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  1 / 2210 MEDLINE  
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[PMID]:29366480
[Au] Autor:Zhang N; Zhang Y; Zhao S; Sun Y
[Ad] Endereço:Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, Liaoning 110001, PR China.
[Ti] Título:Septin4 as a novel binding partner of PARP1 contributes to oxidative stress induced human umbilical vein endothelial cells injure.
[So] Source:Biochem Biophys Res Commun;496(2):621-627, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Oxidative stress induced vascular endothelial cell injure is one of the key and initial event in the development of atherosclerosis. Septin4, as a member of GTP binding protein family, is widely expressed in the eukaryotic cells and considered to be an essential component of the cytoskeleton which is involved in many important physiological processes. However, whether Septin4 is involved in cardiovascular diseases, such as oxidative stress inducted endothelial cell injury still unclear. PARP1 as a DNA repair enzyme can be activated by identifying DNA damaged fragments, which consumes high levels of energy and leads to vascular endothelial cell apoptosis. Here, our results first found that Septin4 is involved in oxidative stress induced endothelial cell ROS production and apoptosis through knock-down and over-expression Septin4 approaches. Furthermore, to explore how Septin4 is involved in oxidative stress induced endothelial cells injure, we first identified that Septin4 is a novel PARP1 interacting protein and the interaction is enhanced under oxidative stress. In conclusions, our founding indicates that Septin4 is a novel essential factor involved in oxidative stress induced vascular endothelial cell injury by interacting with apoptosis-related protein PARP1.
[Mh] Termos MeSH primário: Células Endoteliais/metabolismo
Estresse Oxidativo
Poli(ADP-Ribose) Polimerase-1/metabolismo
Mapas de Interação de Proteínas
Septinas/metabolismo
[Mh] Termos MeSH secundário: Apoptose
Células Endoteliais/citologia
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Ligação Proteica
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Reactive Oxygen Species); EC 2.4.2.30 (PARP1 protein, human); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1); EC 3.6.1.- (SEPT4 protein, human); EC 3.6.1.- (Septins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180126
[St] Status:MEDLINE


  2 / 2210 MEDLINE  
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[PMID]:29362359
[Au] Autor:Naumann M; Pal A; Goswami A; Lojewski X; Japtok J; Vehlow A; Naujock M; Günther R; Jin M; Stanslowsky N; Reinhardt P; Sterneckert J; Frickenhaus M; Pan-Montojo F; Storkebaum E; Poser I; Freischmidt A; Weishaupt JH; Holzmann K; Troost D; Ludolph AC; Boeckers TM; Liebau S; Petri S; Cordes N; Hyman AA; Wegner F; Grill SW; Weis J; Storch A; Hermann A
[Ad] Endereço:Department of Neurology, Technische Universität Dresden, 01307, Dresden, Germany.
[Ti] Título:Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation.
[So] Source:Nat Commun;9(1):335, 2018 01 23.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Cytoplasmic fused in sarcoma (FUS) aggregates are pathological hallmarks of FUS-ALS. Proper shuttling between the nucleus and cytoplasm is essential for physiological cell function. However, the initial event in the pathophysiology of FUS-ALS remains enigmatic. Using human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs), we show that impairment of poly(ADP-ribose) polymerase (PARP)-dependent DNA damage response (DDR) signaling due to mutations in the FUS nuclear localization sequence (NLS) induces additional cytoplasmic FUS mislocalization which in turn results in neurodegeneration and FUS aggregate formation. Our work suggests that a key pathophysiologic event in ALS is upstream of aggregate formation. Targeting DDR signaling could lead to novel therapeutic routes for ameliorating ALS.
