nurr1-mediated BDNF regulation in cortical neurons in activity-dependent and activity-independent states. Mouse primary cortical neurons were treated with the Nurr1 agonist, amodiaquine (AQ). Membrane depolarization was induced by KCl or veratridine and reversed by nimodipine. AQ and membrane depolarization significantly increased Nurr1 (p < 0.001) and BDNF (pAQ < 0.001, pKCl < 0.01) as assessed by real-time qRT-PCR. However, Nurr1 knockdown did not affect BDNF gene expression in resting or depolarized neurons. Accordingly, the positive correlation between Nurr1 and BDNF expression in AQ and membrane depolarization experiments does not imply co-regulation because Nurr1 knockdown did not affect BDNF gene expression in resting or depolarized cortical neurons. Therefore, in contrast to midbrain dopaminergic neurons and cerebellar granule cells, Nurr1 does not regulate BDNF in cortical neurons.
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- 2022
18. Ccr4-Not as a mediator of environmental signaling: a jack of all trades and master of all
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R. Nicholas Laribee
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Receptors, CCR4 ,ved/biology.organism_classification_rank.species ,Regulator ,mTORC1 ,Computational biology ,Environment ,Mechanistic Target of Rapamycin Complex 1 ,Biology ,Proteomics ,Article ,03 medical and health sciences ,Gene Expression Process ,Mediator ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Genetics ,Humans ,Model organism ,Gene ,030304 developmental biology ,0303 health sciences ,ved/biology ,030302 biochemistry & molecular biology ,Intracellular Signaling Peptides and Proteins ,Nutrients ,General Medicine ,Multiprotein Complexes ,Signal transduction ,Signal Transduction - Abstract
The cellular response to environmental exposures, such as nutrient shifts and various forms of stress, requires the integration of the signaling apparatus that senses these environmental changes with the downstream gene regulatory machinery. Delineating this molecular circuitry remains essential for understanding how organisms adapt to environmental flux, and it is critical for determining how dysregulation of these mechanisms causes disease. Ccr4-Not is a highly conserved regulatory complex that controls all aspects of the gene expression process. Recent studies in budding yeast have identified novel roles for Ccr4-Not as a key regulator of core nutrient signaling pathways that control cell growth and proliferation, including signaling through the mechanistic target of rapamycin complex 1 (TORC1) pathway. Herein, I will review the current evidence that implicate Ccr4-Not in nutrient signaling regulation, and I will discuss important unanswered questions that should help guide future efforts to delineate Ccr4-Not's role in linking environmental signaling with the gene regulatory machinery. Ccr4-Not is highly conserved throughout eukaryotes, and increasing evidence indicates it is dysregulated in a variety of diseases. Determining how Ccr4-Not regulates these signaling pathways in model organisms such as yeast will provide a guide for defining how it controls these processes in human cells.
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- 2021
19. Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice
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Yong Huang, Kimberly Paulsen, Rui Ma, Jiwang Zhang, Yue Sheng, Yi Zheng, Zhijian Qian, Chunjie Yu, Hongyu Ni, Steven B. Zhang, and Qiong Wu
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Jumonji Domain-Containing Histone Demethylases ,Genes, APC ,Hematopoiesis and Stem Cells ,Adenomatous polyposis coli ,Adenomatous Polyposis Coli Protein ,Immunology ,Genes, myc ,Apoptosis ,Haploinsufficiency ,Biology ,Biochemistry ,Colony-Forming Units Assay ,Proto-Oncogene Proteins c-myb ,Erythroid Cells ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Nuclear Receptor Subfamily 4, Group A, Member 1 ,medicine ,Animals ,Secretion ,Cell Self Renewal ,Wnt Signaling Pathway ,Bone Marrow Transplantation ,Ineffective Hematopoiesis ,Interleukin-6 ,Wnt signaling pathway ,Endothelial Cells ,Hematopoietic stem cell ,Anemia ,Cell Biology ,Hematology ,Hematopoietic Stem Cells ,Mice, Mutant Strains ,Hematopoiesis ,Cell biology ,Haematopoiesis ,Poly I-C ,medicine.anatomical_structure ,Radiation Chimera ,biology.protein ,Bone marrow ,Gene Deletion - Abstract
This study was conducted to determine the dosage effect of c-Myc on hematopoiesis and its distinct role in mediating the Wnt/β-catenin pathway in hematopoietic stem cell (HSC) and bone marrow niche cells. c-Myc haploinsufficiency led to ineffective hematopoiesis by inhibiting HSC self-renewal and quiescence and by promoting apoptosis. We have identified Nr4a1, Nr4a2, and Jmjd3, which are critical for the maintenance of HSC functions, as previously unrecognized downstream targets of c-Myc in HSCs. c-Myc directly binds to the promoter regions of Nr4a1, Nr4a2, and Jmjd3 and regulates their expression. Our results revealed that Nr4a1 and Nr4a2 mediates the function of c-Myc in regulating HSC quiescence, whereas all 3 genes contribute to the function of c-Myc in the maintenance of HSC survival. Adenomatous polyposis coli (Apc) is a negative regulator of the Wnt/β-catenin pathway. We have provided the first evidence that Apc haploinsufficiency induces a blockage of erythroid lineage differentiation through promoting secretion of IL6 in bone marrow endothelial cells. We found that c-Myc haploinsufficiency failed to rescue defective function of Apc-deficient HSCs in vivo but it was sufficient to prevent the development of severe anemia in Apc–heterozygous mice and to significantly prolong the survival of those mice. Furthermore, we showed that c-Myc–mediated Apc loss induced IL6 secretion in endothelial cells, and c-Myc haploinsufficiency reversed the negative effect of Apc-deficient endothelial cells on erythroid cell differentiation. Our studies indicate that c-Myc has a context-dependent role in mediating the function of Apc in hematopoiesis.
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- 2021
20. The orphan nuclear receptor Nurr1 agonist amodiaquine mediates neuroprotective effects in 6-OHDA Parkinson’s disease animal model by enhancing the phosphorylation of P38 mitogen-activated kinase but not PI3K/AKT signaling pathway
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Kouminin Kanwore, Guo Xiaoxiao, Piniel Alphayo Kambey, Iqra Nadeem, Dianshuai Gao, Ma Chengcheng, Wu Jiao, and Ayanlaja Abiola Abdulrahman
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Male ,0301 basic medicine ,Substantia nigra ,Amodiaquine ,Pharmacology ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Mice ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Parkinsonian Disorders ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,medicine ,Animals ,Enzyme Inhibitors ,Phosphorylation ,Oxidopamine ,Protein kinase B ,Dopamine transporter ,biology ,Tyrosine hydroxylase ,Chemistry ,Kinase ,Brain ,Mice, Inbred C57BL ,Neuroprotective Agents ,030104 developmental biology ,biology.protein ,Neurology (clinical) ,Signal transduction ,Proto-Oncogene Proteins c-akt ,030217 neurology & neurosurgery ,Signal Transduction ,medicine.drug - Abstract
Recent studies implicate the defects or altered expression of the orphan nuclear receptor Nurr1 gene in the substantia nigra in Parkinson's disease pathogenesis. In an attempt to corroborate the treatment-modifying disease that would replicate the effect of Nurr1, it has been found that amodiaquine and Nurr1 had the same chemical scaffolding, indicating a crucial structure-activity relationship. Interestingly, amodiaquine stimulate the transcriptional function of Nurr1 by physical interaction with its ligand-binding domain (LBD). However, the signaling route by which Nurr1 is activated by amodiaquine to cause the protective effect remains to be elucidated. We first demonstrated that amodiaquine treatment ameliorated behavioural deficits in 6-OHDA Parkinson's disease mouse model, and it promoted dopaminergic neurons protection signified by Tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA; Tyrosine hydroxylase (TH) protein expression level and the immunoreactivity in the substantia nigra compacta. Subsequently, we used inhibitors to ascertain the effect of amodiaquine on Akt and P38 Mapk as crucial signaling pathways for neuroprotection. Wortmannin (Akt Inhibitor) induced a significant reduction of Akt mRNA; however, there was no statistical difference between the amodiaquine-treated group and the control group suggesting that amodiaquine may not be the active stimulant of Akt. Western blot analysis confirmed that the phosphorylated Akt decreased significantly in the amodiaquine group compared to the control group. In the same vein, we found that amodiaquine substantially increased the level of phosphorylated P38 Mapk. When P38 Mapk inhibited by SB203580 (P38-Mapk Inhibitor), the total P38 Mapk but not the phosphorylated P38 Mapk decreased significantly, while tyrosine hydroxylase significantly increased. These results collectively suggest that amodiaquine can augment tyrosine hydroxylase expression via phosphorylated P38 Mapk while negatively regulating the phosphorylated Akt in protein expression.
