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[PMID]:28463114
[Au] Autor:Moura M; Osswald M; Leça N; Barbosa J; Pereira AJ; Maiato H; Sunkel CE; Conde C
[Ad] Endereço:i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
[Ti] Título:Protein Phosphatase 1 inactivates Mps1 to ensure efficient Spindle Assembly Checkpoint silencing.
[So] Source:Elife;6, 2017 05 02.
[Is] ISSN:2050-084X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Faithfull genome partitioning during cell division relies on the Spindle Assembly Checkpoint (SAC), a conserved signaling pathway that delays anaphase onset until all chromosomes are attached to spindle microtubules. Mps1 kinase is an upstream SAC regulator that promotes the assembly of an anaphase inhibitor through a sequential multi-target phosphorylation cascade. Thus, the SAC is highly responsive to Mps1, whose activity peaks in early mitosis as a result of its T-loop autophosphorylation. However, the mechanism controlling Mps1 inactivation once kinetochores attach to microtubules and the SAC is satisfied remains unknown. Here we show and in that Protein Phosphatase 1 (PP1) inactivates Mps1 by dephosphorylating its T-loop. PP1-mediated dephosphorylation of Mps1 occurs at kinetochores and in the cytosol, and inactivation of both pools of Mps1 during metaphase is essential to ensure prompt and efficient SAC silencing. Overall, our findings uncover a mechanism of SAC inactivation required for timely mitotic exit.
[Mh] Termos MeSH primário: Proteínas de Ciclo Celular/metabolismo
Divisão Celular
Segregação de Cromossomos
Proteínas de Drosophila/metabolismo
Drosophila/fisiologia
Pontos de Checagem da Fase M do Ciclo Celular
Proteína Fosfatase 1/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
[Mh] Termos MeSH secundário: Animais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (Drosophila Proteins); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (ald protein, Drosophila); EC 3.1.3.16 (Protein Phosphatase 1)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


  2 / 3091 MEDLINE  
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[PMID]:28454724
[Au] Autor:Nagarajan S; Vohra T; Loffing J; Faresse N
[Ad] Endereço:Institute of Anatomy, University of Zurich, 8057 Zurich, Switzerland; National Center of Competence in Research "Kidney.CH", Switzerland.
[Ti] Título:Protein Phosphatase 1α enhances renal aldosterone signaling via mineralocorticoid receptor stabilization.
[So] Source:Mol Cell Endocrinol;450:74-82, 2017 Jul 15.
[Is] ISSN:1872-8057
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Stimulation of the mineralocorticoid receptor (MR) by aldosterone controls several physiological parameters including blood pressure, inflammation or metabolism. We previously showed that MR turnover constitutes a crucial regulatory step in the responses of renal epithelial cells to aldosterone. Here, we identified Protein Phosphatase 1 alpha (PP1α), as a novel cytoplasmic binding partner of MR that promotes the receptor activity. The RT-PCR expression mapping of PP1α reveals a high expression in the kidney, particularly in the distal part of the nephron. At the molecular level, we demonstrate that PP1α inhibits the ubiquitin ligase Mdm2 by dephosphorylation, preventing its interaction with MR. This results in the accumulation of the receptor due to reduction of its proteasomal degradation and consequently a greater aldosterone-induced Na uptake by renal cells. Thus, our findings describe an original mechanism involving a phosphatase in the regulation of aldosterone signaling and provide new and important insights into the molecular mechanism underlying the MR turnover.