[Mh] Termos MeSH primário: Esclerose Amiotrófica Lateral/metabolismo
Dano ao DNA
Neurônios Motores/metabolismo
Mutação
Agregação Patológica de Proteínas/metabolismo
Proteína FUS de Ligação a RNA/metabolismo
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/genética
Idoso
Idoso de 80 Anos ou mais
Esclerose Amiotrófica Lateral/genética
Esclerose Amiotrófica Lateral/patologia
Diferenciação Celular
Núcleo Celular/metabolismo
Citoplasma/metabolismo
Feminino
Expressão Gênica
Seres Humanos
Células-Tronco Pluripotentes Induzidas/metabolismo
Células-Tronco Pluripotentes Induzidas/patologia
Masculino
Meia-Idade
Neurônios Motores/patologia
Sinais de Localização Nuclear/genética
Sinais de Localização Nuclear/metabolismo
Poli(ADP-Ribose) Polimerase-1/genética
Poli(ADP-Ribose) Polimerase-1/metabolismo
Agregação Patológica de Proteínas/genética
Agregação Patológica de Proteínas/patologia
Proteína FUS de Ligação a RNA/genética
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Nuclear Localization Signals); 0 (RNA-Binding Protein FUS); EC 2.4.2.30 (PARP1 protein, human); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180125
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02299-1


  3 / 2210 MEDLINE  
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[PMID]:29421518
[Au] Autor:Luo H; Liang H; Chen Y; Chen S; Xu Y; Xu L; Liu J; Zhou K; Peng J; Guo G; Lai B; Song L; Yang H; Liu L; Peng J; Liu Z; Tang L; Chen W; Tang H
[Ad] Endereço:Department of Environmental and Occupational Health, Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, China.
[Ti] Título:miR-7-5p overexpression suppresses cell proliferation and promotes apoptosis through inhibiting the ability of DNA damage repair of PARP-1 and BRCA1 in TK6 cells exposed to hydroquinone.
[So] Source:Chem Biol Interact;283:84-90, 2018 Mar 01.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Hydroquinone (HQ), one of the major metabolic products of benzene, is a carcinogen, which induces apoptosis and inhibit proliferation in lymphoma cells. microRNA-7-5p (miR-7-5p), a tumor suppressor, participates in various biological processes including cell proliferation and apoptosis regulation by repressing expression of specific oncogenic target genes. To explore whether miR-7-5p is involved in HQ-induced cell proliferation and apoptosis, we assessed the effect of miR-7-5p overexpression on induction of apoptosis analyzed by FACSCalibur flow cytometer in transfection of TK6 cells with miR-7-5p mimic (TK6- miR-7-5p). We observed an increased apoptosis by 25.43% and decreased proliferation by 28.30% in TK6-miR-7-5p cells compared to those negative control cells (TK6-shNC) in response to HQ treatment. Furthermore, HQ might active the apoptotic pathway via partly downregulation the expression of BRCA1 and PARP-1, followed by p53 activation, in TK6-miR-7-5p cells. In contrast, attenuated p53 and BRCA1 expression was observed in shPARP-1 cells than in NC cells after HQ treatment. Therefore, we conclude that HQ may activate apoptotic signals via inhibiting the tumor suppressive effects of miR-7-5p, which may be mediated partly by upregulating the expression of PARP-1 and BRCA1 in control cells. The increase of miR-7-5p expression further intensified downregulation of PARP-1 and BRCA1 in TK6-miR-7-5p cells, resulting in an increase of apoptosis and proliferation inhibited.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Proteína BRCA1/metabolismo
Proliferação Celular/efeitos dos fármacos
Reparo do DNA/efeitos dos fármacos
Hidroquinonas/farmacologia
MicroRNAs/metabolismo
Poli(ADP-Ribose) Polimerase-1/metabolismo
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas
Antagomirs/metabolismo
Proteína BRCA1/genética
Caspase 3/metabolismo
Linhagem Celular Tumoral
Regulação para Baixo/efeitos dos fármacos
Seres Humanos
MicroRNAs/antagonistas & inibidores
MicroRNAs/genética
Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores
Poli(ADP-Ribose) Polimerase-1/genética
Interferência de RNA
RNA Interferente Pequeno/metabolismo
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (Antagomirs); 0 (BRCA1 Protein); 0 (BRCA1 protein, human); 0 (Hydroquinones); 0 (MicroRNAs); 0 (RNA, Small Interfering); 0 (Tumor Suppressor Protein p53); EC 2.4.2.30 (PARP1 protein, human); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1); EC 3.4.22.- (Caspase 3); XV74C1N1AE (hydroquinone)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180209
[St] Status:MEDLINE


  4 / 2210 MEDLINE  
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[PMID]:29330466
[Au] Autor:Carney B; Kossatz S; Lok BH; Schneeberger V; Gangangari KK; Pillarsetty NVK; Weber WA; Rudin CM; Poirier JT; Reiner T
[Ad] Endereço:Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
[Ti] Título:Target engagement imaging of PARP inhibitors in small-cell lung cancer.