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- 2021
21. Potent synthetic and endogenous ligands for the adopted orphan nuclear receptor Nurr1
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Kwang-Soo Kim, Chun-Hyung Kim, Woori Kim, Pierre Leblanc, and Yongwoo Jang
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Conformational change ,Transcriptional Regulatory Elements ,Indoles ,Chemistry ,Drug discovery ,Transcriptional regulatory elements ,Clinical Biochemistry ,Anti-Inflammatory Agents ,Endogeny ,Review Article ,Biochemistry ,Cell biology ,Orphan Nuclear Receptor Nurr1 ,Nuclear receptor ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Prostaglandins ,Molecular Medicine ,Animals ,Humans ,Molecular Biology ,Structural conformation ,Protein Binding - Abstract
Until 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., Neuropharmacology: a potential treatment strategy for dopamine-related brain disorders Compounds that activate a gene-regulating protein called Nurr1 could help treat Parkinson’s disease and other brain disorders related to abnormal dopamine signaling. A team led by Kwang-Soo Kim from Harvard Medical School, Belmont, USA, reviews the various compounds, both synthetic and natural, known to enhance the activity of Nurr1. This protein binds DNA to regulate the expression of target genes and was long thought not to have such triggering molecules or ligands, which have recently been identified by the team. These activating compounds seem to protect dopamine-producing neurons from cell injury in various Parkinson’s-related cell and animal models. Given Nurr1’s role in the development, differentiation, and survival of dopaminergic neurons in the midbrain, these compounds could help boost the capacity of malfunctioning dopaminergic neurons in patients with Parkinson’s disease, schizophrenia, bipolar disorder, and other neuropsychiatric conditions.
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- 2021
22. Exosomal lncRNA Nuclear Paraspeckle Assembly Transcript 1 (NEAT1)contributes to the progression of allergic rhinitis via modulating microRNA-511/Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) axis
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Peihua Wang, Qinwei Wu, Tao Wang, Dong Chen, Weiyu Cai, and Zhou Xu
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Male ,Cell Survival ,medicine.medical_treatment ,nr4a2 ,Bioengineering ,interleukin-13 ,Exosomes ,Applied Microbiology and Biotechnology ,mir-511 ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,microRNA ,medicine ,Humans ,Gene silencing ,Gene Silencing ,Viability assay ,Cells, Cultured ,allergic rhinitis ,Chemistry ,Paraspeckle ,General Medicine ,Rhinitis, Allergic ,Up-Regulation ,MicroRNAs ,Cytokine ,Nuclear receptor ,Apoptosis ,neat1 ,Interleukin 13 ,Cancer research ,Cytokines ,Female ,RNA, Long Noncoding ,TP248.13-248.65 ,Research Article ,Research Paper ,Biotechnology - Abstract
Allergic rhinitis (AR) is a common chronic disease characterized by inflammation of the nasal mucosa. Long non-coding RNA (LncRNA) has been reported to be involved in the pathogenesis of various diseases. However, the biological roles of lncRNA Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) in AR are still unclear. The mRNA levels of NEAT1, miR-511, and Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) were detected by RT-qPCR. The protein levels of exosomal markers were examined by western blot. ELISA was used to assess the levels of GM-CSF, eotaxin-1, and MUC5AC. The cell viability and apoptosis were evaluated by CCK-8 and TUNEL assays. In this study, we found that the NEAT1 level was highly expressed in AR and IL-13-treated HNECs. NEAT1 interference significantly suppressed levels of GM-CSF, eotaxin-1, and MUC5AC and apoptosis rate, but promoted the viability of IL-13-treated human nasal epithelial cells (HNECs). Moreover, exosomes containing NEAT1 induced inflammatory cytokine production and apoptosis, while NEAT1 depletion abrogated these effects. In addition, NEAT1 directly interacted with miR-511, and the inhibition of miR-511 partially restored the inhibitory effects of NEAT1 silencing on inflammatory cytokine, mucus production, and apoptosis in IL-13-stimulated HNECs. Furthermore, miR-511 could bind to the 3ʹUTR of NR4A2, and the inhibition of miR-511 increased levels of inflammatory factors and apoptosis rate, which was counteracted by depleting NR4A2. In conclusion, our data revealed that exosomal NEAT1 contributed to the pathogenesis of AR through the miR-511/NR4A2 axis. These findings might offer novel strategies for the prevention and treatment of AR.
- Published
- 2021
23. NURR1-deficient mice have age- and sex-specific behavioral phenotypes
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Francesca Montarolo, Serena Martire, Francesco Chiara, Sarah Allegra, Silvia De Francia, Eriola Hoxha, Filippo Tempia, Marco Alfonso Capobianco, and Antonio Bertolotto
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NURR1 ,Male ,Mice, Knockout ,Parkinson's disease ,Dopamine ,Dopaminergic Neurons ,Parkinson Disease ,motor impairment ,murine model ,locomotion ,Cellular and Molecular Neuroscience ,Mice ,Phenotype ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Animals ,Female ,dopamine ,Transcription Factors - Abstract
The transcription factor NURR1 is essential to the generation and maintenance of midbrain dopaminergic (mDA) neurons and its deregulation is involved in the development of dopamine (DA)-associated brain disorders, such as Parkinson's disease (PD). The old male NURR1 heterozygous knockout (NURR1-KO) mouse has been proposed as a model of PD due to its altered motor performance that was, however, not confirmed in a subsequent study. Based on these controversial results, we explored the effects of the NURR1 deficiency on locomotor activity, motor coordination, brain and plasma DA levels, blood pressure and heart rate of old mice, also focusing on the potential effect of sex. As a probable consequence of the role of NURR1 in DA pathway, we observed that the old NURR1-KO mouse is characterized by motor impairment, and increased brain DA level and heart rate, independently from sex. However, we also observed an alteration in spontaneous locomotor activity that only affects males. In conclusion, NURR1 deficiency triggers sex- and age-specific alterations of behavioral responses, of DA levels and cardiovascular abnormalities. Further studies in simplified systems will be necessary to dissect the mechanism underlying these observations.
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- 2022
24. [Protective effect of nuclear receptor related 1 (Nurr1) on nerves in rats with cerebral occlusion/reperfusion injury and its mechanism]
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Di, Hu, Xuemei, Xie, and Hui, Zhang
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Male ,Rats, Sprague-Dawley ,Reperfusion Injury ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Animals ,Brain ,Receptors, Cytoplasmic and Nuclear ,Infarction, Middle Cerebral Artery ,Rats - Abstract
Objective To investigate the protective effect of nuclear receptor related 1 (Nurr1) on nerves in rats with cerebral occlusion/reperfusion injury and its mechanism. Methods Healthy male SD rats were chosen to construct the middle cerebral artery occlusion/reperfusion (MCAO/R) model. All rats were randomly divided into control group, model group, negative virus group, and Nurr1 over-expression group. Longa's modified neurological severity score, Triphenyl tetrazolium chloride (TTC) staining, and immunofluorescence histochemical staining were applied respectively to detect the neurological injury, infarct volume, and density of microtubule associated protein-2 (MAP2) positive nerve cells in rats after MCAO/R. Related kits were used to detect the activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA). The protein levels of Nurr1, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), B cell lymphoma 2 (Bcl2), and Bcl2-assaciated X protein (BAX) were detected by Western blot. Results Nurr1 over-expression improved the neurological outcome with lower modified neurological severity scores by decreasing infarct volume, content of MDA, and expressions of inflammatory mediators including TNF-α, IL-1β, and pro-apoptosis related protein BAX. Nurr1 over-expression significantly increased the density of MAP2 positive nerve cells, activity of SOD, and the expression of anti-apoptosis related protein Bcl2. Conclusion Nurr1 may alleviate the cerebral ischemic damage by resisting oxidation, reducing inflammation, and inhibiting mitochondrial apoptotic signaling pathway-mediated cell apoptosis.
