NGFI-B Nuclear Orphan Receptor Nurr1 Interacts with p53 and Suppresses Its Transcriptional Activity

Zhang, Tao; Wang, Pingping; Ren, Haigang; Fan, Jun; Wang, Guanghui

doi:10.1158/1541-7786.mcr-08-0533

Cited by 38 publications

(52 citation statements)

References 46 publications

(48 reference statements)

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“…Recently, the oncogenic activities of NR4A2 are emerging. Usually, the NR4A2 as transcription factor which activation up regulates target genes leading to cell proliferation, survival and migration (Li et al, 2009;Zhang et al, 2009;Maijenburg et al, 2012). However, in this study we did not find a significant association of total NR4A2 expression with clinicopathological variables and overall survival in 84 patients with NPC.…”

Section: Discussioncontrasting

confidence: 77%

High Cytoplasmic Expression of the Orphan Nuclear Receptor NR4A2 Predicts Poor Survival in Nasopharyngeal Carcinoma

Wang

Yang²,

Li³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Section: Discussioncontrasting

confidence: 77%

High Cytoplasmic Expression of the Orphan Nuclear Receptor NR4A2 Predicts Poor Survival in Nasopharyngeal Carcinoma

Wang

Yang²,

Li³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…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%

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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“…NR4A receptors can promote cell growth and survival, activating transcription of downstream antiapoptotic and proproliferative genes. Physiologically, NR4A2 is essential for dopaminergic neuronal survival in the central nervous system, and reduced NR4A2 is implicated in Parkinson disease (5). In vitro, NR4A2 inhibits p53-mediated induction of downstream proapoptotic genes like BAX, a proapoptotic member of the Bcl-2 family (6).…”

Section: Apoptosismentioning

confidence: 99%

Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

Mohan

Aherne

Rogers

et al. 2012

Clinical Cancer Research

155

142

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Nuclear receptors are of integral importance in carcinogenesis. Manipulation of classic ligand-activated nuclear receptors, such as estrogen receptor blockade in breast cancer, is an important established cancer therapy. Orphan nuclear receptors, such as nuclear family 4 subgroup A (NR4A) receptors, have no known natural ligand(s). These elusive receptors are increasingly recognized as molecular switches in cell survival and a molecular link between inflammation and cancer. NR4A receptors act as transcription factors, altering expression of downstream genes in apoptosis (Fas-ligand, TRAIL), proliferation, DNA repair, metabolism, cell migration, inflammation (interleukin-8), and angiogenesis (VEGF). NR4A receptors are modulated by multiple cell-signaling pathways, including protein kinase A/CREB, NF-kB, phosphoinositide 3-kinase/AKT, c-jun-NH 2 -kinase, Wnt, and mitogen-activated protein kinase pathways. NR4A receptor effects are context and tissue specific, influenced by their levels of expression, posttranslational modification, and interaction with other transcription factors (RXR, PPAR-¡). The subcellular location of NR4A "nuclear receptors" is also important functionally; novel roles have been described in the cytoplasm where NR4A proteins act both indirectly and directly on the mitochondria to promote apoptosis via Bcl-2. NR4A receptors are implicated in a wide variety of malignancies, including breast, lung, colon, bladder, and prostate cancer; glioblastoma multiforme; sarcoma; and acute and/or chronic myeloid leukemia. NR4A receptors modulate response to conventional chemotherapy and represent an exciting frontier for chemotherapeutic intervention, as novel agents targeting NR4A receptors have now been developed. This review provides a concise clinical overview of current knowledge of NR4A signaling in cancer and the potential for therapeutic manipulation.

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NGFI-B Nuclear Orphan Receptor Nurr1 Interacts with p53 and Suppresses Its Transcriptional Activity

Cited by 38 publications

References 46 publications

High Cytoplasmic Expression of the Orphan Nuclear Receptor NR4A2 Predicts Poor Survival in Nasopharyngeal Carcinoma

High Cytoplasmic Expression of the Orphan Nuclear Receptor NR4A2 Predicts Poor Survival in Nasopharyngeal Carcinoma

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

Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

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