[So] Source:Nat Commun;9(1):176, 2018 01 12.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Insufficient chemotherapy response and rapid disease progression remain concerns for small-cell lung cancer (SCLC). Oncologists rely on serial CT scanning to guide treatment decisions, but this cannot assess in vivo target engagement of therapeutic agents. Biomarker assessments in biopsy material do not assess contemporaneous target expression, intratumoral drug exposure, or drug-target engagement. Here, we report the use of PARP1/2-targeted imaging to measure target engagement of PARP inhibitors in vivo. Using a panel of clinical PARP inhibitors, we show that PARP imaging can quantify target engagement of chemically diverse small molecule inhibitors in vitro and in vivo. We measure PARP1/2 inhibition over time to calculate effective doses for individual drugs. Using patient-derived xenografts, we demonstrate that different therapeutics achieve similar integrated inhibition efficiencies under different dosing regimens. This imaging approach to non-invasive, quantitative assessment of dynamic intratumoral target inhibition may improve patient care through real-time monitoring of drug delivery.
[Mh] Termos MeSH primário: Neoplasias Pulmonares/tratamento farmacológico
Terapia de Alvo Molecular/métodos
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico
Ensaios Antitumorais Modelo de Xenoenxerto
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Relação Dose-Resposta a Droga
Seres Humanos
Neoplasias Pulmonares/diagnóstico por imagem
Neoplasias Pulmonares/enzimologia
Camundongos Endogâmicos NOD
Camundongos Knockout
Camundongos SCID
Ftalazinas/farmacologia
Piperazinas/farmacologia
Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores
Poli(ADP-Ribose) Polimerase-1/metabolismo
Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem
Carcinoma de Pequenas Células do Pulmão/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Phthalazines); 0 (Piperazines); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 9QHX048FRV (talazoparib); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1); WOH1JD9AR8 (olaparib)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180114
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02096-w


  5 / 2210 MEDLINE  
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[PMID]:28456021
[Au] Autor:Lupey-Green LN; Moquin SA; Martin KA; McDevitt SM; Hulse M; Caruso LB; Pomerantz RT; Miranda JL; Tempera I
[Ad] Endereço:Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
[Ti] Título:PARP1 restricts Epstein Barr Virus lytic reactivation by binding the BZLF1 promoter.
[So] Source:Virology;507:220-230, 2017 07.
[Is] ISSN:1096-0341
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Epstein Barr virus (EBV) genome persists in infected host cells as a chromatinized episome and is subject to chromatin-mediated regulation. Binding of the host insulator protein CTCF to the EBV genome has an established role in maintaining viral latency type, and in other herpesviruses, loss of CTCF binding at specific regions correlates with viral reactivation. Here, we demonstrate that binding of PARP1, an important cofactor of CTCF, at the BZLF1 lytic switch promoter restricts EBV reactivation. Knockdown of PARP1 in the Akata-EBV cell line significantly increases viral copy number and lytic protein expression. Interestingly, CTCF knockdown has no effect on viral reactivation, and CTCF binding across the EBV genome is largely unchanged following reactivation. Moreover, EBV reactivation attenuates PARP activity, and Zta expression alone is sufficient to decrease PARP activity. Here we demonstrate a restrictive function of PARP1 in EBV lytic reactivation.