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- 2022
25. Transcriptional Regulation of the Synaptic Vesicle Protein Synaptogyrin-3 (
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Lingfei, Li, Philip Wing-Lok, Ho, Huifang, Liu, Shirley Yin-Yu, Pang, Eunice Eun-Seo, Chang, Zoe Yuen-Kiu, Choi, Yasine, Malki, Michelle Hiu-Wai, Kung, David Boyer, Ramsden, and Shu-Leong, Ho
- Subjects
Synaptogyrins ,HEK293 Cells ,Gene Expression Regulation ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Humans ,Receptors, Cytoplasmic and Nuclear ,Synaptic Vesicles ,Luciferases ,Transcription Factors - Abstract
Synaptogyrin-3 (SYNGR3) is a synaptic vesicular membrane protein. Amongst four homologues (SYNGR1 to 4), SYNGR1 and 3 are especially abundant in the brain. SYNGR3 interacts with the dopamine transporter (DAT) to facilitate dopamine (DA) uptake and synaptic DA turnover in dopaminergic transmission. Perturbed SYNGR3 expression is observed in Parkinson's disease (PD). The regulatory elements which affect SYNGR3 expression are unknown. Nuclear-receptor-related-1 protein (NURR1) can regulate dopaminergic neuronal differentiation and maintenance via binding to NGFI-B response elements (NBRE). We explored whether NURR1 can regulate SYNGR3 expression using an in silico analysis of the 5'-flanking region of the human SYNGR3 gene, reporter gene activity and an electrophoretic mobility shift assay (EMSA) of potential
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- 2022
26. Scaffold Hopping from Amodiaquine to Novel Nurr1 Agonist Chemotypes via Microscale Analogue Libraries
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Sabine Willems, Marcel Müller, Julia Ohrndorf, Jan Heering, Ewgenij Proschak, Daniel Merk, and Publica
- Subjects
Pharmacology ,pharmacophore model ,Organic Chemistry ,neurodegeneration ,NR4A2 ,Amodiaquine ,Ligands ,Biochemistry ,nuclear receptor-related 1 ,Drug Discovery ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Molecular Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,transcription factor - Abstract
Several lines of evidence suggest the ligand-sensing transcription factor Nurr1 as a promising target to treat neurodegenerative diseases. Nurr1 modulators to validate and exploit this therapeutic potential are rare, however. To identify novel Nurr1 agonist chemotypes, we have employed the Nurr1 activator amodiaquine as template for microscale analogue library synthesis. The first set of analogues was based on the 7-chloroquiolin-4-amine core fragment of amodiaquine and revealed superior N-substituents compared to diethylaminomethylphenol contained in the template. A second library of analogues was subsequently prepared to replace the chloroquinolineamine scaffold. The two sets of analogues enabled a full scaffold hop from amodiaquine to a novel Nurr1 agonist sharing no structural features with the lead but comprising superior potency on Nurr1. Additionally, pharmacophore modeling based on the entire set of active and inactive analogues suggested key features for Nurr1 agonists.
- Published
- 2022
27. Transfer of pathological α-synuclein from neurons to astrocytes via exosomes causes inflammatory responses after METH exposure
- Author
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Yitong He, Pingming Qiu, Jiuyang Ding, Haoliang Fan, Chen Li, and Yunle Meng
- Subjects
Male ,0301 basic medicine ,Synucleinopathies ,animal diseases ,Primary Cell Culture ,Nuclear receptor related-1 protein ,Inflammation ,Exosomes ,Toxicology ,Hippocampus ,Methamphetamine ,Proinflammatory cytokine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,medicine ,Animals ,Humans ,Neurons ,biology ,Neurotoxicity ,General Medicine ,Meth ,medicine.disease ,Coculture Techniques ,Microvesicles ,nervous system diseases ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,nervous system ,chemistry ,Cell culture ,Astrocytes ,alpha-Synuclein ,biology.protein ,Cytokines ,Central Nervous System Stimulants ,Neurotoxicity Syndromes ,medicine.symptom ,Injections, Intraperitoneal ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Methamphetamine (METH) is a highly addictive psychostimulant drug whose abuse can cause many health complications. Our previous studies have shown that METH exposure increases α-synuclein (α-syn) expression. Recently, it was shown that α-syn could be transferred from neurons to astrocytes via exosomes. However, the specific role of astrocytes in α-syn pathology involved in METH neurotoxicity remains unclear. The objective of this study was to determine whether exosomes derived from METH-treated neurons contain pathological α-syn and test the hypothesis that exosomes can transfer pathological α-syn from neurons to astrocytes. To this end, using animal and cell line coculture models, we show that exosomes isolated from METH-treated SH-SY5Y cells contained pathological α-syn. Furthermore, the addition of METH exosomes to the medium of primary cultured astrocytes induced α-syn aggregation and inflammatory responses in astrocytes. Then, we evaluated changes in nuclear receptor related 1 protein (Nurr1) expression and the levels of inflammatory cytokines in primary cultured astrocytes exposed to METH or α-syn. We found that METH or α-syn exposure decreased Nurr1 expression and increased proinflammatory cytokine expression in astrocytes. Our results indicate that α-syn can be transferred from neuronal cells to astrocytes through exosomes. When internalized α-syn accumulated in astrocytes, the cells produced inflammatory responses. Nurr1 may play a crucial role in this process and could be a therapeutic target for inflammatory damage caused by METH.
- Published
- 2020
28. Effect of selected bisphenol derivatives on nuclear receptor expression in ovarian cell line COV434
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Sona Scsukova and Alzbeta Mlynarcikova
- Subjects
0301 basic medicine ,endocrine system ,medicine.medical_specialty ,Cell Survival ,Bisphenol ,Endocrinology, Diabetes and Metabolism ,nuclear receptors ,Gene Expression ,Receptors, Cytoplasmic and Nuclear ,Endocrine Disruptors ,Retinoid X receptor ,Diseases of the endocrine glands. Clinical endocrinology ,granulosa cell line cov434 ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Phenols ,Downregulation and upregulation ,bisphenol analogs ,Internal medicine ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,medicine ,Humans ,PPAR delta ,Viability assay ,Benzhydryl Compounds ,Receptor ,Cells, Cultured ,Granulosa Cells ,Thyroid hormone receptor ,urogenital system ,bisphenol a ,Ovary ,RC648-665 ,030104 developmental biology ,Nuclear receptor ,Endocrine disruptor ,030220 oncology & carcinogenesis ,Female ,hormones, hormone substitutes, and hormone antagonists - Abstract
Objectives. Bisphenol A (BPA), as an indispensable plastic additive, has also been proven as an endocrine disruptor associated with adverse health effects including impaired ovarian function and cancer. Due to the restrictions of its usage, several analogs have been employed to replace BPA. Although many studies revealed a harmfulness in the biological effects of BPA analogs, their specific targets remain largely unknown. Nuclear receptors (NRs) may be one of the most important targets of bisphenols. Therefore, in this study, our attention was directed to explore the effect of BPA and its analogs, AF and S, on the mRNA expression of selected NRs involved in the steroidogenic and carcinogenic pathways in the human granulosa cell line COV434. The NRs investigated included: thyroid hormone receptor α (THRA), peroxisome proliferator activating receptor β/δ (PPARD), retinoid X receptor α (RXRA), chicken ovalbumin upstream promoter-transcription factor II (COUPTFII), nuclear receptor-related protein 1 (NURR1), and liver receptor homolog-1 (LRH1). Methods. COV434 cells were treated with the bisphenols at the concentrations of 10−9 M, 10−7 M, and 10−5 M, and after 24 and 48 h, cell viability was monitored by the MTS assay and gene expressions were analyzed using RT-qPCR. Results. Bisphenol treatment did not alter the COV434 cell viability. After 24 h, the expression of neither of the NRs was changed. Likewise, after 48 h, the expression of the selected genes was not altered. However, both BPAF and BPS increased, at the highest concentration (10−5 M) used, the mRNA levels of both PPARD and NURR1 NRs after 48 h of the treatment. In the BPA-treated groups, no significant upregulation was observed. Conclusions. In the present study, the effect of bisphenols on COUP-TFII, Nurr1, and LRH-1 NRs was investigated for the first time. Although generally we did not observe that BPs provoked any alterations in the expression of the selected NRs in COV434 cells, at specific concentrations and time points they might alter mRNA expression of certain NRs (NURR1, PPARD).
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- 2020
29. TGFβ and Wnt Signaling Pathways Cooperatively Enhance Early Dopaminergic Differentiation of the Unrestricted Somatic Stem Cells
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Azimeh Akhlaghpour, Claude C.A. Bernard, Bahman Zeynali, Eleni Roussa, and Azita Parvaneh Tafreshi
- Subjects
0301 basic medicine ,Neurogenesis ,Dioxoles ,Biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Transforming Growth Factor beta ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,TGF beta signaling pathway ,Humans ,Wnt Signaling Pathway ,Cells, Cultured ,beta Catenin ,Effector ,Dopaminergic Neurons ,Dopaminergic ,Wnt signaling pathway ,Mesenchymal Stem Cells ,General Medicine ,Fetal Blood ,Cell biology ,030104 developmental biology ,DKK1 ,Benzamides ,Neuron differentiation ,Signal transduction ,030217 neurology & neurosurgery ,Adult stem cell - Abstract
So far no evidence is available as to whether TGFβ and Wnt signaling pathways cooperatively modulate dopaminergic differentiation of the adult stem cells. To investigate the interaction between the two pathways in early dopaminergic differentiation, we cultured the newly introduced unrestricted somatic stem cells (USSCs) in neuron differentiation media followed by treatments with inducers and inhibitors of Wnt and TGF beta pathways either alone or in combinations. Our results showed that the level of Nurr-1 as a marker for dopaminergic neuron precursors and that of the nuclear β-catenin as the key effector of the active Wnt pathway were significantly elevated following the treatment with either TGFβ or BIO (the Wnt pathway inducer). Conversely, Nurr-1 expression was significantly reduced following the combined treatments with SB431542 (the TGFβ inhibitor) plus BIO or with TGFβ plus Dkk1 (the specific Wnt inhibitor). Nuclear β-catenin was also significantly reduced following combined treatments with SB431542 plus either BIO or TGFβ. Altogether, our results imply that Wnt and TGFβ signaling pathways cooperatively ensure the early dopaminergic differentiation of the USSC adult stem cells.