[Mh] Termos MeSH primário: Aldosterona/metabolismo
Rim/metabolismo
Proteína Fosfatase 1/metabolismo
Receptores de Mineralocorticoides/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Células Epiteliais/efeitos dos fármacos
Células Epiteliais/metabolismo
Células HEK293
Seres Humanos
Camundongos Endogâmicos C57BL
Complexo de Endopeptidases do Proteassoma/metabolismo
Ligação Proteica/efeitos dos fármacos
Domínios Proteicos
Estabilidade Proteica/efeitos dos fármacos
Proteólise/efeitos dos fármacos
Proteínas Proto-Oncogênicas c-mdm2/metabolismo
Receptores de Mineralocorticoides/química
Transdução de Sinais/efeitos dos fármacos
Sódio/metabolismo
Transcrição Genética/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Mineralocorticoid); 4964P6T9RB (Aldosterone); 9NEZ333N27 (Sodium); EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2); EC 3.1.3.16 (Protein Phosphatase 1); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


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[PMID]:29338035
[Au] Autor:Bradai M; Mahjoubi H; Chini A; Chabouté ME; Hanin M; Ebel C
[Ad] Endereço:Laboratory of Biotechnology and Plant Improvement, Center of Biotechnology of Sfax, Sfax, Tunisia.
[Ti] Título:Genome wide identification of wheat and Brachypodium type one protein phosphatases and functional characterization of durum wheat TdPP1a.
[So] Source:PLoS One;13(1):e0191272, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Reversible phosphorylation is an essential mechanism regulating signal transduction during development and environmental stress responses. An important number of dephosphorylation events in the cell are catalyzed by type one protein phosphatases (PP1), which catalytic activity is driven by the binding of regulatory proteins that control their substrate specificity or subcellular localization. Plants harbor several PP1 isoforms accounting for large functional redundancies. While animal PP1s were reported to play relevant roles in controlling multiple cellular processes, plant orthologs remain poorly studied. To decipher the role of plant PP1s, we compared PP1 genes from three monocot species, Brachypodium, common wheat and rice at the genomic and transcriptomic levels. To gain more insight into the wheat PP1 proteins, we identified and characterized TdPP1a, the first wheat type one protein phosphatase from a Tunisian durum wheat variety Oum Rabiaa3. TdPP1a is highly conserved in sequence and structure when compared to mammalian, yeast and other plant PP1s. We demonstrate that TdPP1a is an active, metallo-dependent phosphatase in vitro and is able to interact with AtI2, a typical regulator of PP1 functions. Also, TdPP1a is capable to complement the heat stress sensitivity of the yeast mutant indicating that TdPP1a is functional also in vivo. Moreover, transient expression of TdPP1a::GFP in tobacco leaves revealed that it is ubiquitously distributed within the cell, with a strong accumulation in the nucleus. Finally, transcriptional analyses showed similar expression levels in roots and leaves of durum wheat seedlings. Interestingly, the expression in leaves is significantly induced following salinity stress, suggesting a potential role of TdPP1a in wheat salt stress response.
[Mh] Termos MeSH primário: Brachypodium/enzimologia
Brachypodium/genética
Fosfoproteínas Fosfatases/genética
Proteínas de Plantas/genética
Triticum/enzimologia
Triticum/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Sequência Conservada
Evolução Molecular
Regulação Enzimológica da Expressão Gênica
Regulação da Expressão Gênica de Plantas
Isoenzimas/genética
Isoenzimas/metabolismo
Oryza/enzimologia
Oryza/genética
Fosfoproteínas Fosfatases/metabolismo
Filogenia
Proteínas de Plantas/metabolismo
Proteína Fosfatase 1/genética
Proteína Fosfatase 1/metabolismo
Homologia de Sequência de Aminoácidos
Especificidade da Espécie
Estresse Fisiológico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Isoenzymes); 0 (Plant Proteins); EC 3.1.3.16 (Phosphoprotein Phosphatases); EC 3.1.3.16 (Protein Phosphatase 1)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191272


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[PMID]:29227599
[Au] Autor:Minchenko OH; Kryvdiuk IV; Riabovol OO; Minchenko DO; Danilovskyi SV; Ratushna OO
[Ti] Título:Inhibition of IRE1 modifies the hypoxic regulation of GADD family gene expressions in U87 glioma cells.
[So] Source:Ukr Biochem J;88(2):25-34, 2016 Mar-Apr.
