Non-genomic effects of the NR4A1/Nur77/TR3/NGFIB orphan nuclear receptor

Pawlak, A.L.; Strządała, Leon; Kałas, Wojciech

doi:10.1016/j.steroids.2014.12.020

Cited by 46 publications

(44 citation statements)

References 56 publications

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“…Nur77 functions through both genomic and nongenomic actions, depending on the stimuli and its subcellular localization (68). Nur77 primarily locates in the nucleus, where it acts as a transcription factor by binding to its DNA response elements to regulate the expression of multiple target genes.…”

Section: Discussionmentioning

confidence: 99%

“…Nur77 primarily locates in the nucleus, where it acts as a transcription factor by binding to its DNA response elements to regulate the expression of multiple target genes. However, Nur77 expression is induced in response to certain proapoptotic agents, and subsequently transfers from nucleus to cytoplasm and functions nongenomically through protein-protein interactions (68). …”

Section: Discussionmentioning

confidence: 99%

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Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model

Jiang

Zeng

Huang

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Acute respiratory distress syndrome (ARDS) is characterized by inflammatory injury to the alveolar and capillary barriers that results in impaired gas exchange and severe acute respiratory failure. Nuclear orphan receptor Nur77 has emerged as a regulator of gene expression in inflammation, and its role in the pathogenesis of ARDS is not clear. The objective of this study is to investigate the potential role of Nur77 and its underlying mechanism in the regulation of endothelin-1 (ET-1) expression in lipopolysaccharide (LPS)-induced A549 cells and an ARDS rat model. We demonstrate that LPS induced Nur77 expression and nuclear export in A549 cells. Overexpression of Nur77 markedly decreased basal and LPS-induced ET-1 expression in A549 cells, whereas knockdown of Nur77 increased the ET-1 expression. LPS-induced phosphorylation and nuclear translocation of NF-κB and p38 MAPK were blocked by Nur77 overexpression and augmented by Nur77 knockdown in A549 cells. In vivo, LPS induced Nur77 expression in lung in ARDS rats. Pharmacological activation of Nur77 by cytosporone B (CsnB) inhibited ET-1 expression in ARDS rats, decreased LPS-induced phosphorylation of NF-κB and p38 MAPK, and relieved lung, liver, and kidney injury. Pharmacological deactivation of Nur77 by 1,1-bis-(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH, C-DIM8) had no effect on ET-1 expression and lung injury. These results indicated that Nur77 decreases ET-1 expression by suppressing NF-κB and p38 MAPK in LPS-stimulated A549 cells in vitro, and, in an LPS-induced ARDS rat model, CsnB reduced ET-1 expression and lung injury in ARDS rats.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model

Jiang

Zeng

Huang

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Nuclear receptors represent a family of transcription factors responsible for the regulation of many intracellular pathways, such as cancer, metabolic and proliferative diseases [57,58]. They are termed orphan because their endogenous ligands have not yet been identified.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

Zhao

Yang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Mitochondrial homeostasis is implicated in the development and progression of endometriosis through poorly defined mechanisms. Mst1 is the major growth suppressor related to cancer migration, apoptosis and proliferation. However, whether Mst1 is involved in endometriosis apoptosis and migration via regulating the mitochondrial function remains to be elucidated. Methods: Expression of Mst1 in endometriosis was examined via western blots. Cellular apoptosis was detected via MTT and TUNEL assay. Gain of function assay about Mst1 was conducted via adenovirus over-expression. Mitochondrial functions were evaluated via mitochondrial membrane potential JC-1 staining, ROS flow cytometry analysis, mPTP opening assessment and immunofluorescence of HtrA2/Omi. The mitophagy activity were examined via western blots and immunofluorescence. Results: First, we found that Mst1 was significantly downregulated in the ectopic endometrium of endometriosis compared to the normal endometrium. However, the recovery of Mst1 function was closely associated with the inability of endometrial stromal cells (ESCs) to migrate and survive. A functional study indicated that regaining Mst1 enhanced Drp1 post-transcriptional phosphorylation at Ser616 and repressed Parkin transcription activity via p53, leading to mitochondrial fission activation and mitophagy inhibition. Excessive Drp1-related fission forced the mitochondria to liberate HtrA2/Omi into the cytoplasm. Moreover, Mst1-induced defective mitophagy evoked cellular

