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Pesquisa : D12.644.360.024.306 [Categoria DeCS]
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[PMID]:29331651
[Au] Autor:Shen Z; Wang Y; Su Z; Kou R; Xie K; Song F
[Ad] Endereço:Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China.
[Ti] Título:Activation of p62-keap1-Nrf2 antioxidant pathway in the early stage of acetaminophen-induced acute liver injury in mice.
[So] Source:Chem Biol Interact;282:22-28, 2018 Feb 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Acetaminophen (APAP) overdose can cause severe liver failure even death. Nearly half of drug-induced liver injury is attributed to APAP in the US and many European countries. Oxidative stress has been validated as a critical event involved in APAP-induced liver failure. p62/SQSTM1, a selective autophagy adaptor protein, is reported to regulate Nrf2-ARE antioxidant pathway in response to oxidative stress. However, the exact role of p62-keap1-Nrf2 antioxidant pathway in APAP-induced hepatotoxicity remains unknown. In the present study, the dose-response and time-course model in C57/BL6 mice were established by intraperitoneal injection of APAP. The results of serum alanine/aspartate aminotransferases (ALT/AST) and histological examination demonstrated that APAP overdose resulted in the severe liver injury. In the meantime, the levels of p62, phospho-p62 and nuclear Nrf2 were significantly increased by APAP in mice liver, suggesting an activation of p62-keap1-Nrf2 pathway. In addition, the expression of GSTA1 mRNA was increased in a dose-dependent manner, while the mRNA levels of HO-1 and GCLC were decreased with the increase of APAP dose. Our further investigation found that expression of HO-1 and GCLC peaked at 3 h∼6 h, and then were decreased gradually. Taken together, these results indicated that p62-keap1-Nrf2 antioxidant pathway was primarily activated in the early stage of APAP hepatotoxicity, which might play a protective role in the process of APAP-induced acute liver injury.
[Mh] Termos MeSH primário: Antioxidantes/metabolismo
Doença Hepática Induzida por Substâncias e Drogas/metabolismo
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo
Fígado/metabolismo
Fator 2 Relacionado a NF-E2/metabolismo
Proteína Sequestossoma-1/metabolismo
[Mh] Termos MeSH secundário: Acetaminofen/farmacologia
Animais
Modelos Animais de Doenças
Fígado/efeitos dos fármacos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Estresse Oxidativo/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Keap1 protein, mouse); 0 (Kelch-Like ECH-Associated Protein 1); 0 (NF-E2-Related Factor 2); 0 (Nfe2l2 protein, mouse); 0 (Sequestosome-1 Protein); 0 (Sqstm1 protein, mouse); 362O9ITL9D (Acetaminophen)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180115
[St] Status:MEDLINE


  2 / 923 MEDLINE  
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[PMID]:29223570
[Au] Autor:Tian B; Lu ZN; Guo XL
[Ad] Endereço:Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
[Ti] Título:Regulation and role of nuclear factor-E2-related factor 2 (Nrf2) in multidrug resistance of hepatocellular carcinoma.
[So] Source:Chem Biol Interact;280:70-76, 2018 Jan 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Hepatocellular carcinoma (HCC) chemoresistance, which is regarded as a kind of stress management reaction to chemotherapy drugs, severely hinders the therapy outcomes of HCC treatment. Stress management is generally achieved by activating certain signal pathways and chemical factors, among which, nuclear factor-E2-related factor2 (Nrf2) is a key factor in HCC chemoresistance formation. Nrf2 is a nuclear factor that coordinates the induction and expression of a battery of genes encoding cytoprotective proteins when participating in the Nrf2antioxidant response element (Nrf2/ARE) pathway, which is one of the most important intracellular antioxidant stress pathways. This review summarizes the recent understanding of the involvement of Nrf2 in the chemoresistance of liver cancer, its target proteins, expression regulation and potential Nrf2 inhibitors that sensitize chemotherapy drugs in HCC.