- Published
- 2020
30. Loss‐of‐Function Mutations in NR4A2 Cause Dopa‐Responsive Dystonia Parkinsonism
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Louise Laure Mariani, Gorazd Rudolf, Thomas Wirth, Jamel Chelly, Emmanuelle Ollivier, Nathalie Drouot, Mathieu Anheim, Gaber Bergant, Patrick Nitschke, Christine Tranchant, Emmanuel Roze, Marie-Odile Habert, Michel Baulac, Alenka Hodžić, and Gabrielle Rudolf
- Subjects
Adult ,0301 basic medicine ,Bioinformatics ,Frameshift mutation ,03 medical and health sciences ,0302 clinical medicine ,Parkinsonian Disorders ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Intellectual disability ,otorhinolaryngologic diseases ,Humans ,Medicine ,Child ,Loss function ,Exome sequencing ,Dystonia ,business.industry ,Parkinsonism ,Dopaminergic ,medicine.disease ,nervous system diseases ,030104 developmental biology ,Neurology ,Dystonic Disorders ,Mutation ,Neurology (clinical) ,business ,Haploinsufficiency ,030217 neurology & neurosurgery - Abstract
BACKGROUND The group of dystonia genes is expanding, and mutations of these genes have been associated with various combined dystonia syndromes. Among the latter, the cause of some dystonia parkinsonism cases remains unknown. OBJECTIVE To report patients with early-onset dystonia parkinsonism as a result of loss-of-function mutations in nuclear receptor subfamily 4 group A member 2. METHODS Phenotypic characterization and exome sequencing were carried out in 2 families. RESULTS The 2 patients reported here both had a history of mild intellectual disability in childhood and subsequently developed dystonia parkinsonism in early adulthood. Brain magnetic resonance imaging was normal, and DATscan suggested bilateral dopaminergic denervation. Two frameshift mutations in NR4A2 were identified: a de novo insertion (NM_006186.3; c.326dupA) in the first case and another small insertion (NM_006186.3; c.881dupA) in the second. CONCLUSIONS NR4A2 haploinsufficiency mutations have been recently reported in neurodevelopmental phenotypes. Our findings indicate that dystonia and/or parkinsonism may appear years after initial symptoms. Mutations in NR4A2 should be considered in patients with unexplained dystonia parkinsonism. © 2020 International Parkinson and Movement Disorder Society.
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- 2020
31. A Nurr1 ligand C-DIM12 attenuates brain inflammation and improves functional recovery after intracerebral hemorrhage in mice
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Keita Kinoshita, Ayaka Yoshimizu, Yusei Ichihara, Keisuke Ushida, Shunsuke Kotani, Yuki Kurauchi, Takahiro Seki, and Hiroshi Katsuki
- Subjects
Mice ,Multidisciplinary ,Indoles ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Amodiaquine ,Animals ,Encephalitis ,Nitric Oxide Synthase Type II ,Ligands ,Cerebral Hemorrhage - Abstract
We have previously reported that amodiaquine, a compound that binds to the ligand-binding domain of a nuclear receptor Nurr1, attenuates inflammatory responses and neurological deficits after intracerebral hemorrhage (ICH) in mice. 1,1-Bis(3′-indolyl)-1-(p-chlorophenyl)methane (C-DIM12) is another Nurr1 ligand that recognizes a domain of Nurr1 different from the ligand-binding domain. In the present study, mice were treated daily with C-DIM12 (50 or 100 mg/kg, p.o.) or amodiaquine (40 mg/kg, i.p.), or twice daily with 1400 W (20 mg/kg, i.p.), an inducible nitric oxide synthase (iNOS) inhibitor, from 3 h after ICH induction by microinjection of collagenase into the striatum. C-DIM12 improved the recovery of neurological function and prevented neuron loss in the hematoma, while suppressed activation of microglia/macrophages and expression of inflammatory mediators interleukin-6 and CC chemokine ligand 2. In addition, C-DIM12 as well as amodiaquine preserved axonal structures in the internal capsule and axonal transport function. We also found that C-DIM12 and amodiaquine suppressed the increases of iNOS mRNA expression after ICH. Moreover, 1400 W improved neurological function and prevented neuron loss, activation of microglia/macrophages and axonal transport dysfunction. These results suggest that suppression of iNOS induction contributes to several features of the therapeutic effects of Nurr1 ligands.
- Published
- 2022
32. Prostaglandin A2 Interacts with Nurr1 and Ameliorates Behavioral Deficits in Parkinson's Disease Fly Model
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Sreekanth Rajan, Hui Ting Toh, Hong Ye, Ziyin Wang, Adeline Henry Basil, Tanvi Parnaik, Jun Yeob Yoo, Kah-Leong Lim, Ho Sup Yoon, Lee Kong Chian School of Medicine (LKCMedicine), and School of Biological Sciences
- Subjects
Prostaglandins A ,Parkinson Disease ,Ligands ,Animals, Genetically Modified ,Nurr1 ,Cellular and Molecular Neuroscience ,Disease Models, Animal ,Neurology ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Molecular Medicine ,Humans ,Medicine [Science] ,Drosophila ,Nuclear Receptor - Abstract
The orphan nuclear receptor Nurr1 is critical for the development, maintenance, and protection of midbrain dopaminergic neurons. Recently, we demonstrated that prostaglandins E1 (PGE1) and PGA1 directly bind to the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional activation function. In this direction, here we report the transcriptional activation of Nurr1 by PGA2, a dehydrated metabolite of PGE2, through physical binding ably supported by NMR titration and crystal structure. The co-crystal structure of Nurr1-LBD bound to PGA2 revealed the covalent coupling of PGA2 with Nurr1-LBD through Cys566. PGA2 binding also induces a 21° shift of the activation function 2 (AF-2) helix H12 away from the protein core, similar to that observed in the Nurr1-LBD-PGA1 complex. We also show that PGA2 can rescue the locomotor deficits and neuronal degeneration in LRRK2 G2019S transgenic fly models. Ministry of Education (MOE) Ministry of Health (MOH) This work was supported by the Ministry of Education Singapore AcRF Tier 2 Grant (MOE2016-T2-2-055) (YHS) and Ministry of Health NMRC-LCG Singapore Parkinson’s disease Translational Clinical Programme (MOH-000207) (LKL).
- Published
- 2022
33. BMS-470539 Attenuates Oxidative Stress and Neuronal Apoptosis via MC1R/cAMP/PKA/Nurr1 Signaling Pathway in a Neonatal Hypoxic-Ischemic Rat Model
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Shufeng Yu, Desislava Met Doycheva, Marcin Gamdzyk, Yuanyuan Gao, Yong Guo, Zachary D. Travis, Jiping Tang, Wen-Xiong Chen, and John H. Zhang
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Male ,Aging ,Article Subject ,Apoptosis ,Biochemistry ,Antioxidants ,Rats, Sprague-Dawley ,Gene Knockout Techniques ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Cyclic AMP ,Animals ,Administration, Intranasal ,Neurons ,QH573-671 ,Imidazoles ,Cell Biology ,General Medicine ,Cyclic AMP-Dependent Protein Kinases ,Rats ,Oxidative Stress ,Neuroprotective Agents ,Treatment Outcome ,Animals, Newborn ,Hypoxia-Ischemia, Brain ,Female ,Cytology ,Receptor, Melanocortin, Type 1 ,Signal Transduction ,Research Article - Abstract
Neuronal apoptosis induced by oxidative stress plays an important role in the pathogenesis and progression of hypoxic-ischemic encephalopathy (HIE). Previous studies reported that activation of melanocortin-1 receptor (MC1R) exerts antioxidative stress, antiapoptotic, and neuroprotective effects in various neurological diseases. However, whether MC1R activation can attenuate oxidative stress and neuronal apoptosis after hypoxic-ischemic- (HI-) induced brain injury remains unknown. Herein, we have investigated the role of MC1R activation with BMS-470539 in attenuating oxidative stress and neuronal apoptosis induced by HI and the underlying mechanisms. 159 ten-day-old unsexed Sprague-Dawley rat pups were used. HI was induced by right common carotid artery ligation followed by 2.5 h of hypoxia. The novel-selective MC1R agonist BMS-470539 was administered intranasally at 1 h after HI induction. MC1R CRISPR KO plasmid and Nurr1 CRISPR KO plasmid were administered intracerebroventricularly at 48 h before HI induction. Percent brain infarct area, short-term neurobehavioral tests, Western blot, immunofluorescence staining, Fluoro-Jade C staining, and MitoSox Staining were performed. We found that the expression of MC1R and Nurr1 increased, peaking at 48 h post-HI. MC1R and Nurr1 were expressed on neurons at 48 h post-HI. BMS-470539 administration significantly attenuated short-term neurological deficits and infarct area, accompanied by a reduction in cleaved caspase-3-positive neurons at 48 h post-HI. Moreover, BMS-470539 administration significantly upregulated the expression of MC1R, cAMP, p-PKA, Nurr1, HO-1, and Bcl-2. However, it downregulated the expression of 4-HNE and Bax, as well as reduced FJC-positive cells, MitoSox-positive cells, and 8-OHdG-positive cells at 48 h post-HI. MC1R CRISPR and Nurr1 CRISPR abolished the antioxidative stress, antiapoptotic, and neuroprotective effects of BMS-470539. In conclusion, our findings demonstrated that BMS-470539 administration attenuated oxidative stress and neuronal apoptosis and improved neurological deficits in a neonatal HI rat model, partially via the MC1R/cAMP/PKA/Nurr1 signaling pathway. Early administration of BMS-470539 may be a novel therapeutic strategy for infants with HIE.
