Nuclear receptor signaling最新文献_第3页

Post-translational modifications of nuclear receptors and human disease. 核受体的翻译后修饰与人类疾病。

Nuclear receptor signaling Pub Date : 2012-01-01 Epub Date: 2012-02-27 DOI: 10.1621/nrs.10001

Muralidharan Anbalagan, Brandy Huderson, Leigh Murphy, Brian G Rowan

{"title":"Post-translational modifications of nuclear receptors and human disease.","authors":"Muralidharan Anbalagan, Brandy Huderson, Leigh Murphy, Brian G Rowan","doi":"10.1621/nrs.10001","DOIUrl":"https://doi.org/10.1621/nrs.10001","url":null,"abstract":"Nuclear receptors (NR) impact a myriad of physiological processes including homeostasis, reproduction, development, and metabolism. NRs are regulated by post-translational modifications (PTM) that markedly impact receptor function. Recent studies have identified NR PTMs that are involved in the onset and progression of human diseases, including cancer. The majority of evidence linking NR PTMs with disease has been demonstrated for phosphorylation, acetylation and sumoylation of androgen receptor (AR), estrogen receptor α (ERα), glucocorticoid receptor (GR) and peroxisome proliferator activated receptor γ (PPARγ). Phosphorylation of AR has been associated with hormone refractory prostate cancer and decreased disease-specific survival. AR acetylation and sumoylation increased growth of prostate cancer tumor models. AR phosphorylation reduced the toxicity of the expanded polyglutamine AR in Kennedy's Disease as a consequence of reduced ligand binding. A comprehensive evaluation of ERα phosphorylation in breast cancer revealed several sites associated with better clinical outcome to tamoxifen therapy, whereas other phosphorylation sites were associated with poorer clinical outcome. ERα acetylation and sumoylation may also have predictive value for breast cancer. GR phosphorylation and acetylation impact GR responsiveness to glucocorticoids that are used as anti-inflammatory drugs. PPARγ phosphorylation can regulate the balance between growth and differentiation in adipose tissue that is linked to obesity and insulin resistance. Sumoylation of PPARγ is linked to repression of inflammatory genes important in patients with inflammatory diseases. NR PTMs provide an additional measure of NR function that can be used as both biomarkers of disease progression, and predictive markers for patient response to NR-directed treatments.","PeriodicalId":87415,"journal":{"name":"Nuclear receptor signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1621/nrs.10001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30521203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 181

EMBO Retinoids 2011: Mechanisms, biology and pathology of signaling by retinoic acid and retinoic acid receptors. EMBO类维生素a 2011:维甲酸和维甲酸受体信号传导的机制、生物学和病理学。

Nuclear receptor signaling Pub Date : 2012-01-01 Epub Date: 2012-02-27 DOI: 10.1621/nrs.10003

Neil J McKenna

{"title":"EMBO Retinoids 2011: Mechanisms, biology and pathology of signaling by retinoic acid and retinoic acid receptors.","authors":"Neil J McKenna","doi":"10.1621/nrs.10003","DOIUrl":"https://doi.org/10.1621/nrs.10003","url":null,"abstract":"Retinoic acid (RA) is one of the principal active metabolites of vitamin A (retinol) which mediates a spectrum of critical physiological and developmental processes. Transcriptional regulation by RA is mediated primarily by members of the retinoic acid receptor (RAR) subfamily of the nuclear receptor (NR) superfamily of transcription factors. NRs bind specific genomic DNA sequence motifs and engage coregulators and components of the basal transcription machinery to effect transcriptional regulation at target gene promoters. Disruption of signaling by retinoic acid is thought to underlie the etiology of a number of inflammatory and neoplastic diseases including breast cancer and haematological malignancies. A meeting of international researchers in retinoid signaling was convened in Strasbourg in September 2011 under the auspices of the European Molecular Biology Organization (EMBO). Retinoids 2011 encompassed myriad mechanistic, biological and pathological aspects of these hormones and their cognate receptors, as well as setting these advances in the context of wider current questions on signaling by members of the NR superfamily.","PeriodicalId":87415,"journal":{"name":"Nuclear receptor signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1621/nrs.10003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30521205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 28