[Mh] Termos MeSH primário: Infecções por Vírus Epstein-Barr/enzimologia
Infecções por Vírus Epstein-Barr/virologia
Herpesvirus Humano 4/fisiologia
Poli(ADP-Ribose) Polimerase-1/metabolismo
Regiões Promotoras Genéticas
Transativadores/genética
Ativação Viral
[Mh] Termos MeSH secundário: Linhagem Celular
Infecções por Vírus Epstein-Barr/genética
Regulação Viral da Expressão Gênica
Herpesvirus Humano 4/genética
Interações Hospedeiro-Patógeno
Seres Humanos
Poli(ADP-Ribose) Polimerase-1/genética
Ligação Proteica
Transativadores/metabolismo
Latência Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (BZLF1 protein, Herpesvirus 4, Human); 0 (Trans-Activators); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:180304
[Lr] Data última revisão:
180304
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


  6 / 2210 MEDLINE  
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[PMID]:28454547
[Au] Autor:Pignochino Y; Capozzi F; D'Ambrosio L; Dell'Aglio C; Basiricò M; Canta M; Lorenzato A; Vignolo Lutati F; Aliberti S; Palesandro E; Boccone P; Galizia D; Miano S; Chiabotto G; Napione L; Gammaitoni L; Sangiolo D; Benassi MS; Pasini B; Chiorino G; Aglietta M; Grignani G
[Ad] Endereço:Sarcoma Unit, Medical Oncology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy. ymera.pignochino@ircc.it.
[Ti] Título:PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models.
[So] Source:Mol Cancer;16(1):86, 2017 04 28.
[Is] ISSN:1476-4598
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Enhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate trabectedin-induced DNA damage in tumor cells leading finally to cell death. METHODS: We investigated trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role. RESULTS: Trabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. Olaparib was the most active PARP1 inhibitor to combine with trabectedin and we confirmed the antitumor and antimetastatic activity of trabectedin/olaparib combination in mice models. However, we observed different degree of trabectedin/olaparib synergism among different cell lines. Namely, in DMR leiomyosarcoma models the combination was significantly more active than single agents, while in SJSA-1 osteosarcoma models no further advantage was obtained if compared to trabectedin alone. aCGH and GEP revealed that key components of DNA-repair pathways were involved in trabectedin/olaparib synergism. In particular, PARP1 expression dictated the degree of the synergism. Indeed, trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing. CONCLUSIONS: PARP1 inhibition potentiated trabectedin activity in a PARP1-dependent manner and PARP1 expression in tumor cells might be a useful predictive biomarker that deserves clinical evaluation.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/genética
Dioxóis/administração & dosagem
Poli(ADP-Ribose) Polimerase-1/genética
Sarcoma/tratamento farmacológico
Tetra-Hidroisoquinolinas/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Hibridização Genômica Comparativa
Dano ao DNA/efeitos dos fármacos
Sinergismo Farmacológico
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Camundongos
Ftalazinas/administração & dosagem
Piperazinas/administração & dosagem
Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores
Sarcoma/genética
Sarcoma/patologia
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Dioxoles); 0 (Phthalazines); 0 (Piperazines); 0 (Tetrahydroisoquinolines); EC 2.4.2.30 (PARP1 protein, human); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1); ID0YZQ2TCP (trabectedin); WOH1JD9AR8 (olaparib)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.1186/s12943-017-0652-5


  7 / 2210 MEDLINE  
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[PMID]:29235817
[Au] Autor:Guda BB; Pushkarev VV; Zhuravel OV; Kovalenko AY; Pushkarev VM; Taraschenko YM; Tronko MD
[Ti] Título:Protein kinase Akt activity in human thyroid tumors.