[Mh] Termos MeSH primário: Carcinoma Hepatocelular/patologia
Neoplasias Hepáticas/patologia
Fator 2 Relacionado a NF-E2/metabolismo
[Mh] Termos MeSH secundário: Transportadores de Cassetes de Ligação de ATP/metabolismo
Antineoplásicos/farmacologia
Antineoplásicos/uso terapêutico
Carcinoma Hepatocelular/tratamento farmacológico
Carcinoma Hepatocelular/metabolismo
Proteínas Culina/metabolismo
Resistência a Medicamentos Antineoplásicos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo
Neoplasias Hepáticas/tratamento farmacológico
Neoplasias Hepáticas/metabolismo
Fator 2 Relacionado a NF-E2/antagonistas & inibidores
Fator 2 Relacionado a NF-E2/genética
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (ATP-Binding Cassette Transporters); 0 (Antineoplastic Agents); 0 (CUL3 protein, human); 0 (Cullin Proteins); 0 (KEAP1 protein, human); 0 (Kelch-Like ECH-Associated Protein 1); 0 (NF-E2-Related Factor 2)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180129
[Lr] Data última revisão:
180129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171211
[St] Status:MEDLINE


  3 / 923 MEDLINE  
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[PMID]:28965760
[Au] Autor:Bar-Peled L; Kemper EK; Suciu RM; Vinogradova EV; Backus KM; Horning BD; Paul TA; Ichu TA; Svensson RU; Olucha J; Chang MW; Kok BP; Zhu Z; Ihle NT; Dix MM; Jiang P; Hayward MM; Saez E; Shaw RJ; Cravatt BF
[Ad] Endereço:The Skaggs Institute for Chemical Biology and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: lironbp@scripps.edu.
[Ti] Título:Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer.
[So] Source:Cell;171(3):696-709.e23, 2017 Oct 19.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The transcription factor NRF2 is a master regulator of the cellular antioxidant response, and it is often genetically activated in non-small-cell lung cancers (NSCLCs) by, for instance, mutations in the negative regulator KEAP1. While direct pharmacological inhibition of NRF2 has proven challenging, its aberrant activation rewires biochemical networks in cancer cells that may create special vulnerabilities. Here, we use chemical proteomics to map druggable proteins that are selectively expressed in KEAP1-mutant NSCLC cells. Principal among these is NR0B1, an atypical orphan nuclear receptor that we show engages in a multimeric protein complex to regulate the transcriptional output of KEAP1-mutant NSCLC cells. We further identify small molecules that covalently target a conserved cysteine within the NR0B1 protein interaction domain, and we demonstrate that these compounds disrupt NR0B1 complexes and impair the anchorage-independent growth of KEAP1-mutant cancer cells. Our findings designate NR0B1 as a druggable transcriptional regulator that supports NRF2-dependent lung cancers.
[Mh] Termos MeSH primário: Carcinoma Pulmonar de Células não Pequenas/química
Carcinoma Pulmonar de Células não Pequenas/genética
Neoplasias Pulmonares/química
Neoplasias Pulmonares/genética
Proteoma/análise
Transcriptoma
[Mh] Termos MeSH secundário: Carcinoma Pulmonar de Células não Pequenas/metabolismo
Linhagem Celular Tumoral
Cisteína/metabolismo
Receptor Nuclear Órfão DAX-1/metabolismo
Redes Reguladoras de Genes
Seres Humanos
Proteína 1 Associada a ECH Semelhante a Kelch/genética
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo
Ligantes
Neoplasias Pulmonares/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DAX-1 Orphan Nuclear Receptor); 0 (KEAP1 protein, human); 0 (Kelch-Like ECH-Associated Protein 1); 0 (Ligands); 0 (NR0B1 protein, human); 0 (Proteome); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171112
[Lr] Data última revisão:
171112
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171003
[St] Status:MEDLINE


  4 / 923 MEDLINE  
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[PMID]:28928081
[Au] Autor:Liao W; Fu Z; Zou Y; Wen D; Ma H; Zhou F; Chen Y; Zhang M; Zhang W
[Ad] Endereço:Department of Nephrology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
[Ti] Título:MicroRNA-140-5p attenuated oxidative stress in Cisplatin induced acute kidney injury by activating Nrf2/ARE pathway through a Keap1-independent mechanism.
