Nuclear Import and Export Signals Control the Subcellular Localization of Nurr1 Protein in Response to Oxidative Stress*

García-Yagüe, Ángel Juan; Rada, Patricia; Rojo, Ana I.; Lastres‐Becker, Isabel; Cuadrado, Antonio

doi:10.1074/jbc.m112.439190

Cited by 60 publications

(53 citation statements)

References 52 publications

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“…Although Nurr1 is primarily located in the nucleus in neurons and cancer cells (Boldingh Debernard et al, 2012;Li et al, 2012;García-Yagüe et al, 2013), our data in primary microglia suggest that Nurr1 is dynamically regulated in glial cells and that its subcellular localization changes after inflammatory stimulation with LPS (Fig. 5).…”

Section: Discussionmentioning

confidence: 72%

“…In non-neuronal cells, nuclear import signals on Nurr1 may be alternatively uncovered for import into the nucleus for feedback inhibitory control over inflammatory proteins, although the mechanism is not well established (García-Yagüe et al, 2013). Here, we report that the translocation of Nurr1 from the cytosol to the nucleus in primary microglia treated with LPS occurred in both the presence and absence of C-DIM12 (Fig.…”

Section: Discussionmentioning

confidence: 76%

“…Additionally, the cellular distribution of Nurr1 appears to vary between cell types. In SH-SY5Y and MN9D neuronal cell lines, changes in the subcellular localization of Nurr1 occurred within 1 hour of sodium arsenite-induced oxidative stress, which caused exposure of a nuclear export signal (García-Yagüe et al, 2013) and thereby decreased its transcriptional activity. Similarly, the intracellular location of NR4A1/Nur77 in cancer cells is variable; for example, treatment with apoptosisinducing agents induces nuclear export of Nur77 where it forms a complex with Bcl-2 on mitochondria (Zhang et al, 2009), whereas the C-DIMs that bind the receptor activate or inactivate nuclear Nur77 (Lee et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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The Nurr1 Activator 1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane Blocks Inflammatory Gene Expression in BV-2 Microglial Cells by Inhibiting Nuclear Factor κB

et al. 2015

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NR4A family orphan nuclear receptors are an important class of transcription factors for development and homeostasis of dopaminergic neurons that also inhibit expression of inflammatory genes in glial cells. The identification of NR4A2 (Nurr1) as a suppressor of nuclear factor kB (NF-kB)-related neuroinflammatory genes in microglia and astrocytes suggests that this receptor could be a target for pharmacologic intervention in neurologic disease, but compounds that promote this activity are lacking. Selected diindolylmethane compounds (C-DIMs) have been shown to activate or inactivate nuclear receptors, including Nurr1, in cancer cells and also suppress astrocyte inflammatory signaling in vitro. Based upon these data, we postulated that C-DIM12 [1,1-bis(39-indolyl)-1-(p-chlorophenyl) methane] would suppress inflammatory signaling in microglia by a Nurr1-dependent mechanism. C-DIM12 inhibited lipopolysaccharide (LPS)-induced expression of NF-kB-regulated genes in BV-2 microglia including nitric oxide synthase (NOS2), interleukin-6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2), and the effects were attenuated by Nurr1-RNA interference. Additionally, C-DIM12 decreased NF-kB activation in NF-kB-GFP (green fluorescent protein) reporter cells and enhanced nuclear translocation of Nurr1 primary microglia. Chromatin immunoprecipitation assays indicated that C-DIM12 decreased lipopolysaccharide-induced p65 binding to the NOS2 promoter and concurrently enhanced binding of Nurr1 to the p65-binding site. Consistent with these findings, C-DIM12 also stabilized binding of the Corepressor for Repressor Element 1 Silencing Transcription Factor (CoREST) and the Nuclear Receptor Corepressor 2 (NCOR2). Collectively, these data identify C-DIM12 as a modulator of Nurr1 activity that results in inhibition of NF-kBdependent gene expression in glial cells by stabilizing nuclear corepressor proteins, which reduces binding of p65 to inflammatory gene promoters.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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The Nurr1 Activator 1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane Blocks Inflammatory Gene Expression in BV-2 Microglial Cells by Inhibiting Nuclear Factor κB

et al. 2015

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“…Unexpected data came from localization of Nurr1 immunoreactivity inside ENTs; while it was localized in the nucleus of TH-immunoreactive cells in 2D culture (plating of cells coming from dissociated neurospheres), in ENT, Nurr1 immunoreactivity was mainly localized in the cytoplasm. Oxidative stress [39] or toxicity [40] could explain this redistribution. However, in the brain and depending on the region considered, Nurr1 could be also localized in the cell cytoplasm [41].…”

Section: Fig 4 Characterization Of Th Cells Present In 2d and Ent Cmentioning

confidence: 99%

Engineering of Midbrain Organoids Containing Long-Lived Dopaminergic Neurons

TiengVannary

StoppiniLuc

VillySabrina

et al. 2014

Stem Cells and Development

103

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The possibility to generate dopaminergic (DA) neurons from pluripotent stem cells represents an unlimited source of material for tissue engineering and cell therapy for neurodegenerative disease. We set up a protocol based on the generation of size-calibrated neurospheres for a rapid production (3 weeks) of a high amount of DA neurons ( > 60%) oriented toward a midbrain-like phenotype, characterized by the expression of FOXA2, LMX1A, tyrosine hydroxylase (TH), NURR1, and EN1. By using g-secretase inhibitors and varying culture time of neurospheres, we controlled maturation and cellular composition of a three-dimensional (3D) engineered nervous tissue (ENT). ENT contained neurons and glial cells expressing various markers of maturity, such as synaptophysin, neuronal nuclei-specific protein (NeuN), and glial fibrillary acidic protein (GFAP), and were electrophysiologically active. We found that 3-week-old neurospheres were optimal to generate 3D tissue containing DA neurons with typical A9 morphology. ENT generated from 4-week-old neurospheres launched glial cell type since astrocytes and myelin could be detected massively at the expense of TH-immunoreactive neurons. All g-secretase inhibitors were not equivalent; compound E was more efficient than DAPT in generating DA neurons. This DA tissue provides a tool for drug screening, and toxicology. It should also become a useful biomaterial for studies on Parkinson's disease.

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“…Nurr1 is primarily regulated by phosphorylation of ERK/AKT, SUMOylation by protein inhibitor of activated STAT-γ, or dimerization with glucocorticoid or retinoid receptors in brain [38] . Phosphorylation of NR factors plays an important role in their subcellular translocation and Nurr1 dependent induction of apoptosis [39,40,41] .…”

Section: Regulation Of Nurr1 Expressionmentioning

confidence: 99%

Nurr1: A New Insight to Protects Dopaminergic Neurodegeneration in Parkinson’s disease

Rekha

Sivakamasundari

2015

Ther Targets Neurol Dis

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Nuclear Import and Export Signals Control the Subcellular Localization of Nurr1 Protein in Response to Oxidative Stress*

Cited by 60 publications

References 52 publications

The Nurr1 Activator 1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane Blocks Inflammatory Gene Expression in BV-2 Microglial Cells by Inhibiting Nuclear Factor κB

The Nurr1 Activator 1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane Blocks Inflammatory Gene Expression in BV-2 Microglial Cells by Inhibiting Nuclear Factor κB

Engineering of Midbrain Organoids Containing Long-Lived Dopaminergic Neurons

Nurr1: A New Insight to Protects Dopaminergic Neurodegeneration in Parkinson’s disease

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