The NR4A nuclear receptors as potential targets for anti-aging interventions

Paillasse, Michaël R.; Médina, Philippe de

doi:10.1016/j.mehy.2014.12.003

Cited by 37 publications

(27 citation statements)

References 91 publications

(137 reference statements)

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“…In support of this, an increase in metabolism is observed in muscle cells overexpressing NR4A receptors [47–49]. Thus, our findings support the hypothesis that increasing NR4A transcription or function could be a potential angle to counteract some of the effects associated with human brain aging as previously proposed [42]. …”

Section: Discussionsupporting

confidence: 88%

“…The role of NR4A receptors in brain aging is currently unknown. With human brain aging, increased DNA damage is found and since NR4A receptors may protect against DNA damage [42, 43] our finding of decreased NR4A receptors with age may contribute to loss of DNA repair in brain cells, as has been observed in damaged skin cells [44]. Another prominent event that occurs as humans age is a decrease in metabolic rate particularly in brain [45, 46] and the down regulation of NR4A synthesis may also play a role in down-regulating cellular metabolism.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptomic Analysis Shows Decreased Cortical Expression of NR4A1, NR4A2 and RXRB in Schizophrenia and Provides Evidence for Nuclear Receptor Dysregulation

et al. 2016

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Many genes are differentially expressed in the cortex of people with schizophrenia, implicating factors that control transcription more generally. Hormone nuclear receptors dimerize to coordinate context-dependent changes in gene expression. We hypothesized that members of two families of nuclear receptors (NR4As), and retinoid receptors (RARs and RXRs), are altered in the dorsal lateral prefrontal cortex (DLPFC) of people with schizophrenia. We used next generation sequencing and then qPCR analysis to test for changes in mRNA levels for transcripts encoding nuclear receptors: orphan nuclear receptors (3 in the NR4A, 3 in the RAR, 3 in the RXR families and KLF4) in total RNA extracted from the DLPFC from people with schizophrenia compared to controls (n = 74). We also correlated mRNA levels with demographic factors and with estimates of antipsychotic drug exposure (schizophrenia group only). We tested for correlations between levels of transcription factor family members and levels of genes putatively regulated by these transcription factors. We found significantly down regulated expression of NR4A1 (Nurr 77) and KLF4 mRNAs in people with schizophrenia compared to controls, by both NGS and qPCR (p = or <0.01). We also detected decreases in NR4A2 (Nurr1) and RXRB mRNAs by using qPCR in the larger cohort (p<0.05 and p<0.01, respectively). We detected decreased expression of RARG and NR4A2 mRNAs in females with schizophrenia (p<0.05). The mRNA levels of NR4A1, NR4A2 and NR4A3 were all negative correlated with lifetime estimates of antipsychotic exposure. These novel findings, which may be influenced by antipsychotic drug exposure, implicate the orphan and retinoid nuclear receptors in the cortical pathology found in schizophrenia. Genes down stream of these receptors can be dysregulated as well, but the direction of change is not immediately predictable based on the putative transcription factor changes.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis Shows Decreased Cortical Expression of NR4A1, NR4A2 and RXRB in Schizophrenia and Provides Evidence for Nuclear Receptor Dysregulation

et al. 2016

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“…NR4A receptors regulate multiple processes such as metabolism, proliferation, migration, apoptosis, DNA repair and autophagy. Accordingly, NR4A receptors are involved in several pathological processes like cardiovascular diseases, diabetes, atherosclerosis and neurodegeneration (40). Interestingly, NR4A1 expression is also induced by caloric restriction, and a reduction in expression of at least NR4A2 accompanies human aging (2).…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, in cancers from different origins, such as melanoma, breast, colon and pancreas, both pro- and anti-tumorigenic activities have been described for NR4A family proteins (7, 41). Indeed, pharmacological regulation of NR4A activity has been proposed to not only counteract aging, including cognitive decline (40), but also cancer and metabolic diseases. Therefore, understanding the mechanisms that regulate NR4A function is an active area of research.…”

Section: Discussionmentioning

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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“…Additionally, overexpression of NR4A receptors in monocytes has been shown to reduce expression and production of pro-inflammatory cytokines [63]. This appears to be at odds with what we have observed in our cohort, although it may be explained by the relationship of NR4A receptors with aging: brain NR4A receptors decrease with age [43, 65, 66] and neuroinflammation is elevated with age [67]; therefore, the decrease in NR4A receptors in the high inflammation schizophrenia group may be attributable to accelerated age-related changes associated with inflammation, the effect of which may be different in the brain compared to peripheral tissues. It may also be that the brain’s ability to decrease retinoid receptors and increase NR4A receptors may reflect a lack of normal neuroinflammatory response, rendering the brain more vulnerable to deleterious effects of inflammation in those with schizophrenia.…”

Section: Discussionmentioning

confidence: 51%

Nuclear Receptors and Neuroinflammation in Schizophrenia

et al. 2017

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Introduction: Several nuclear receptor family members have been associated with schizophrenia and inflammation. Vitamins A and D exert anti-inflammatory actions, but their receptors (mainly nuclear receptors) have not been extensively studied in either schizophrenia brains or in association with neuroinflammation. We examined the expression of vitamin A (RARs and RXRs) and vitamin D and protein disulphide-isomerase A3 (PDIA3) receptors, as well as nuclear orphan receptors (NR4As), in the context of elevated cytokine expression in the dorsolateral prefrontal cortex (DLPFC). Methods: mRNA levels of nuclear receptors were measured in DLPFC tissues via RT-qPCR. ANCOVAs comparing high inflammation schizophrenia, low inflammation schizophrenia and low inflammation control groups were performed. Results: RARG, RXRB, NR4A1 and NR4A3 transcripts showed significant differential expression across the three groups (ANCOVA p = 0.02–0.001). Post hoc testing revealed significant reductions in RARG expression in schizophrenia with low inflammation compared to schizophrenia with high inflammation and to controls, and RXRB mRNA was significantly reduced in schizophrenia with low inflammation compared to controls. NR4A1 and NR4A3 mRNAs were decreased in schizophrenia with high inflammation compared to schizophrenia with low inflammation, with NR4A1 also significantly different to controls. Conclusion: In schizophrenia, changes in nuclear receptor mRNA levels involved with mediating actions of vitamin A derivatives vary according to the inflammatory state of brains.

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The NR4A nuclear receptors as potential targets for anti-aging interventions

Cited by 37 publications

References 91 publications

Transcriptomic Analysis Shows Decreased Cortical Expression of NR4A1, NR4A2 and RXRB in Schizophrenia and Provides Evidence for Nuclear Receptor Dysregulation

Transcriptomic Analysis Shows Decreased Cortical Expression of NR4A1, NR4A2 and RXRB in Schizophrenia and Provides Evidence for Nuclear Receptor Dysregulation

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

Nuclear Receptors and Neuroinflammation in Schizophrenia

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