Use of differential scanning fluorimetry as a high-throughput assay to identify nuclear receptor ligands. 使用差示扫描荧光法作为一种高通量测定方法来鉴定核受体配体。

Nuclear receptor signaling Pub Date : 2012-01-01 Epub Date: 2012-02-27 DOI: 10.1621/nrs.10002

Kara DeSantis, Aaron Reed, Raneen Rahhal, Jeff Reinking

{"title":"Use of differential scanning fluorimetry as a high-throughput assay to identify nuclear receptor ligands.","authors":"Kara DeSantis, Aaron Reed, Raneen Rahhal, Jeff Reinking","doi":"10.1621/nrs.10002","DOIUrl":"https://doi.org/10.1621/nrs.10002","url":null,"abstract":"Identification of ligands that interact with nuclear receptors is both a major biological problem and an important initial step in drug discovery. Several in vitro and in vivo techniques are commonly used to screen ligand candidates against nuclear receptors; however, none of the current assays allow screening without modification of either the protein and/or the ligand in a high-throughput fashion. Differential scanning fluorimetry (DSF) allows unmodified potential ligands to be screened as 10µL reactions in 96-well format against partially purified protein, revealing specific interactors. As a proof of principle, we used a commercially-available nuclear receptor ligand candidate chemical library to identify interactors of the human estrogen receptor α ligand binding domain (ERα LBD). Compounds that interact specifically with ERα LBD stabilize the protein and result in an elevation of the thermal denaturation point, as monitored by the environmentally-sensitive dye SYPRO orange. We successfully identified all three compounds in the library that have previously been identified to interact with ERα, with no false positive results.","PeriodicalId":87415,"journal":{"name":"Nuclear receptor signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1621/nrs.10002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30521204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 38

Mutual information identifies sequence positions conserved within the nuclear receptor superfamily: approach reveals functionally important regions for DNA binding specificity. 互信息识别核受体超家族中保守的序列位置:方法揭示了DNA结合特异性的功能重要区域。

Nuclear receptor signaling Pub Date : 2011-02-25 DOI: 10.1621/nrs.09001

Scooter Willis, Patrick R Griffin

{"title":"Mutual information identifies sequence positions conserved within the nuclear receptor superfamily: approach reveals functionally important regions for DNA binding specificity.","authors":"Scooter Willis, Patrick R Griffin","doi":"10.1621/nrs.09001","DOIUrl":"https://doi.org/10.1621/nrs.09001","url":null,"abstract":"Members of the nuclear receptor superfamily differentiate in terms of specificity for DNA recognition and binding, oligomeric state, and ligand binding. The wide range of specificities are impressive given the high degree of sequence conservation in the DNA binding domain (DBD) and moderate sequence conservation with high structural similarity within the ligand binding domains (LBDs). Determining sequence positions that are conserved within nuclear receptor subfamilies can provide important indicators into the structural dynamics that translate to oligomeric state of the active receptor, DNA binding specificity and ligand affinity and selectivity. Here we present a method to analyze sequence data from all nuclear receptors that facilitates detection of co-evolving pairs using Mutual Information (MI). Using this method we demonstrate that MI can reveal functionally important sequence positions within the superfamily and the approach identified three sequence positions that have conserved sequence patterns across all nuclear receptors and subfamilies. Interestingly, two of the sequence positions identified are located within the DBD CII and the third was within Helix c of the DBD. These sequences are located within the heterodimer interface of PPARγ (CII) and RXRα (Helix c) based on PDB:3DZU. Helix c of PPARγ, which is not involved in the DBD dimer interface, binds the minor groove in the 5' flanking region in a consensus PPARγ response element (PPRE) and the corresponding RXRα (CII) is found in the 3' flanking region of RXRE (3DZU). As these three sequence positions represent unique identifiers for all nuclear receptors and they are located within the dimer interface of PPARγ-RXRα DBD (3DZU) interfacing with the flanking regions of the NRRE, we conclude they are critical sequence positions perhaps dictating nuclear receptor (NR) DNA binding specificity.","PeriodicalId":87415,"journal":{"name":"Nuclear receptor signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2011-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1621/nrs.09001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29723802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 5

