p53 mediates the negative regulation of MDM2 by orphan receptor TR3

Zhao, Bixing; Chen, Hang-zi; Lei, Nazi; Li, Guideng; Zhao, Wenxiu; Zhan, Yan-yan; Liu, Bo; Lin, Sheng-Cai; Wu, Qiao

doi:10.1038/sj.emboj.7601435

Cited by 62 publications

(72 citation statements)

References 46 publications

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“…This is supported by the observation that K/Q mutants, especially at K69, K100, and K558 residues, bind MMP-2 in the extracellular medium. Eustace and colleagues (12) had clearly documented that the presence of hsp90a on the cell surface was critical for the in vitro invasiveness of HT-1080 fibrosarcoma cells (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). We further elucidate that sublethal concentrations of LBH589, which was associated with increased extracellular binding of acetylated hsp90a with MMP-2, increased invasiveness of breast cancer cells.…”

Section: Discussionmentioning

confidence: 95%

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Role of Acetylation and Extracellular Location of Heat Shock Protein 90α in Tumor Cell Invasion

Yang¹,

Rao²,

et al. 2008

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Heat shock protein (hsp) 90 is an ATP-dependent molecular chaperone that maintains the active conformation of client oncoproteins in cancer cells. An isoform, hsp90A, promotes extracellular maturation of matrix metalloproteinase (MMP)-2, involved in tumor invasion and metastasis. Knockdown of histone deacetylase (HDAC) 6, which deacetylates lysine residues in hsp90, induces reversible hyperacetylation and attenuates ATP binding and chaperone function of hsp90. Here, using mass spectrometry, we identified seven lysine residues in hsp90A that are hyperacetylated after treatment of eukaryotic cells with a pan-HDAC inhibitor that also inhibits HDAC6. Depending on the specific lysine residue in the middle domain involved, although acetylation affects ATP, cochaperone, and client protein binding to hsp90A, acetylation of all seven lysines increased the binding of hsp90A to 17-allyl-amino-demethoxy geldanamycin. Notably, after treatment with the pan-HDAC inhibitor panobinostat (LBH589), the extracellular hsp90A was hyperacetylated and it bound to MMP-2, which was associated with increased in vitro tumor cell invasiveness. Treatment with antiacetylated hsp90A antibody inhibited in vitro invasion by tumor cells. Thus, reversible hyperacetylation modulates the intracellular and extracellular chaperone function of hsp90, and targeting extracellular hyperacetylated hsp90A may undermine tumor invasion and metastasis. [Cancer Res 2008;68(12):4833-42]

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Section: Discussionmentioning

confidence: 95%

“…); and anti-FLAG (M2 monoclonal and F polyclonal), ANTI-FLAG M2 agarose, anti-h-actin (Sigma), and agarose conjugates (Upstate). Plasmids expressing FLAG (F)-hsp90 and HA-p300 have previously been described (21,22). Hsp90 mutants were generated by site-directed mutagenesis using the QuikChange kit from Stratagene (23).…”

Section: Methodsmentioning

confidence: 99%

Role of Acetylation and Extracellular Location of Heat Shock Protein 90α in Tumor Cell Invasion

Yang¹,

Rao²,

et al. 2008

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“…NR4A1 binds and inactivates p53 (Zhao et al 2006), whereas knockdown of NR4A1 or treatment of p53 WT lung cancer cells with an NR4A1 antagonist or transfection with siNR4A1 results in activation of p53 and induction of SESN2 which activates AMPKa and inhibits the mTOR pathway (Lee et al 2012). mTOR pathway inhibitors have been extensively developed for cancer chemotherapy (Baselga et al 2012, Ciruelos Gil 2014.…”