[Is] ISSN:2409-4943
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:We have studied hypoxic regulation of the expression of genes encoded GADD (growth arrest and DNA damage) family proteins in U87 glioma cells in relation to inhibition of IRE1 (inositol requiring enzyme-1), which controls cell proliferation and tumor growth as a central mediator of endoplasmic reticulum stress. We have shown that hypoxia up-regulates the expression of GADD34, GADD45A, GADD45B, and GADD153 genes, which are related to cell proliferation and apoptosis, in control (transfected by empty vector) glioma cells in gene specific manner. At the same time, the expression level of EIF2AK 1 (eukaryotic translation initiation factor 2-alpha kinase 1) and AI FM1 (apoptosis inducing factor, mitochondria associated 1) genes in these cells is down-regulated upon hypoxic condition. It was also shown that inhibition of ІRE1 signaling enzyme function in U87 glioma cells enhances the effect of hypoxia on these genes expression, except EIF2AK 1 and AI FM1 genes. Furthermore, the expression of all studied genes in ІRE1 knockdown cells is significantly decreased upon normoxic condition, except GADD45B gene, which expression level is strongly up-regulated. Therefore, the expression level of genes encoding GADD34, GADD45A, GADD45B, GADD153, EIF2AK 1, and AI FM1 is affected by hypoxia and by inhibition of IRE1-mediated endoplasmic reticulum stress signaling in gene specific manner and correlates with suppression of glioma cell proliferation upon inhibition of the IRE1 enzyme function.
[Mh] Termos MeSH primário: Proteínas de Ciclo Celular/genética
Estresse do Retículo Endoplasmático/genética
Endorribonucleases/genética
Regulação Neoplásica da Expressão Gênica
Neuroglia/metabolismo
Proteínas Nucleares/genética
Proteína Fosfatase 1/genética
Proteínas Serina-Treonina Quinases/genética
[Mh] Termos MeSH secundário: Antígenos de Diferenciação/genética
Antígenos de Diferenciação/metabolismo
Apoptose/genética
Fator de Indução de Apoptose/genética
Fator de Indução de Apoptose/metabolismo
Proteínas de Ciclo Celular/metabolismo
Hipóxia Celular
Linhagem Celular Tumoral
Proliferação Celular
Endorribonucleases/deficiência
Técnicas de Silenciamento de Genes
Seres Humanos
Neuroglia/patologia
Proteínas Nucleares/metabolismo
Plasmídeos/química
Plasmídeos/metabolismo
Proteína Fosfatase 1/metabolismo
Proteínas Serina-Treonina Quinases/deficiência
Transdução de Sinais
Fator de Transcrição CHOP/genética
Fator de Transcrição CHOP/metabolismo
Transfecção
eIF-2 Quinase/genética
eIF-2 Quinase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AIFM1 protein, human); 0 (Antigens, Differentiation); 0 (Apoptosis Inducing Factor); 0 (Cell Cycle Proteins); 0 (DDIT3 protein, human); 0 (GADD45A protein, human); 0 (GADD45B protein, human); 0 (Nuclear Proteins); 147336-12-7 (Transcription Factor CHOP); EC 2.7.11.1 (EIF2AK1 protein, human); EC 2.7.11.1 (ERN1 protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (eIF-2 Kinase); EC 3.1.- (Endoribonucleases); EC 3.1.3.16 (PPP1R15A protein, human); EC 3.1.3.16 (Protein Phosphatase 1)
[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:171212
[St] Status:MEDLINE
[do] DOI:10.15407/ubj88.02.025


  5 / 3091 MEDLINE  
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[PMID]:29187447
[Au] Autor:Minami S; Matsumoto K; Nagashio R; Hagiuda D; Fukuda E; Goshima N; Hattori M; Tsuchiya B; Hachimura K; Jiang SX; Saegusa M; Iwamura M; Sato Y
[Ad] Endereço:Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.
[Ti] Título:Analysis of Autoantibodies Related to Tumor Progression in Sera from Patients with High-grade Non-muscle-invasive Bladder Cancer.