[So] Source:Exp Cell Res;360(2):292-302, 2017 Nov 15.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Oxidative stress was predominantly involved in the pathogenesis of acute kidney injury (AKI). Recent studies had reported the protective role of specific microRNAs (miRNAs) against oxidative stress. Hence, we investigated the levels of miR140-5p and its functional role in the pathogenesis of Cisplatin induced AKI. A mice Cisplatin induced-AKI model was established. We found that miR-140-5p expression was markedly increased in mice kidney. Bioinformatics analysis revealed nuclear factor erythroid 2-related factor (Nrf2) was a potential target of miR-140-5p, We demonstrated that miR-140-5p did not affect Kelch-like ECH-associated protein 1 (Keap1) level but directly targeted the 3'-UTR of Nrf2 mRNA and played a positive role in the regulation of Nrf2 expression which was confirmed by luciferase activity assay and western blot. What was more, consistent with miR140-5p expression, the mRNA and protein levels of Nrf2, as well as antioxidant response element (ARE)-driven genes Heme Oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase l (NQO1) were significantly increased in mice kidney tissues. In vitro study, Enforced expression of miR-140-5p in HK2 cells significantly attenuated oxidative stress by decreasing ROS level and increasing the expression of manganese superoxide dismutase (MnSOD). Simultaneously, miR-140-5p decreased lactate dehydrogenase (LDH) leakage and improved cell vitality in HK2 cells under Cisplatin-induced oxidative stress. However, HK2 cells transfected with a siRNA targeting Nrf2 abrogated the protective effects of miR-140-5p against oxidative stress. These results indicated that miR-140-5p might exert its anti-oxidative stress function via targeting Nrf2. Our findings showed the novel transcriptional role of miR140-5p in the expression of Nrf2 and miR-140-5p protected against Cisplatin induced oxidative stress by activating Nrf2-dependent antioxidant pathway, providing a potentially therapeutic target in acute kidney injury.
[Mh] Termos MeSH primário: Lesão Renal Aguda/induzido quimicamente
Elementos de Resposta Antioxidante/efeitos dos fármacos
Cisplatino/farmacologia
Citoproteção/genética
MicroRNAs/fisiologia
Fator 2 Relacionado a NF-E2/genética
Estresse Oxidativo/genética
[Mh] Termos MeSH secundário: Lesão Renal Aguda/genética
Lesão Renal Aguda/metabolismo
Animais
Elementos de Resposta Antioxidante/fisiologia
Células Cultivadas
Citoproteção/efeitos dos fármacos
Células HEK293
Seres Humanos
Proteína 1 Associada a ECH Semelhante a Kelch/fisiologia
Rim/efeitos dos fármacos
Rim/metabolismo
Rim/patologia
Masculino
Camundongos
Fator 2 Relacionado a NF-E2/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
Transdução de Sinais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Keap1 protein, mouse); 0 (Kelch-Like ECH-Associated Protein 1); 0 (MIRN140 microRNA, mouse); 0 (MicroRNAs); 0 (NF-E2-Related Factor 2); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE


  5 / 923 MEDLINE  
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[PMID]:28842501
[Au] Autor:Suzuki T; Yamamoto M
[Ad] Endereço:From the Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
[Ti] Título:Stress-sensing mechanisms and the physiological roles of the Keap1-Nrf2 system during cellular stress.