[So] Source:Ukr Biochem J;88(5):90-5, 2016 Sep-Oct.
[Is] ISSN:2409-4943
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:We studied the expression and activation of the main effector protein kinase of phosphatidylinositol-3-kinase cascade (PI3K) ­ Akt in conventionally normal tissues, benign and highly differentiated (with and without metastases) human thyroid tumors. There was a difference in the Akt1 amount in tumor tissue compared with normal tissue in papillary carcinomas and tissue of multinodular goiter. Akt expression both in tumor and conventionally normal tissues of follicular adenoma was significantly lower than in follicular carcinoma. The lowest level of Akt expression was observed in tissues of multinodular goiter. Total activity of all three isoforms of Akt1/2/3 was lower in tumors compared to conventionally normal tissue. Thus, Akt activity (according to Thr308 phosphorylation) is not associated with proliferative processes in the tumor tissue of the thyroid. Apoptosis level detected in these tissues was not associated with the protein kinase activity either. Possible mechanisms of signaling cascade PI3K/Akt inhibition in thyroid tumors are discussed.
[Mh] Termos MeSH primário: Adenocarcinoma Folicular/genética
Adenoma/genética
Carcinoma Papilar/genética
Bócio Nodular/genética
Fosfatidilinositol 3-Quinases/genética
Proteínas Proto-Oncogênicas c-akt/genética
Neoplasias da Glândula Tireoide/genética
[Mh] Termos MeSH secundário: Adenocarcinoma Folicular/enzimologia
Adenocarcinoma Folicular/patologia
Adenocarcinoma Folicular/cirurgia
Adenoma/enzimologia
Adenoma/patologia
Adenoma/cirurgia
Apoptose
Carcinoma Papilar/enzimologia
Carcinoma Papilar/patologia
Carcinoma Papilar/cirurgia
Regulação Neoplásica da Expressão Gênica
Bócio Nodular/enzimologia
Bócio Nodular/patologia
Bócio Nodular/cirurgia
Seres Humanos
Fosfatidilinositol 3-Quinases/metabolismo
Fosforilação
Poli(ADP-Ribose) Polimerase-1/genética
Poli(ADP-Ribose) Polimerase-1/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Transdução de Sinais
Glândula Tireoide/enzimologia
Glândula Tireoide/patologia
Glândula Tireoide/cirurgia
Neoplasias da Glândula Tireoide/enzimologia
Neoplasias da Glândula Tireoide/patologia
Neoplasias da Glândula Tireoide/cirurgia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.4.2.30 (PARP1 protein, human); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (AKT1 protein, human); EC 2.7.11.1 (AKT2 protein, human); EC 2.7.11.1 (AKT3 protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.15407/ubj88.05.090


  8 / 2210 MEDLINE  
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[PMID]:29220652
[Au] Autor:Lehmann LC; Hewitt G; Aibara S; Leitner A; Marklund E; Maslen SL; Maturi V; Chen Y; van der Spoel D; Skehel JM; Moustakas A; Boulton SJ; Deindl S
[Ad] Endereço:Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, 75124 Uppsala, Sweden.
[Ti] Título:Mechanistic Insights into Autoinhibition of the Oncogenic Chromatin Remodeler ALC1.
[So] Source:Mol Cell;68(5):847-859.e7, 2017 Dec 07.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human ALC1 is an oncogene-encoded chromatin-remodeling enzyme required for DNA repair that possesses a poly(ADP-ribose) (PAR)-binding macro domain. Its engagement with PARylated PARP1 activates ALC1 at sites of DNA damage, but the underlying mechanism remains unclear. Here, we establish a dual role for the macro domain in autoinhibition of ALC1 ATPase activity and coupling to nucleosome mobilization. In the absence of DNA damage, an inactive conformation of the ATPase is maintained by juxtaposition of the macro domain against predominantly the C-terminal ATPase lobe through conserved electrostatic interactions. Mutations within this interface displace the macro domain, constitutively activate the ALC1 ATPase independent of PARylated PARP1, and alter the dynamics of ALC1 recruitment at DNA damage sites. Upon DNA damage, binding of PARylated PARP1 by the macro domain induces a conformational change that relieves autoinhibitory interactions with the ATPase motor, which selectively activates ALC1 remodeling upon recruitment to sites of DNA damage.