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- 2022
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34. Nuclear receptor 4A2 (NR4A2) is a druggable target for glioblastomas
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Stephen Safe, Keshav Karki, Mahsa Zarei, Un Ho Jin, Sandeep Mittal, Kumaravel Mohankumar, Ronald B. Tjalkens, Xi Li, and Sharon K. Michelhaugh
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Cancer Research ,Indoles ,Cell ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,Article ,Mice ,03 medical and health sciences ,Transactivation ,0302 clinical medicine ,Cell Movement ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Biomarkers, Tumor ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Gene silencing ,RNA, Small Interfering ,Cell Proliferation ,Reporter gene ,Gene knockdown ,Chemistry ,Cell growth ,Prognosis ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Survival Rate ,medicine.anatomical_structure ,Neurology ,Oncology ,Nuclear receptor ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Neurology (clinical) ,Glioblastoma ,030217 neurology & neurosurgery - Abstract
INTRODUCTION: The orphan nuclear receptor 4A2 (NR4A2) has been extensively characterized in subcellular regions of the brain and is necessary for the function of dopaminergic neurons. The NR4A2 ligand, 1,1-bis (3(1)-indoly1)-1-(p-chlorophenyl)methane (DIM-C-pPhCl) inhibits markers of neuroinflammation and degeneration in mouse models and in this study we investigated expression and function of NR4A2 in glioblastoma (GBM). METHODS: Established and patient-derived cell lines were used as models and the expression and functions of NR4A2 were determined by western blots and NR4A2 gene silencing by antisense oligonucleotides respectively. Effects of NR4A2 knockdown and DIM-C-pPhCl on cell growth, induction of apoptosis (Annexin V Staining) and migration/invasion (Boyden chamber and spheroid invasion assay) and transactivation of NR4A2-regulated reporter genes were determined. Tumor growth was investigated in athymic nude mice bearing U87-MG cells as xenografts. RESULTS: NR4A2 knockdown and DIM-C-pPhCl inhibited GBM cell and tumor growth, induced apoptosis and inhibited migration and invasion of GBM cells. DIM-C-pPhCl and related analogs also inhibited NR4A2-regulated transactivation (luciferase activity) confirming that DIM-C-pPhCl acts as an NR4A2 antagonist and blocks NR4A2-dependent pro-oncogenic responses in GBM. CONCLUSION: We demonstrate for the first time that NR4A2 is pro-oncogenic in GBM and thus a potential druggable target for patients with tumors expressing this receptor. Moreover, our bis-indole-derived NR4A2 antagonists represent a novel class of anti-cancer agents with potential future clinical applications for treating GBM.
- Published
- 2019
35. Altered Nurr1 protein expression in the hippocampal CA1 region following transient global cerebral ischemia
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Choong Hyun Lee, Young-Eun Park, Joon Ha Park, Jae-Chul Lee, Ji Hyeon Ahn, Moo Ho Won, Go Eun Yang, Tae‑Kyeong Lee, Cheolwoo Park, Dae Won Kim, and Hyang Ah Lee
- Subjects
0301 basic medicine ,Male ,Cancer Research ,medicine.medical_specialty ,nuclear receptor related 1 protein ,Ischemia ,Hippocampus ,microglia ,Nuclear receptor related-1 protein ,Hippocampal formation ,Gerbil ,Biochemistry ,transient global cerebral ischemia ,Brain Ischemia ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Genetics ,medicine ,Animals ,Molecular Biology ,CA1 Region, Hippocampal ,delayed neuronal death ,CA1-3 subfields ,biology ,Microglia ,Chemistry ,Hippocampus proper ,Pyramidal Cells ,Articles ,medicine.disease ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Oncology ,Nuclear receptor ,nervous system ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,Gerbillinae - Abstract
Nuclear receptor related 1 protein (Nurr1), a member of the nuclear receptor 4 family of orphan nuclear receptors, has been reported to display anti‑inflammatory properties. The present study investigated the alteration of Nurr1 immunoreactivity in the gerbil hippocampus proper following 5 min of transient global cerebral ischemia. In sham operated gerbils, Nurr1 immunoreactivity was observed in pyramidal neurons in all cornu ammonis 1‑3 (CA1‑3) subfields of the hippocampus proper. In ischemia‑operated gerbils, Nurr1 immunoreactivity was altered in the CA1 subfield. Nurr1 immunoreactivity in CA1 pyramidal neurons gradually decreased until 2 days post‑ischemia, and, at 4 days post‑ischemia, Nurr1 immunoreactivity was concentrated in CA1 pyramidal neurons. Additionally, Nurr1 immunoreactivity was newly expressed in microglia in the CA1 subfield at 4 days post‑ischemia. Conversely, in the CA2/3 subfield, time‑dependent alteration of Nurr1 immunoreactivity was not identified at any time following ischemia. These results indicated that the alteration of Nurr1 expression in the CA1 subfield in the hippocampus may be associated with the death of CA1 pyramidal neurons.
- Published
- 2019
36. Nuclear receptors of NR1 and NR4 subfamilies in the regulation of microglial functions and pathology
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Hiroshi Katsuki
- Subjects
Apolipoprotein E ,Cell signaling ,Glia Pharmacology in Asia & Beyond ,Nerve growth factor IB ,Reviews ,Stimulation ,Review ,suppressor of cytokine signaling protein ,RM1-950 ,Biology ,Receptors, N-Methyl-D-Aspartate ,Central Nervous System Diseases ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Nuclear Receptor Subfamily 4, Group A, Member 1 ,Animals ,Humans ,mitogen‐activated protein kinase ,General Pharmacology, Toxicology and Pharmaceutics ,Receptor ,Liver X receptor ,apolipoprotein E ,toll‐like receptor ,Toll-like receptor ,interleukin ,Disease Models, Animal ,Neurology ,Nuclear receptor ,Receptors, Calcitriol ,Microglia ,Therapeutics. Pharmacology ,CD36 ,Neuroscience ,NF‐kappa B - Abstract
This review provides an overview of researches on the NR1 and NR4 nuclear receptors involved in the regulation of microglial functions. Nuclear receptors are attractive candidates for drug targets in the therapies of the central nervous system disorders, because the activation of these receptors is expected to regulate the functions and the phenotypes of microglia, by controlling the expression of specific gene subsets and also by regulating the cellular signaling mechanisms in a nongenomic manner. Several members of NR1 nuclear receptor subfamily have been examined for their ability to regulate microglial functions. For example, stimulation of vitamin D receptor inhibits the production of pro‐inflammatory factors and increases the production of anti‐inflammatory cytokines. Similar regulatory actions of nuclear receptor ligands on inflammation‐related genes have also been reported for other NR1 members such as retinoic acid receptors, peroxisome proliferator‐activated receptors (PPARs), and liver X receptors (LXRs). In addition, stimulation of PPARγ and LXRs may also result in increased phagocytic activities of microglia. Consistent with these actions, the agonists at nuclear receptors of NR1 subfamily are shown to produce therapeutic effects on animal models of various neurological disorders such as experimental allergic encephalomyelitis, Alzheimer's disease, Parkinson's disease, and ischemic/hemorrhagic stroke. On the other hand, increasing lines of evidence suggest that the stimulation of NR4 subfamily members of nuclear receptors such as Nur77 and Nurr1 also regulates microglial functions and alleviates neuropathological events in several disease models. Further advancement of these research fields may prove novel therapeutic opportunities., Nuclear receptors of NR1 (VDR, RARs, PPARs, and LXRs) and NR4 (Nur77 and Nurr1) subfamilies inhibit the production of pro‐inflammatory factors from microglia. Some of them also promote the production of anti‐inflammatory cytokines and enhance the phagocytic activity of microglia.