Deciphering the nuclear bile acid receptor FXR paradigm. 破解核胆汁酸受体FXR范式。

Nuclear receptor signaling Pub Date : 2010-11-19 DOI: 10.1621/nrs.08005

Salvatore Modica, Raffaella M Gadaleta, Antonio Moschetta

引用次数: 8

PPARgamma1 and LXRalpha face a new regulator of macrophage cholesterol homeostasis and inflammatory responsiveness, AEBP1. PPARgamma1和LXRalpha面临巨噬细胞胆固醇稳态和炎症反应的新调节因子AEBP1。

Nuclear receptor signaling Pub Date : 2010-04-16 DOI: 10.1621/nrs.08004

Amin Majdalawieh, Hyo-Sung Ro

{"title":"PPARgamma1 and LXRalpha face a new regulator of macrophage cholesterol homeostasis and inflammatory responsiveness, AEBP1.","authors":"Amin Majdalawieh, Hyo-Sung Ro","doi":"10.1621/nrs.08004","DOIUrl":"https://doi.org/10.1621/nrs.08004","url":null,"abstract":"Peroxisome proliferator-activated receptor gamma1 (PPARgamma1) and liver X receptor alpha (LXRalpha) are nuclear receptors that play pivotal roles in macrophage cholesterol homeostasis and inflammation; key biological processes in atherogenesis. The activation of PPARgamma1 and LXRalpha by natural or synthetic ligands results in the transactivation of ABCA1, ABCG1, and ApoE; integral players in cholesterol efflux and reverse cholesterol transport. In this review, we describe the structure, isoforms, expression pattern, and functional specificity of PPARs and LXRs. Control of PPARs and LXRs transcriptional activity by coactivators and corepressors is also highlighted. The specific roles that PPARgamma1 and LXRalpha play in inducing macrophage cholesterol efflux mediators and antagonizing macrophage inflammatory responsiveness are summarized. Finally, this review focuses on the recently reported regulatory functions that adipocyte enhancer-binding protein 1 (AEBP1) exerts on PPARgamma1 and LXRalpha transcriptional activity in the context of macrophage cholesterol homeostasis and inflammation.","PeriodicalId":87415,"journal":{"name":"Nuclear receptor signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2010-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1621/nrs.08004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28945233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 187

DamIP: a novel method to identify DNA binding sites in vivo. DamIP:一种鉴定体内DNA结合位点的新方法。

Nuclear receptor signaling Pub Date : 2010-04-16 DOI: 10.1621/nrs.08003

Rui Xiao, Ramon Roman-Sanchez, David D Moore

{"title":"DamIP: a novel method to identify DNA binding sites in vivo.","authors":"Rui Xiao, Ramon Roman-Sanchez, David D Moore","doi":"10.1621/nrs.08003","DOIUrl":"https://doi.org/10.1621/nrs.08003","url":null,"abstract":"Identifying binding sites and target genes of transcription factors is a major biologic problem. The most commonly used current technique, chromatin immunoprecipitation (ChIP), is dependent on a high quality antibody for each protein of interest, which is not always available, and is also cumbersome, involving sequential cross-linking and reversal of cross-linking. We have developed a novel strategy to study protein DNA binding sites in vivo, which we term DamIP. By tethering a mutant form of E. coli DNA adenine methyltransferase to the target protein, the fusion protein introduces N-6-adenosine methylation to sequences proximal to the protein binding sites. DNA fragments with this modification, which is absent in eukaryotes, are detected using an antibody directed against methylated adenosine. For an initial test of the method we used human estrogen receptor alpha (hERalpha), one of the best studied transcription factors. We found that expression of Dam-hERalpha fusion proteins in MCF-7 cells introduces adenosine methylation near a series of known direct hERalpha binding sites. Specific methylation tags are also found at indirect hERalpha binding sites, including both primary binding sites for the ER interactors AP-1 and SP1, and promoters that are activated by upstream ER bound enhancers. DamIP provides a new tool for the study of DNA interacting protein function in vivo.","PeriodicalId":87415,"journal":{"name":"Nuclear receptor signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2010-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1621/nrs.08003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28945836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 20

Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism. 核受体Rev-erbalpha:一种协调昼夜节律和新陈代谢的血红素受体。

Nuclear receptor signaling Pub Date : 2010-04-16 DOI: 10.1621/nrs.08001

Lei Yin, Nan Wu, Mitchell A Lazar

引用次数: 137

PPARalpha: energy combustion, hypolipidemia, inflammation and cancer. PPARα：能量燃烧、低脂血症、炎症和癌症。

Nuclear receptor signaling Pub Date : 2010-04-16 DOI: 10.1621/nrs.08002

Sean R Pyper, Navin Viswakarma, Songtao Yu, Janardan K Reddy

{"title":"PPARalpha: energy combustion, hypolipidemia, inflammation and cancer.","authors":"Sean R Pyper, Navin Viswakarma, Songtao Yu, Janardan K Reddy","doi":"10.1621/nrs.08002","DOIUrl":"10.1621/nrs.08002","url":null,"abstract":"The peroxisome proliferator-activated receptor alpha (PPARalpha, or NR1C1) is a nuclear hormone receptor activated by a structurally diverse array of synthetic chemicals known as peroxisome proliferators. Endogenous activation of PPARalpha in liver has also been observed in certain gene knockout mouse models of lipid metabolism, implying the existence of enzymes that either generate (synthesize) or degrade endogenous PPARalpha agonists. For example, substrates involved in fatty acid oxidation can function as PPARalpha ligands. PPARalpha serves as a xenobiotic and lipid sensor to regulate energy combustion, hepatic steatosis, lipoprotein synthesis, inflammation and liver cancer. Mainly, PPARalpha modulates the activities of all three fatty acid oxidation systems, namely mitochondrial and peroxisomal beta-oxidation and microsomal omega-oxidation, and thus plays a key role in energy expenditure. Sustained activation of PPARalpha by either exogenous or endogenous agonists leads to the development of hepatocellular carcinoma resulting from sustained oxidative and possibly endoplasmic reticulum stress and liver cell proliferation. PPARalpha requires transcription coactivator PPAR-binding protein (PBP)/mediator subunit 1(MED1) for its transcriptional activity.","PeriodicalId":87415,"journal":{"name":"Nuclear receptor signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2010-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2858266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28942285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Control of oocyte release by progesterone receptor-regulated gene expression. 孕激素受体调控基因表达对卵母细胞释放的控制。

Nuclear receptor signaling Pub Date : 2009-12-31 DOI: 10.1621/nrs.07012

Rebecca L Robker, Lisa K Akison, Darryl L Russell

{"title":"Control of oocyte release by progesterone receptor-regulated gene expression.","authors":"Rebecca L Robker, Lisa K Akison, Darryl L Russell","doi":"10.1621/nrs.07012","DOIUrl":"https://doi.org/10.1621/nrs.07012","url":null,"abstract":"The progesterone receptor (PGR) is a nuclear receptor transcription factor that is essential for female fertility, in part due to its control of oocyte release from the ovary, or ovulation. In all mammals studied to date, ovarian expression of PGR is restricted primarily to granulosa cells of follicles destined to ovulate. Granulosa cell expression of PGR is induced by the pituitary Luteinizing Hormone (LH) surge via mechanisms that are not entirely understood, but which involve activation of Protein Kinase A and modification of Sp1/Sp3 transcription factors on the PGR promoter. Null mutations for PGR or treatment with PGR antagonists block ovulation in all species analyzed, including humans. The cellular mechanisms by which PGR regulates ovulation are currently under investigation, with several downstream pathways having been identified as PGR-regulated and potentially involved in follicular rupture. Interestingly, none of these PGR-regulated genes has been demonstrated to be a direct transcriptional target of PGR. Rather, in ovarian granulosa cells, PGR may act as an inducible coregulator for constitutively bound Sp1/Sp3 transcription factors, which are key regulators for a discrete cohort of ovulatory genes.","PeriodicalId":87415,"journal":{"name":"Nuclear receptor signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2009-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1621/nrs.07012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28658448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 80