[Mh] Termos MeSH primário: Montagem e Desmontagem da Cromatina
Dano ao DNA
DNA Helicases/metabolismo
Reparo do DNA
Proteínas de Ligação a DNA/metabolismo
Nucleossomos/enzimologia
[Mh] Termos MeSH secundário: Domínio Catalítico
Linhagem Celular Tumoral
DNA Helicases/química
DNA Helicases/genética
Proteínas de Ligação a DNA/química
Proteínas de Ligação a DNA/genética
Ativação Enzimática
Seres Humanos
Microscopia Eletrônica
Simulação de Dinâmica Molecular
Mutação
Nucleossomos/química
Poli(ADP-Ribose) Polimerase-1/química
Poli(ADP-Ribose) Polimerase-1/metabolismo
Poli ADP Ribosilação
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Transporte Proteico
Espalhamento a Baixo Ângulo
Eletricidade Estática
Relação Estrutura-Atividade
Fatores de Tempo
Difração de Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (Nucleosomes); EC 2.4.2.30 (PARP1 protein, human); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1); EC 3.6.4.- (DNA Helicases); EC 3.6.4.12 (CHD1L protein, human)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE


  9 / 2210 MEDLINE  
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[PMID]:29220653
[Au] Autor:Singh HR; Nardozza AP; Möller IR; Knobloch G; Kistemaker HAV; Hassler M; Harrer N; Blessing C; Eustermann S; Kotthoff C; Huet S; Mueller-Planitz F; Filippov DV; Timinszky G; Rand KD; Ladurner AG
[Ad] Endereço:Biomedical Center Munich, Faculty of Medicine, Ludwig-Maximilians-Universität München, Großhaderner Street 9, 82152 Planegg-Martinsried, Germany.
[Ti] Título:A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene.
[So] Source:Mol Cell;68(5):860-871.e7, 2017 Dec 07.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DNA damage triggers chromatin remodeling by mechanisms that are poorly understood. The oncogene and chromatin remodeler ALC1/CHD1L massively decompacts chromatin in vivo yet is inactive prior to DNA-damage-mediated PARP1 induction. We show that the interaction of the ALC1 macrodomain with the ATPase module mediates auto-inhibition. PARP1 activation suppresses this inhibitory interaction. Crucially, release from auto-inhibition requires a poly-ADP-ribose (PAR) binding macrodomain. We identify tri-ADP-ribose as a potent PAR-mimic and synthetic allosteric effector that abrogates ATPase-macrodomain interactions, promotes an ungated conformation, and activates the remodeler's ATPase. ALC1 fragments lacking the regulatory macrodomain relax chromatin in vivo without requiring PARP1 activation. Further, the ATPase restricts the macrodomain's interaction with PARP1 under non-DNA damage conditions. Somatic cancer mutants disrupt ALC1's auto-inhibition and activate chromatin remodeling. Our data show that the NAD -metabolite and nucleic acid PAR triggers ALC1 to drive chromatin relaxation. Modular allostery in this oncogene tightly controls its robust, DNA-damage-dependent activation.