- Published
- 2021
37. Variability in Behavioral Phenotypes after Forced Swimming-Induced Stress in Rats Is Associated with Expression of the Glucocorticoid Receptor, Nurr1, and IL-1β in the Hippocampus
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Aldo Arturo Reséndiz-Albor, Elizabeth Ruiz-Sánchez, Patricia Rojas, Minerva Calvillo, Arely M. López-Ramírez, Brenda Anguiano, and Angel Ruiz-Chow
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Male ,Behavioral phenotypes ,Interleukin-1beta ,Hippocampus ,Hippocampal formation ,stress resilience ,Glucocorticoid receptor ,Neurotrophic factors ,Adaptation, Psychological ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,glucocorticoid receptor ,Biology (General) ,Spectroscopy ,Behavior, Animal ,General Medicine ,vulnerable phenotype ,Phenotype ,Computer Science Applications ,Chemistry ,Nurr1 ,IL-1β ,Female ,medicine.medical_specialty ,QH301-705.5 ,Biology ,Article ,Catalysis ,Inorganic Chemistry ,Receptors, Glucocorticoid ,resilient phenotype ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Rats, Wistar ,Physical and Theoretical Chemistry ,Beta (finance) ,QD1-999 ,individual differences ,Molecular Biology ,Gene ,Swimming ,Brain-Derived Neurotrophic Factor ,Organic Chemistry ,behavioral phenotype ,Rats ,Disease Models, Animal ,Endocrinology ,Stress, Psychological - Abstract
Individual differences in coping with stress may determine either a vulnerable or resilient phenotype. Therefore, it is important to better understand the biology underlying the behavioral phenotype. We assessed whether individual behavioral phenotype to acute stress is related with the hippocampal expression of glucocorticoid receptor (GR), Nurr1, interleukin-1 beta (IL-1β) or brain-derived neurotrophic factor (BDNF). Wistar male rats were exposed to forced swimming for 15 min and sacrificed at different times. Behavioral response was analyzed, and it was compared with the gene and protein expression of GR, Nurr1, IL-1β and BDNF in the hippocampus for each time point. Behavioral phenotyping showed a group with high immobility (vulnerable) while another had low immobility (resilient). No significant differences were found in the Nurr1, IL-1β and BDNF mRNA levels between resilient and vulnerable rats at different recovery times except for Nr3c1 (gene for GR). However, exposure to stress caused significantly higher levels of GR, Nurr1 and IL-1β proteins of vulnerable compared to resilient rats. This variability of behavioral phenotypes is associated with a differential molecular response to stress that involves GR, Nurr1, and IL-1β as mediators in coping with stress. This contributes to identifying biomarkers of susceptibility to stress.
- Published
- 2021
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38. Recruitment of the CoREST transcription repressor complexes by Nerve Growth factor IB-like receptor (Nurr1/NR4A2) mediates silencing of HIV in microglial cells
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Fengchun Ye, David Alvarez-Carbonell, Kien Nguyen, Konstantin Leskov, Yoelvis Garcia-Mesa, Sheetal Sreeram, Saba Valadkhan, and Jonathan Karn
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Inflammation ,Immunology ,HIV Infections ,Microbiology ,Proviruses ,Virology ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Genetics ,HIV-1 ,Humans ,Parasitology ,Microglia ,Nerve Growth Factors ,Molecular Biology - Abstract
Human immune deficiency virus (HIV) infection in the brain leads to chronic neuroinflammation due to the production of pro-inflammatory cytokines, which in turn promotes HIV transcription in infected microglial cells. However, powerful counteracting silencing mechanisms in microglial cells result in the rapid shutdown of HIV expression after viral reactivation to limit neuronal damage. Here we investigated whether the Nerve Growth Factor IB-like nuclear receptor Nurr1 (NR4A2), which is a repressor of inflammation in the brain, acts directly to restrict HIV expression. HIV silencing following activation by TNF-α, or a variety of toll-like receptor (TLR) agonists, in both immortalized human microglial cells (hμglia) and induced pluripotent stem cells (iPSC)-derived human microglial cells (iMG) was enhanced by Nurr1 agonists. Similarly, overexpression of Nurr1 led to viral suppression, while conversely, knock down (KD) of endogenous Nurr1 blocked HIV silencing. The effect of Nurr1 on HIV silencing is direct: Nurr1 binds directly to the specific consensus binding sites in the U3 region of the HIV LTR and mutation of the Nurr1 DNA binding domain blocked its ability to suppress HIV-1 transcription. Chromatin immunoprecipitation (ChIP) assays also showed that after Nurr1 binding to the LTR, the CoREST/HDAC1/G9a/EZH2 transcription repressor complex is recruited to the HIV provirus. Finally, transcriptomic studies demonstrated that in addition to repressing HIV transcription, Nurr1 also downregulated numerous cellular genes involved in inflammation, cell cycle, and metabolism, further promoting HIV latency and microglial homoeostasis. Nurr1 therefore plays a pivotal role in modulating the cycles of proviral reactivation by potentiating the subsequent proviral transcriptional shutdown. These data highlight the therapeutic potential of Nurr1 agonists for inducing HIV silencing and microglial homeostasis and ultimately for the amelioration of the neuroinflammation associated with HIV-associated neurocognitive disorders (HAND).
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- 2021
39. Development and Profiling of Inverse Agonist Tools for the Neuroprotective Transcription Factor Nurr1
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Jan Heering, Daniel Merk, Simone Schierle, Daniel Zaienne, and Sabine Willems
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Agonist ,Indoles ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,medicine.drug_class ,Neuroprotection ,Cell biology ,Structure-Activity Relationship ,Nuclear receptor ,Drug Development ,Drug Discovery ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,medicine ,Molecular Medicine ,Gene silencing ,Inverse agonist ,Humans ,Receptor ,Transcription factor ,Neuroinflammation - Abstract
The ligand-sensing transcription factor nuclear receptor related 1 (Nurr1) evolves as an appealing target to treat neurodegenerative diseases. Despite its therapeutic potential observed in various rodent models, potent modulators for Nurr1 are lacking as pharmacological tools. Here, we report the structure-activity relationship and systematic optimization of indole-based inverse Nurr1 agonists. Optimized analogues decreased the receptor's intrinsic transcriptional activity by up to more than 90% and revealed preference for inhibiting Nurr1 monomer activity. In orthogonal cell-free settings, we detected displacement of NCoRs and disruption of the Nurr1 homodimer as molecular modes of action. The inverse Nurr1 agonists reduced the expression of Nurr1-regulated genes in T98G cells, and treatment with an inverse Nurr1 agonist mimicked the effect of Nurr1 silencing on interleukin-6 release from LPS-stimulated human astrocytes. The indole-based inverse Nurr1 agonists valuably extend the toolbox of Nurr1 modulators to further probe the role of Nurr1 in neuroinflammation, cancer, and beyond.
- Published
- 2021
40. Neuroprotective effects of a lead compound from coral via modulation of the orphan nuclear receptor Nurr1.
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Su JW, Yang P, Xing MM, Chen B, Xie XH, Ding JH, Lu M, Liu Y, Guo YW, and Hu G
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- Animals, Humans, Nuclear Receptor Subfamily 4, Group A, Member 2, Caenorhabditis elegans metabolism, Dopaminergic Neurons metabolism, Cell Line, Tumor, Neuroprotective Agents therapeutic use, Neuroblastoma
- Abstract
Aims: To screen coral-derived compounds with neuroprotective activity and clarify the potential mechanism of lead compounds., Methods: The lead compounds with neuroprotective effects were screened by H
2 O2 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP+ )-induced cell damage models in SH-SY5Y cells. CCK8 and LDH assays were used to detect cell viability. The anti-apoptosis of lead compounds was evaluated by flow cytometry. JC-1 and MitoSox assays were performed to examine the changes in mitochondrial membrane potential and mitochondrial ROS level. Survival of primary cortical and dopaminergic midbrain neurons was measured by MAP2 and TH immunoreactivities. The Caenorhabditis elegans (C. elegans) model was established to determine the effect of lead compounds on dopaminergic neurons and behavior changes., Results: Three compounds (No. 63, 68, and 74), derived from marine corals, could markedly alleviate the cell damage and notably reverse the loss of worm dopaminergic neurons. Further investigation indicated that compound 63 could promote the expression of Nurr1 and inhibit neuronal apoptosis signaling pathways., Conclusion: Lead compounds from marine corals exerted significant neuroprotective effects, which indicated that coral might be a new and potential resource for screening and isolating novel natural compounds with neuroprotective effects. Furthermore, this study also provided a new strategy for the clinical treatment of neurodegenerative diseases such as Parkinson's disease., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)- Published
- 2023
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41. A Novel Mechanism of Coactivator Recruitment by the Nurr1 Nuclear Receptor
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Ishwar Radhakrishnan and Nicolas Daffern
- Subjects
Transcriptional Activation ,Nuclear Receptor Coactivator 1 ,Protein Domains ,Structural Biology ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Amino Acid Sequence ,STAT6 Transcription Factor ,Molecular Biology ,Article ,Protein Binding - Abstract
Nuclear receptors constitute one of the largest families of transcription factors that regulate genes in metazoans in response to small molecule ligands. Many receptors harbor two transactivation domains, one at each end of the protein sequence. Whereas the molecular mechanisms of transactivation mediated by the ligand-binding domain at the C-terminus of the protein are generally well established, the mechanism involving the N-terminal domain called activation function 1 (AF1) has remained elusive. Previous studies implicated the AF1 domain as a significant contributor towards the overall transcriptional activity of the NR4A family of nuclear receptors and suggested that the steroid receptor coactivators (SRCs) play an important role in this process. Here we show that a short segment within the AF1 domain of the NR4A receptor Nurr1 can directly engage with the SRC1 PAS-B domain. We also show that this segment forms a helix upon binding to a largely hydrophobic groove on PAS-B, overlapping with the surface engaged by the STAT6 transcription factor, suggesting that this mode of recruitment could be shared by diverse transcription factors including other nuclear receptors.