[So] Source:J Biol Chem;292(41):16817-16824, 2017 Oct 13.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Transcription factor Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes and suppresses the induction of pro-inflammatory cytokine genes. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of Cullin 3-based E3 ubiquitin ligase. Keap1 regulates the activity of Nrf2 and acts as a sensor for oxidative and electrophilic stresses. In this review, we discuss the molecular mechanisms by which the Keap1-Nrf2 system senses and regulates the cellular response to environmental stresses. In particular, we focus on the multiple stress-sensing mechanisms of Keap1 and novel regulatory functions of Nrf2.
[Mh] Termos MeSH primário: Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo
Fator 2 Relacionado a NF-E2/metabolismo
Estresse Fisiológico
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Oxirredução
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (KEAP1 protein, human); 0 (Kelch-Like ECH-Associated Protein 1); 0 (NF-E2-Related Factor 2); 0 (NFE2L2 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170827
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.R117.800169


  6 / 923 MEDLINE  
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[PMID]:28801166
[Au] Autor:Bresciani A; Missineo A; Gallo M; Cerretani M; Fezzardi P; Tomei L; Cicero DO; Altamura S; Santoprete A; Ingenito R; Bianchi E; Pacifici R; Dominguez C; Munoz-Sanjuan I; Harper S; Toledo-Sherman L; Park LC
[Ad] Endereço:IRBM Science Park S.p.A., Pomezia, Roma, Italy.
[Ti] Título:Nuclear factor (erythroid-derived 2)-like 2 (NRF2) drug discovery: Biochemical toolbox to develop NRF2 activators by reversible binding of Kelch-like ECH-associated protein 1 (KEAP1).
[So] Source:Arch Biochem Biophys;631:31-41, 2017 Oct 01.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mechanisms that activate innate antioxidant responses, as a way to mitigate oxidative stress at the site of action, hold much therapeutic potential in diseases, such as Parkinson's disease, Alzheimer's disease and Huntington's disease, where the use of antioxidants as monotherapy has not yielded positive results. The nuclear factor NRF2 is a transcription factor whose activity upregulates the expression of cell detoxifying enzymes in response to oxidative stress. NRF2 levels are modulated by KEAP1, a sensor of oxidative stress. KEAP1 binds NRF2 and facilitates its ubiquitination and subsequent degradation. Recently, compounds that reversibly disrupt the NRF2-KEAP1 interaction have been described, opening the field to a new era of safer NRF2 activators. This paper describes a set of new, robust and informative biochemical assays that enable the selection and optimization of non-covalent KEAP1 binders. These include a time-resolved fluorescence resonance energy transfer (TR-FRET) primary assay with high modularity and robustness, a surface plasmon resonance (SPR) based KEAP1 direct binding assay that enables the quantification and analysis of full kinetic binding parameters and finally a H- N heteronuclear single quantum coherence (HSQC) NMR assay suited to study the interaction surface of KEAP1 with residue-specific information to validate the interaction of ligands in the KEAP1 binding site.
[Mh] Termos MeSH primário: Antioxidantes/farmacologia
Descoberta de Drogas/métodos
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo
Fator 2 Relacionado a NF-E2/agonistas
Fator 2 Relacionado a NF-E2/metabolismo
Mapas de Interação de Proteínas/efeitos dos fármacos
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Antioxidantes/química
Sítios de Ligação
Transferência Ressonante de Energia de Fluorescência/métodos
Seres Humanos
Repetição Kelch/efeitos dos fármacos
Proteína 1 Associada a ECH Semelhante a Kelch/química
Ligantes
Espectroscopia de Ressonância Magnética/métodos
Modelos Moleculares
Estresse Oxidativo/efeitos dos fármacos
Bibliotecas de Moléculas Pequenas/química
Bibliotecas de Moléculas Pequenas/farmacologia
Ressonância de Plasmônio de Superfície/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antioxidants); 0 (KEAP1 protein, human); 0 (Kelch-Like ECH-Associated Protein 1); 0 (Ligands); 0 (NF-E2-Related Factor 2); 0 (NFE2L2 protein, human); 0 (Small Molecule Libraries)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170813
[St] Status:MEDLINE


  7 / 923 MEDLINE  
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[PMID]:28778421
[Au] Autor:Goto Y; Koyasu S; Kobayashi M; Harada H
[Ad] Endereço:Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
[Ti] Título:The emerging roles of the ubiquitination/deubiquitination system in tumor radioresistance regarding DNA damage responses, cell cycle regulation, hypoxic responses, and antioxidant properties: Insight into the development of novel radiosensitizing strategies.