[Mh] Termos MeSH primário: Montagem e Desmontagem da Cromatina
Dano ao DNA
DNA Helicases/metabolismo
Proteínas de Ligação a DNA/metabolismo
Neoplasias/enzimologia
Poli(ADP-Ribose) Polimerase-1/metabolismo
Poli Adenosina Difosfato Ribose/metabolismo
[Mh] Termos MeSH secundário: Regulação Alostérica
Sítios de Ligação
Linhagem Celular Tumoral
DNA Helicases/química
DNA Helicases/genética
Proteínas de Ligação a DNA/química
Proteínas de Ligação a DNA/genética
Ativação Enzimática
Seres Humanos
Mutação
Neoplasias/genética
Neoplasias/patologia
Conformação de Ácido Nucleico
Poli(ADP-Ribose) Polimerase-1/química
Poli(ADP-Ribose) Polimerase-1/genética
Poli ADP Ribosilação
Poli Adenosina Difosfato Ribose/química
Ligação Proteica
Relação Estrutura-Atividade
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 26656-46-2 (Poly Adenosine Diphosphate Ribose); EC 2.4.2.30 (PARP1 protein, human); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1); EC 3.6.4.- (DNA Helicases); EC 3.6.4.12 (CHD1L protein, human)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171226
[Lr] Data última revisão:
171226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE


  10 / 2210 MEDLINE  
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[PMID]:29063620
[Au] Autor:Stark TW; Hensley PJ; Spear A; Pu H; Strup SS; Kyprianou N
[Ad] Endereço:Departments of Urology, University of Kentucky College of Medicine, Lexington, Kentucky.
[Ti] Título:Predictive value of epithelial-mesenchymal-transition (EMT) signature and PARP-1 in prostate cancer radioresistance.
[So] Source:Prostate;77(16):1583-1591, 2017 Dec.
[Is] ISSN:1097-0045
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Epithelial-mesenchymal-transition (EMT) has been previously identified as a contributor to prostate cancer progression to metastasis and therapeutic resistance to antiandrogens and radiotherapy. In this study we conducted a retrospective analysis to investigate the significance of radiation-induced EMT and consequential changes to the tumor microenvironment in biochemical recurrence and response to radiotherapy in prostate cancer patients. METHODS: Expression profiling and localization for EMT effectors, E-Cadherin, N-Cadherin, ß-catenin and Vimentin was assessed in human prostate tumor specimens pre- and post-radiotherapy and correlated with biochemical recurrence. In addition, immunoreactivity of the DNA repair enzyme, polymerase (PARP-1) and the cytoskeletal-remodeling regulator, cofilin was evaluated in prostate tumor specimens pre- and post-radiotherapy and correlated with pre-treatment prostate-specific antigen levels (PSA). RESULTS: Our findings identified that characteristic changes associated with the EMT phenotype and its reversal to mesenchymal-epithelial-transition (MET) within the tumor microenvironment correlate with biochemical recurrence and resistance to radiotherapy among prostate cancer patients. Moreover, elevated PARP-1 expression among the tumor cells undergoing EMT implicates that DNA repair mechanisms may potentially reverse the cytotoxic effects of radiotherapy-induced DNA breaks. CONCLUSIONS: Our results suggest that EMT programming effectors, integrated with the actin cytoskeleton regulator cofilin and mesenchymal PARP-1 expression profile provide a signature of potential predictive significance of therapeutic response to radiotherapy in a subset of prostate cancer patients.
[Mh] Termos MeSH primário: Transição Epitelial-Mesenquimal/fisiologia
Poli(ADP-Ribose) Polimerase-1/biossíntese
Neoplasias da Próstata/metabolismo
Neoplasias da Próstata/radioterapia
Tolerância a Radiação/fisiologia
[Mh] Termos MeSH secundário: Idoso
Estudos de Coortes
Seres Humanos
Masculino
Meia-Idade
Poli(ADP-Ribose) Polimerase-1/genética
Valor Preditivo dos Testes
Neoplasias da Próstata/genética
Estudos Retrospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.4.2.30 (PARP1 protein, human); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171025
[St] Status:MEDLINE
[do] DOI:10.1002/pros.23435



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