- Published
- 2022
42. Transcriptional Profiling of Monocytes Deficient in Nuclear Orphan Receptors NR4A2 and NR4A3 Reveals Distinct Signalling Roles Related to Antigen Presentation and Viral Response
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David E. Phelan, Masahiko Shigemura, Sarah Aldhafiri, Catarina Mota, Thomas J. Hall, Jacob I. Sznajder, Evelyn P. Murphy, Daniel Crean, and Eoin P. Cummins
- Subjects
Lipopolysaccharides ,0301 basic medicine ,Receptors, Steroid ,Cell signaling ,THP-1 Cells ,NR4A3 ,Immunology ,Antigen presentation ,NR4A2 ,Biology ,Major histocompatibility complex ,Interactome ,Monocytes ,Transcriptome ,transcriptomics ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Humans ,Immunology and Allergy ,nuclear receptor ,RNA-Seq ,Transcription factor ,Original Research ,Antigen Presentation ,Receptors, Thyroid Hormone ,Antigen processing ,Computational Biology ,nuclear orphan receptor ,cell signalling ,RC581-607 ,NR4A ,Cell biology ,DNA-Binding Proteins ,030104 developmental biology ,Gene Expression Regulation ,Nuclear receptor ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,biology.protein ,Immunologic diseases. Allergy ,Signal Transduction - Abstract
The nuclear receptor sub-family 4 group A (NR4A) family are early response genes that encode proteins that are activated in several tissues/cells in response to a variety of stressors. The NR4A family comprises NR4A1, NR4A2 and NR4A3 of which NR4A2 and NR4A3 are under researched and less understood, particularly in the context of immune cells. NR4A expression is associated with multiple diseases e.g. arthritis and atherosclerosis and the development of NR4A-targetting molecules as therapeutics is a current focus in this research field. Here, we use a combination of RNA-sequencing coupled with strategic bioinformatic analysis to investigate the down-stream effects of NR4A2 and NR4A3 in monocytes and dissect their common and distinct signalling roles. Our data reveals that NR4A2 and NR4A3 depletion has a robust and broad-reaching effect on transcription in both the unstimulated state and in the presence of LPS. Interestingly, many of the genes affected were present in both the unstimulated and stimulated states revealing a previously unappreciated role for the NR4As in unstimulated cells. Strategic clustering and bioinformatic analysis identified both distinct and common transcriptional roles for NR4A2 and NR4A3 in monocytes. NR4A2 notably was linked by both bioinformatic clustering analysis and transcription factor interactome analysis to pathways associated with antigen presentation and regulation of MHC genes. NR4A3 in contrast was more closely linked to pathways associated with viral response. Functional studies further support our data analysis pointing towards preferential/selective roles for NR4A2 in the regulation of antigen processing with common roles for NR4A2 and NR4A3 evident with respect to cell migration. Taken together this study provides novel mechanistic insights into the role of the enigmatic nuclear receptors NR4A2 and NR4A3 in monocytes.
- Published
- 2021
43. Regulation of Early Lymphocyte Development
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Taishin, Akiyama and Tadashi, Yamamoto
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Receptors, CCR4 ,Lymphopoiesis ,RNA Stability ,Mini Review ,Immunology ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Apoptosis ,CCR4-NOT complex ,lymphocyte development ,VDJ recombination ,mRNA decay ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Animals ,Humans ,Lymphocytes ,RNA, Messenger ,RNA Processing, Post-Transcriptional ,Transcription Factors - Abstract
Development of lymphocytes is precisely regulated by various mechanisms. In addition to transcriptional rates, post-transcriptional regulation of mRNA abundance contributes to differentiation of lymphocytes. mRNA decay is a post-transcriptional mechanism controlling mRNA abundance. The carbon catabolite repression 4 (CCR4)-negative on TATA-less (NOT) complex controls mRNA longevity by catalyzing mRNA deadenylation, which is the rate-limiting step in the mRNA decay pathway. mRNA decay, regulated by the CCR4-NOT complex, is required for differentiation of pro-B to pre-B cells and V(D)J recombination in pro-B cells. In this process, it is likely that the RNA-binding proteins, ZFP36 ring finger protein like 1 and 2, recruit the CCR4-NOT complex to specific target mRNAs, thereby inducing cell quiescence of pro-B cells. A recent study showed that the CCR4-NOT complex participates in positive selection of thymocytes. Mechanistically, the CCR4-NOT deadenylase complex inhibits abnormal apoptosis by reducing the expression level of mRNAs encoding pro-apoptotic proteins, which are otherwise up-regulated during positive selection. We discuss mechanisms regulating CCR4-NOT complex-dependent mRNA decay in lymphocyte development and selection.
- Published
- 2021
44. Nuclear receptor subfamily 4 group A member 2 inhibits activation of ERK signaling and cell growth in response to β-adrenergic stimulation in adult rat cardiomyocytes
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Yassmin K. Hegazy, Romain Harmancey, and Sadia Ashraf
- Subjects
Male ,0301 basic medicine ,MAPK/ERK pathway ,medicine.medical_specialty ,Subfamily ,MAP Kinase Signaling System ,Physiology ,heart failure ,030204 cardiovascular system & hematology ,Group A ,Muscle hypertrophy ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Receptors, Adrenergic, beta ,medicine ,Animals ,adrenergic signaling ,Myocytes, Cardiac ,nuclear receptor ,Pathological ,Cells, Cultured ,Cell Proliferation ,Cell growth ,business.industry ,Age Factors ,Cell Biology ,Adrenergic beta-Agonists ,medicine.disease ,MAPK ,Rats ,030104 developmental biology ,Endocrinology ,Nuclear receptor ,Heart failure ,hypertrophy ,business ,Research Article - Abstract
Sustained elevation of sympathetic activity is an important contributor to pathological cardiac hypertrophy, ventricular arrhythmias, and left ventricular contractile dysfunction in chronic heart failure. The orphan nuclear receptor NR4A2 is an immediate early-response gene activated in the heart under β-adrenergic stimulation. The goal of this study was to identify the transcriptional remodeling events induced by increased NR4A2 expression in cardiomyocytes and their impact on the physiological response of those cells to sustained β-adrenergic stimulation. Treatment of adult rat ventricular myocytes with isoproterenol induced a rapid (
- Published
- 2019
45. Low-dose ionizing radiation attenuates mast cell migration through suppression of monocyte chemoattractant protein-1 (MCP-1) expression by Nr4a2
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Hae Mi Joo, Jeong-In Kim, Chin-Hee Song, Seon Young Nam, So Hyun Han, and Jiyoung Kim
- Subjects
Phalloidine ,030218 nuclear medicine & medical imaging ,Ionizing radiation ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Cell Line, Tumor ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Animals ,Radiology, Nuclear Medicine and imaging ,Mast Cells ,Transcription factor ,Chemokine CCL2 ,Radiological and Ultrasound Technology ,Chemistry ,Chemotaxis ,Gene Expression Profiling ,Low dose ,Actins ,Rats ,Cell biology ,Gene Expression Regulation ,Cesium Radioisotopes ,Gamma Rays ,030220 oncology & carcinogenesis ,Cytokines ,RNA Interference ,Signal transduction ,Mast cell migration ,Signal Transduction ,Monocyte chemoattractant protein - Abstract
Purpose: The aim of this study was to investigate whether low-dose ionizing radiation attenuates mast cell migration by modulating migration-associated signaling pathways and the expression of chem...