[So] Source:Mutat Res;803-805:76-81, 2017 Oct.
[Is] ISSN:1873-135X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Radiation therapy is one of the first-line treatments for many cancers, with no less than half of cancer patients receiving it in the US. Despite the development of innovative and high-precision radiation therapy strategies, many patients still experience local tumor recurrence after the treatment, at least in part, due to the existence of radioresistant cells in malignant tumor tissues. Among the various biological processes known to induce radioresistance, a post-translational protein modification, ubiquitination, has received marked attention in recent years. Ubiquitination, in which highly conserved ubiquitin polypeptides are covalently attached to their target proteins, has long been recognized as a system to tag unnecessary proteins for 26S proteasome-dependent proteolysis. However, accumulating lines of evidence recently revealed that it acts as a signal molecule in diverse biological processes as well, and its functional disorder was found to cause not only tumor development and various diseases but also tumor radioresistance. The present review summarizes the latest knowledge about how the cancer-related disorder of the ubiquitination systems induces the radioresistance of cancer cells by influencing intrinsic pathways, each of which potentially affects the radioresistance/radiosensitivity of cells, such as DNA damage responses, cell cycle regulation, hypoxic responses, and antioxidant properties. In addition, this review aims to provide insights into how we can exploit the disorders in order to develop novel radiosensitizing strategies.
[Mh] Termos MeSH primário: Pontos de Checagem do Ciclo Celular
Dano ao DNA
Tolerância a Radiação
Ubiquitinação
[Mh] Termos MeSH secundário: Antioxidantes/farmacologia
Hipóxia Celular
Linhagem Celular Tumoral
Ensaios Clínicos Fase I como Assunto
Seres Humanos
Proteína 1 Associada a ECH Semelhante a Kelch/genética
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo
Fator 2 Relacionado a NF-E2/genética
Fator 2 Relacionado a NF-E2/metabolismo
Processamento de Proteína Pós-Traducional
Radiossensibilizantes/farmacologia
Proteína Supressora de Tumor p53/genética
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antioxidants); 0 (KEAP1 protein, human); 0 (Kelch-Like ECH-Associated Protein 1); 0 (NF-E2-Related Factor 2); 0 (NFE2L2 protein, human); 0 (Radiation-Sensitizing Agents); 0 (Tumor Suppressor Protein p53)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171011
[Lr] Data última revisão:
171011
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170806
[St] Status:MEDLINE


  8 / 923 MEDLINE  
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[PMID]:28736239
[Au] Autor:Long MJ; Lin HY; Parvez S; Zhao Y; Poganik JR; Huang P; Aye Y
[Ad] Endereço:Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
[Ti] Título:ß-TrCP1 Is a Vacillatory Regulator of Wnt Signaling.
[So] Source:Cell Chem Biol;24(8):944-957.e7, 2017 Aug 17.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Simultaneous hyperactivation of Wnt and antioxidant response (AR) are often observed during oncogenesis. However, it remains unclear how the ß-catenin-driven Wnt and the Nrf2-driven AR mutually regulate each other. The situation is compounded because many players in these two pathways are redox sensors, rendering bolus redox signal-dosing methods uninformative. Herein we examine the ramifications of single-protein target-specific AR upregulation in various knockdown lines. Our data document that Nrf2/AR strongly inhibits ß-catenin/Wnt. The magnitude and mechanism of this negative regulation are dependent on the direct interaction between ß-catenin N terminus and ß-TrCP1 (an antagonist of both Nrf2 and ß-catenin), and independent of binding between Nrf2 and ß-TrCP1. Intriguingly, ß-catenin positively regulates AR. Because AR is a negative regulator of Wnt regardless of ß-catenin N terminus, this switch of function is likely sufficient to establish a new Wnt/AR equilibrium during tumorigenesis.