Section: Discussionmentioning

confidence: 99%

Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy

Hedrick¹,

Lee²,

Doddapaneni³

et al. 2015

Endocrine-Related Cancer

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The orphan nuclear receptor 4A1 (NR4A1) is overexpressed in mammary tumors and breast cancer cell lines. The functional activity of this receptor was investigated by RNA interference with oligonucleotides targeted to NR4A1 (siNR4A1) and by treatment with NR4A1 antagonists. Breast cancer cells were treated with NR4A1 antagonists or transfected with siNR4A. Effects on cell proliferation and apoptosis as well as specific genes associated with these responses were investigated in MCF-7, SKBR3, and MDA-MB-231 cells, and in athymic nude mice bearing MDA-MB-231 cells as xenografts. Transfection of MCF-7, MDA-MB-231, and SKBR3 breast cancer cells with siNR4A1 decreased cell proliferation and induced apoptosis in these cell lines. Transfection of breast cancer cells with siNR4A1 also decreased expression of Sp-regulated genes including survivin, bcl-2, and epidermal growth factor receptor, inhibited mTOR signaling in MCF-7 cells that express WT p53, and activated oxidative and endoplasmic reticulum stress through downregulation of thioredoxin domain-containing 5 and isocitrate dehydrogenase 1. 1,1-Bis(3 0 -indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) are NR4A1 ligands that act as NR4A1 antagonists. Treatment with selected analogs also inhibited breast cancer cell and tumor growth and induced apoptosis.The effects of C-DIM/NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. Results with siNR4A1 or C-DIMs/NR4A1 antagonists in breast cancer cells and tumors were similar to those previously reported in pancreatic, lung, and colon cancer cells. They demonstrate the potential clinical applications of NR4A1 antagonists in patients with tumors that overexpress this receptor.

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“…While knockout NR4A1 resulted in reduced p53 expression, therefore, NR4A1 might indirectly modulate the expression of SREBP‐1c via p53, then hinder excess fat accumulation in adipocytes 18, 19. It has been reported that NR4A1 could either enhance DNA‐dependent protein kinase to increase p53 transcription activity 36 or to cause mouse 3T3 cell double minute 2 (MDM2) to separation from p53, thus to protect p53 from MDM2‐mediated ubiquitination and degradation 37. Herein we confirmed the presence of p53 in adipose tissue and found that p53 expression was reduced in adipose tissues of KO mice compared to WT.…”

Section: Discussionmentioning

confidence: 99%

NR4A1 retards adipocyte differentiation or maturation via enhancing GATA2 and p53 expression

Qin

Yang

et al. 2018

J Cellular Molecular Medi

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Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor with diverse functions. It has been reported that NR4A1, as a transcriptional activator, is implicated in glucose and lipid metabolism. The aim of this study was to investigate the regulatory role of NR4A1 in adipogenesis and explore the underlying mechanisms. Quantitative real‐time PCR and Western blotting were used to analyse the expression of genes involved in synthesis and mobilization of fats in vivo and in vitro. Dual‐luciferase reporter assay was conducted to study the regulatory mechanisms of NR4A1. Our data from in vivo study confirmed that NR4A1 knockout (KO) mice fed with high‐fat diet were more prone to obesity, and gene expression levels of PPARγ and FAS were increased in KO mice compared to controls; our data from in vitro study showed that NR4A1 overexpression in 3T3‐L1 pre‐adipocytes inhibited adipogenesis. Moreover, NR4A1 enhanced GATA binding protein 2 (GATA2) expression, which in turn inhibited peroxisome proliferator‐activated receptor γ (PPARγ); NR4A1 inhibited sterol regulatory element binding transcription factor 1 (SREBP1) and its downstream gene fatty acid synthase (FAS) by up‐regulating p53. NR4A1 inhibits the differentiation and lipid accumulation of adipocytes by enhancing the expression of GATA2 and p53.

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p53 mediates the negative regulation of MDM2 by orphan receptor TR3

Cited by 62 publications

References 46 publications

Role of Acetylation and Extracellular Location of Heat Shock Protein 90α in Tumor Cell Invasion

Role of Acetylation and Extracellular Location of Heat Shock Protein 90α in Tumor Cell Invasion

Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy

NR4A1 retards adipocyte differentiation or maturation via enhancing GATA2 and p53 expression

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