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“…In the case of melanoma cells treated with THPN, a chemical compound targeting NR4A1, cell death occurs after induction of excessive mitophagy, due to NR4A1 translocation to the inner membrane of the mitochondria, causing dissipation of mitochondrial membrane potential by the permeability pore complex ANT1/VDAC (14). Furthermore, Dendrogenin A, a mammalian cholesterol metabolite ligand of liver-X-receptors (LCRs) induces Nr4a1 expression in association with excessive autophagic cell death both in vitro and in vivo (15, 16), displaying anticancer and chemopreventive properties in mice(17). Interestingly, NR4A1 interaction with anti-apoptotic BCL2 family members outside the BH3 domain induces autophagic cell death (18), which seems to be mediated by releasing BECN1 in a model of cigarette smoke-induced autophagic cell death(19).…”

Section: Introductionmentioning

confidence: 99%

The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death

Castro-Obregón

Zárraga

Muciño-Hernández

et al. 2019

Preprint

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242 25 Abstract 26 NR4A is a nuclear receptor protein family whose members act as sensors of cellular 27 environment and regulate multiple processes such as metabolism, proliferation, migration, 28 apoptosis, and autophagy. Since the ligand binding domains of these receptors have no 29 cavity for ligand interaction, their function is most likely regulated by protein abundance 30 and post-translational modifications. In particular, NR4A1 is regulated by protein 31 abundance, phosphorylation, and subcellular distribution (nuclear-cytoplasmic 32 translocation), and acts both as a transcription factor and as a regulator of other 33 interacting proteins. SUMOylation is a post-translational modification that can affect protein 34 stability, transcriptional activity, alter protein-protein interactions and modify intracellular 35 localization of target proteins. In the present study we evaluated the role of SUMOylation 36 as a posttranslational modification that can regulate the activity of NR4A1 to induce 37 autophagy-dependent cell death. We focused on a model potentially relevant for neuronal 38 cell death and demonstrated that NR4A1 needs to be SUMOylated to induce autophagic 39 cell death. We observed that a triple mutant in SUMOylation sites has reduced 40 SUMOylation, increased transcriptional activity, altered intracellular distribution, and more 41 importantly, its ability to induce autophagic cell death is impaired. 42 43 Summary Statement 44 The modification of the nuclear receptor NR4A1 by SUMO regulates its transcriptional 45 activity, intracellular localization and is required to induce autophagic cell death.46 47 Short title: SUMOylated NR4A1 induces autosis 48 49 Keywords: 50 NR4A1, SUMO, autophagy, cell death, Substance P, NK 1 R3 51 52 Abbreviations list 53 NR4A Nuclear receptor group family A 54 NR4A1 Nuclear receptor group 4 family A member 1 (Nur77, NGF1B, TR3, etc.) 55 NR4A2 Nuclear receptor group 4 family A member 2 (Nurr1, NOT1, etc) 56 NR4A3 Nuclear receptor group 4 family A member 3 (Nor1, MINOR) 57 SUMO small ubiquitin-like modifier 58 SP Substance P 59 NK 1 R Neurokinin 1 Receptor 60 TAD Trans-Activation Domain 61 DBD DNA Binding Domain 62 LBD Ligand Binding Domain 63 PTM Post Translational Modifications 4 64 Introduction 65 Nuclear receptors are a superfamily of transcription factors involved in a vast number of 66 biological processes. They share three common structural domains: a N-terminal 67 transactivation domain (TAD), a central double zinc finger DNA binding domain (DBD) and 68 a C-terminal ligand binding domain (LBD). Among the known human nuclear receptors, 69 the ones belonging to the NR4A family act as sensors of the cellular environment and 70 contribute to cell fate decisions, such as cell proliferation, differentiation, migration, cell 71 death, etc. Physiologically, NR4A members influence the adaptive and innate immune 72 system, angiogenesis, metabolism and brain function. The NR4A family is comprised of 73 three members that bind the same DNA elements (1): NR4A1 (Nur77, TR3, ...

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Non-genomic effects of the NR4A1/Nur77/TR3/NGFIB orphan nuclear receptor

Cited by 46 publications

References 56 publications

Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model

Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death

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