[Mh] Termos MeSH primário: Proteínas Wnt/metabolismo
Proteínas Contendo Repetições de beta-Transducina/metabolismo
[Mh] Termos MeSH secundário: Aldeídos/toxicidade
Antioxidantes/química
Antioxidantes/metabolismo
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores
Glicogênio Sintase Quinase 3 beta/genética
Glicogênio Sintase Quinase 3 beta/metabolismo
Células HEK293
Células HeLa
Seres Humanos
Proteína 1 Associada a ECH Semelhante a Kelch/química
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo
Fator 2 Relacionado a NF-E2/antagonistas & inibidores
Fator 2 Relacionado a NF-E2/metabolismo
PTEN Fosfo-Hidrolase/antagonistas & inibidores
PTEN Fosfo-Hidrolase/genética
PTEN Fosfo-Hidrolase/metabolismo
Ligação Proteica
Isoformas de Proteínas/antagonistas & inibidores
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Interferência de RNA
RNA Interferente Pequeno/metabolismo
Via de Sinalização Wnt/efeitos dos fármacos
beta Catenina/antagonistas & inibidores
beta Catenina/metabolismo
Proteínas Contendo Repetições de beta-Transducina/antagonistas & inibidores
Proteínas Contendo Repetições de beta-Transducina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aldehydes); 0 (Antioxidants); 0 (Kelch-Like ECH-Associated Protein 1); 0 (NF-E2-Related Factor 2); 0 (Protein Isoforms); 0 (RNA, Small Interfering); 0 (Wnt Proteins); 0 (beta Catenin); 0 (beta-Transducin Repeat-Containing Proteins); 0 (tert-4-hydroxy-2-nonenal); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta); EC 3.1.3.67 (PTEN Phosphohydrolase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170725
[St] Status:MEDLINE


  9 / 923 MEDLINE  
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[PMID]:28684421
[Au] Autor:Perez-Leal O; Barrero CA; Merali S
[Ad] Endereço:From the Department of Pharmaceutical Sciences, Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140 operez@temple.edu.
[Ti] Título:Pharmacological stimulation of nuclear factor (erythroid-derived 2)-like 2 translation activates antioxidant responses.
[So] Source:J Biol Chem;292(34):14108-14121, 2017 Aug 25.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of the antioxidant response, and its function is tightly regulated at the transcriptional, translational, and post-translational levels. It is well-known that Nrf2 is regulated at the protein level by proteasomal degradation via Kelch-like ECH-associated protein 1 (Keap1), but how Nrf2 is regulated at the translational level is less clear. Here, we show that pharmacological stimulation increases Nrf2 levels by overcoming basal translational repression. We developed a novel reporter assay that enabled identification of natural compounds that induce Nrf2 translation by a mechanism independent of Keap1-mediated degradation. Apigenin, resveratrol, and piceatannol all induced Nrf2 translation. More importantly, the pharmacologically induced Nrf2 overcomes Keap1 regulation, translocates to the nucleus, and activates the antioxidant response. We conclude that translational regulation controls physiological levels of Nrf2, and this can be modulated by apigenin, resveratrol, and piceatannol. Also, targeting this mechanism with novel compounds could provide new insights into prevention and treatment of multiple diseases in which oxidative stress plays a significant role.