- Published
- 2019
46. Reconstitution of recombinant human CCR4-NOT reveals molecular insights into regulated deadenylation
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Tobias Raisch, Eugene Valkov, Yevgen Levdansky, Chung Te Chang, Sowndarya Muthukumar, and Stefan Raunser
- Subjects
0301 basic medicine ,Multiprotein complex ,Receptors, CCR4 ,Science ,General Physics and Astronomy ,Multienzyme complexes ,02 engineering and technology ,RNA decay ,General Biochemistry, Genetics and Molecular Biology ,Article ,law.invention ,03 medical and health sciences ,Ribonucleases ,law ,Gene expression ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Humans ,Short linear motif ,RNA, Messenger ,Receptor ,lcsh:Science ,Messenger RNA ,Multidisciplinary ,Chemistry ,RNA ,General Chemistry ,021001 nanoscience & nanotechnology ,In vitro ,Recombinant Proteins ,3. Good health ,Cell biology ,030104 developmental biology ,Multiprotein Complexes ,Exoribonucleases ,Recombinant DNA ,lcsh:Q ,0210 nano-technology ,Poly A ,Transcription Factors - Abstract
CCR4-NOT is a conserved multiprotein complex which regulates eukaryotic gene expression principally via shortening of poly(A) tails of messenger RNA or deadenylation. Here, we reconstitute a complete, recombinant human CCR4-NOT complex. Our reconstitution strategy permits strict compositional control to test mechanistic hypotheses with purified component variants. CCR4-NOT is more active and selective for poly(A) than the isolated exonucleases, CCR4a and CAF1, which have distinct deadenylation profiles in vitro. The exonucleases require at least two out of three conserved non-enzymatic modules (CAF40, NOT10:NOT11 or NOT) for full activity in CCR4-NOT. CAF40 and the NOT10:NOT11 module both bind RNA directly and stimulate deadenylation in a partially redundant manner. Linear motifs from different RNA-binding factors that recruit CCR4-NOT to specific mRNAs via protein-protein interactions with CAF40 can inhibit bulk deadenylation. We reveal an additional layer of regulatory complexity to the human deadenylation machinery, which may prime it either for general or target-specific degradation., The CCR4-NOT complex shortens poly(A) tails of messenger RNAs. By biochemical reconstitution of the entire human CCR4-NOT complex, the authors show the stimulatory roles of non-enzymatic subunits and the importance of the interaction between CAF40 and RNA binding proteins in targeted deadenylation.
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- 2019
47. A low-complexity region in human XRN1 directly recruits deadenylation and decapping factors in 5′–3′ messenger RNA decay
- Author
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Cátia Igreja, Ying Chen, Lara Wohlbold, Ramona Weber, Dipankar Bhandari, Eugene Valkov, Chung Te Chang, Yevgen Levdansky, Sowndarya Muthukumar, and Elisa Izaurralde
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RNA Caps ,Receptors, CCR4 ,Translational efficiency ,RNA Stability ,Biology ,Ribosome ,Exoribonuclease ,Endoribonucleases ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Genetics ,RNA and RNA-protein complexes ,Humans ,Ribosome profiling ,RNA, Messenger ,Messenger RNA ,Activator (genetics) ,RNA ,Proteins ,Cell biology ,DNA-Binding Proteins ,Repressor Proteins ,Cytoplasm ,Multiprotein Complexes ,Exoribonucleases ,Trans-Activators ,Microtubule-Associated Proteins ,Transcription Factors - Abstract
XRN1 is the major cytoplasmic exoribonuclease in eukaryotes, which degrades deadenylated and decapped mRNAs in the last step of the 5′–3′ mRNA decay pathway. Metazoan XRN1 interacts with decapping factors coupling the final stages of decay. Here, we reveal a direct interaction between XRN1 and the CCR4–NOT deadenylase complex mediated by a low-complexity region in XRN1, which we term the ‘C-terminal interacting region’ or CIR. The CIR represses reporter mRNA deadenylation in human cells when overexpressed and inhibits CCR4–NOT and isolated CAF1 deadenylase activity in vitro. Through complementation studies in an XRN1-null cell line, we dissect the specific contributions of XRN1 domains and regions toward decay of an mRNA reporter. We observe that XRN1 binding to the decapping activator EDC4 counteracts the dominant negative effect of CIR overexpression on decay. Another decapping activator PatL1 directly interacts with CIR and alleviates the CIR-mediated inhibition of CCR4–NOT activity in vitro. Ribosome profiling revealed that XRN1 loss impacts not only on mRNA levels but also on the translational efficiency of many cellular transcripts likely as a consequence of incomplete decay. Our findings reveal an additional layer of direct interactions in a tightly integrated network of factors mediating deadenylation, decapping and 5′–3′ exonucleolytic decay.
- Published
- 2019
48. Pyrethroid exposure and neurotoxicity: a mechanistic approach
- Author
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Obeid Malakshah, Nasrin Ghassemi-Barghi, Hamidreza Mohammadi, and Sorour Ashari
- Subjects
Insecticides ,Parkinson's disease ,NF-E2-Related Factor 2 ,Pharmacology ,Toxicology ,medicine.disease_cause ,chemistry.chemical_compound ,Nitriles ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Pyrethrins ,parasitic diseases ,medicine ,Humans ,PPAR alpha ,Permethrin ,Pyrethroid ,business.industry ,Dopaminergic ,Neurodegeneration ,Public Health, Environmental and Occupational Health ,Neurotoxicity ,Parkinson Disease ,medicine.disease ,Deltamethrin ,chemistry ,Neurotoxicity Syndromes ,Antitoxins ,business ,Oxidative stress ,medicine.drug - Abstract
Pyrethroids are a class of synthetic insecticides that are used widely in and around households to control the pest. Concerns about exposure to this group of pesticides are now mainly related to their neurotoxicity and nigrostriatal dopaminergic neurodegeneration seen in Parkinson’s disease. The main neurotoxic mechanisms include oxidative stress, inflammation, neuronal cell loss, and mitochondrial dysfunction. The main neurodegeneration targets are ion channels. However, other receptors, enzymes, and several signalling pathways can also participate in disorders induced by pyrethroids. The aim of this review is to elucidate the main mechanisms involved in neurotoxicity caused by pyrethroids deltamethrin, permethrin, and cypermethrin. We also review common targets and pathways of Parkinson’s disease therapy, including Nrf2, Nurr1, and PPARγ, and how they are affected by exposure to pyrethroids. We conclude with possibilities to be addressed by future research of novel methods of protection against neurological disorders caused by pesticides that may also find their use in the management/treatment of Parkinson’s disease.
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- 2019
49. Activation of Peroxisome Proliferator-Activated Receptor-α Increases the Expression of Nuclear Receptor Related 1 Protein (Nurr1) in Dopaminergic Neurons
- Author
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Malabendu Jana, Carl G. Gottschalk, Kalipada Pahan, Avik Roy, and Madhuchhanda Kundu
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0301 basic medicine ,Neuroscience (miscellaneous) ,Administration, Oral ,Peroxisome proliferator-activated receptor ,Nuclear receptor related-1 protein ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Fenofibrate ,Downregulation and upregulation ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Animals ,PPAR alpha ,Promoter Regions, Genetic ,Receptor ,Transcription factor ,Neurons ,chemistry.chemical_classification ,Messenger RNA ,Base Sequence ,biology ,Dopaminergic Neurons ,Dopaminergic ,Up-Regulation ,Cell biology ,Mice, Inbred C57BL ,Substantia Nigra ,030104 developmental biology ,Neurology ,chemistry ,biology.protein ,Female ,Gemfibrozil ,Chromatin immunoprecipitation ,030217 neurology & neurosurgery - Abstract
Nuclear receptor related 1 protein (Nurr1) is an important transcription factor required for differentiation and maintenance of midbrain dopaminergic (DA) neurons. Since decrease in Nurr1 function either due to diminished expression or rare mutation is associated with Parkinson’s disease (PD), upregulation of Nurr1 may be beneficial for PD. However, such mechanisms are poorly understood. This study underlines the importance of peroxisome proliferator-activated receptor (PPAR)α in controlling the transcription of Nurr1. Our mRNA analyses followed by different immunoassays clearly indicated that PPARα agonist gemfibrozil strongly upregulated the expression of Nurr1 in wild-type, but not PPARα(−/−), DA neurons. Moreover, identification of conserved PPRE in the promoter of Nurr1 gene followed by chromatin immunoprecipitation analysis, PPRE luciferase assay, and manipulation of Nurr1 gene by viral transduction of different PPARα plasmids confirmed that PPARα was indeed involved in the expression of Nurr1. Finally, oral administration of gemfibrozil increased Nurr1 expression in vivo in nigra of wild-type, but not PPARα(−/−), mice identifying PPARα as a novel regulator of Nurr1 expression and associated protection of DA neurons.
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- 2019
50. NURR1 activation in skeletal muscle controls systemic energy homeostasis
- Author
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Joel K. Elmquist, Leonela Amoasii, Teppei Fujikawa, Eric N. Olson, Rhonda Bassel-Duby, and Efrain Sanchez-Ortiz
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Male ,medicine.medical_specialty ,Transcription, Genetic ,Transgene ,Glucose uptake ,Carbohydrate metabolism ,Energy homeostasis ,Mice ,chemistry.chemical_compound ,Physical Conditioning, Animal ,Internal medicine ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,medicine ,Animals ,Homeostasis ,Humans ,Obesity ,Muscle, Skeletal ,Multidisciplinary ,Glycogen ,business.industry ,Skeletal muscle ,Metabolism ,medicine.disease ,Up-Regulation ,Fatty Liver ,Mice, Inbred C57BL ,Glucose ,medicine.anatomical_structure ,Endocrinology ,PNAS Plus ,Liver ,chemistry ,Hyperglycemia ,Carbohydrate Metabolism ,Steatosis ,Energy Metabolism ,business - Abstract
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.
- Published
- 2019
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