[Mh] Termos MeSH primário: Elementos de Resposta Antioxidante/efeitos dos fármacos
Antioxidantes/farmacologia
Núcleo Celular/efeitos dos fármacos
Regulação da Expressão Gênica/efeitos dos fármacos
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo
Fator 2 Relacionado a NF-E2/agonistas
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/efeitos dos fármacos
Apigenina/farmacologia
Sistemas CRISPR-Cas
Núcleo Celular/metabolismo
Genes Reporter/efeitos dos fármacos
Células HEK293
Células Hep G2
Seres Humanos
Proteína 1 Associada a ECH Semelhante a Kelch/antagonistas & inibidores
Proteína 1 Associada a ECH Semelhante a Kelch/genética
Luciferases/genética
Luciferases/metabolismo
Mutação
Fator 2 Relacionado a NF-E2/química
Fator 2 Relacionado a NF-E2/genética
Fator 2 Relacionado a NF-E2/metabolismo
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos
Complexo de Endopeptidases do Proteassoma/metabolismo
Proteólise/efeitos dos fármacos
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Bibliotecas de Moléculas Pequenas
Estilbenos/farmacologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (KEAP1 protein, human); 0 (Kelch-Like ECH-Associated Protein 1); 0 (NF-E2-Related Factor 2); 0 (NFE2L2 protein, human); 0 (Peptide Fragments); 0 (Recombinant Fusion Proteins); 0 (Small Molecule Libraries); 0 (Stilbenes); 6KS3LS0D4F (3,3',4,5'-tetrahydroxystilbene); 7V515PI7F6 (Apigenin); EC 1.13.12.- (Luciferases); EC 3.4.25.1 (Proteasome Endopeptidase Complex); Q369O8926L (resveratrol)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.770925


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[PMID]:28674188
[Au] Autor:Murakami S; Suzuki T; Harigae H; Romeo PH; Yamamoto M; Motohashi H
[Ad] Endereço:Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
[Ti] Título:NRF2 Activation Impairs Quiescence and Bone Marrow Reconstitution Capacity of Hematopoietic Stem Cells.
[So] Source:Mol Cell Biol;37(19), 2017 Oct 01.
[Is] ISSN:1098-5549
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tissue stem cells are maintained in quiescence under physiological conditions but proliferate and differentiate to replenish mature cells under stressed conditions. The KEAP1-NRF2 system plays an essential role in stress response and cytoprotection against redox disturbance. To clarify the role of the KEAP1-NRF2 system in tissue stem cells, we focused on hematopoiesis in this study and used -deficient mice to examine the effects of persistent activation of NRF2 on long-term hematopoietic stem cells (LT-HSCs). We found that persistent activation of NRF2 due to deficiency did not change the number of LT-HSCs but reduced their quiescence in steady-state hematopoiesis. During hematopoietic regeneration after bone marrow (BM) transplantation, persistent activation of NRF2 reduced the BM reconstitution capacity of LT-HSCs, suggesting that NRF2 reduces the quiescence of LT-HSCs and promotes their differentiation, leading to eventual exhaustion. Transient activation of NRF2 by an electrophilic reagent also promotes the entry of LT-HSCs into the cell cycle. Taken together, our findings show that NRF2 drives the cell cycle entry and differentiation of LT-HSCs at the expense of their quiescence and maintenance, an effect that appears to be beneficial for prompt recovery from blood loss. We propose that the appropriate control of NRF2 activity by KEAP1 is essential for maintaining HSCs and guarantees their stress-induced regenerative response.
[Mh] Termos MeSH primário: Células-Tronco Hematopoéticas/citologia
Proteína 1 Associada a ECH Semelhante a Kelch/genética
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo
Fator 2 Relacionado a NF-E2/genética
Fator 2 Relacionado a NF-E2/metabolismo
[Mh] Termos MeSH secundário: Animais
Transplante de Medula Óssea
Regeneração Óssea
Ciclo Celular
Diferenciação Celular
Proliferação Celular
Células Cultivadas
Células-Tronco Hematopoéticas/metabolismo
Camundongos
Camundongos Transgênicos
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KEAP1 protein, human); 0 (Kelch-Like ECH-Associated Protein 1); 0 (NF-E2-Related Factor 2); 0 (Nfe2l2 protein, mouse); 0 (Reactive Oxygen Species)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170705
[St] Status:MEDLINE



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