[So] Source:Anticancer Res;37(12):6705-6714, 2017 12.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: Bladder cancer (BC) has a high recurrence rate and may progress to being a muscle-invasive lesion, that is potentially associated with a poor prognosis. We identified tumor-associated proteins that were recognized by autoantibodies in sera from patients with high-grade non-muscle-invasive bladder cancer (HG-NMIBC) by proteomic analysis. MATERIALS AND METHODS: The serum levels of these autoantibodies against identified proteins were validated by dot blot analysis with sera from 95 patients with BC and 35 healthy controls. The expression of identified proteins was immunohistochemically analyzed in 115 BC tissues. RESULTS: Autoantibody against protein phosphatase 1, catalytic subunit, alpha isoform (PPP1CA) protein was detected in pretreated sera from patients with HG-NMIBC who showed progression. The serum IgG level of anti-PPP1CA autoantibody was significantly correlated with pathological stage, grade, lymphovascular invasion, and prognosis. The immunoreactions for PPP1CA protein in BC was significantly correlated with pathological stage, grade, and lymphovascular invasion. CONCLUSION: PPP1CA is a candidate sero-diagnostic and prognostic marker for patients with BC.
[Mh] Termos MeSH primário: Autoanticorpos/imunologia
Proteoma/imunologia
Proteômica/métodos
Neoplasias da Bexiga Urinária/imunologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Autoanticorpos/sangue
Progressão da Doença
Feminino
Seres Humanos
Imunoglobulina G/sangue
Imunoglobulina G/imunologia
Imuno-Histoquímica
Masculino
Meia-Idade
Gradação de Tumores
Prognóstico
Proteína Fosfatase 1/imunologia
Proteína Fosfatase 1/metabolismo
Neoplasias da Bexiga Urinária/sangue
Neoplasias da Bexiga Urinária/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantibodies); 0 (Immunoglobulin G); 0 (Proteome); EC 3.1.3.16 (PPP1CA protein, human); EC 3.1.3.16 (Protein Phosphatase 1)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171201
[St] Status:MEDLINE


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[PMID]:28468835
[Au] Autor:Hovsepian J; Defenouillère Q; Albanèse V; Váchová L; Garcia C; Palková Z; Léon S
[Ad] Endereço:Institut Jacques Monod, UMR 7592 Centre National de la Recherche Scientifique/Université Paris-Diderot, Sorbonne Paris Cité, 75013 Paris, France.
[Ti] Título:Multilevel regulation of an α-arrestin by glucose depletion controls hexose transporter endocytosis.
[So] Source:J Cell Biol;216(6):1811-1831, 2017 Jun 05.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nutrient availability controls the landscape of nutrient transporters present at the plasma membrane, notably by regulating their ubiquitylation and subsequent endocytosis. In yeast, this involves the Nedd4 ubiquitin ligase Rsp5 and arrestin-related trafficking adaptors (ARTs). ARTs are targeted by signaling pathways and warrant that cargo ubiquitylation and endocytosis appropriately respond to nutritional inputs. Here, we show that glucose deprivation regulates the ART protein Csr2/Art8 at multiple levels to trigger high-affinity glucose transporter endocytosis. Csr2 is transcriptionally induced in these conditions through the AMPK orthologue Snf1 and downstream transcriptional repressors. Upon synthesis, Csr2 becomes activated by ubiquitylation. In contrast, glucose replenishment induces transcriptional shutdown and switches Csr2 to an inactive, deubiquitylated form. This glucose-induced deubiquitylation of Csr2 correlates with its phospho-dependent association with 14-3-3 proteins and involves protein kinase A. Thus, two glucose signaling pathways converge onto Csr2 to regulate hexose transporter endocytosis by glucose availability. These data illustrate novel mechanisms by which nutrients modulate ART activity and endocytosis.
[Mh] Termos MeSH primário: Arrestina/metabolismo
Endocitose
Glucose/deficiência
Proteínas de Transporte de Monossacarídeos/metabolismo
Proteínas Nucleares/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: Proteínas 14-3-3/metabolismo
Arrestina/genética
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Regulação Fúngica da Expressão Gênica
Proteínas de Transporte de Monossacarídeos/genética
Mutação
Proteínas Nucleares/genética
Proteína Fosfatase 1/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Repressoras/metabolismo
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/genética
Fatores de Tempo
Transcrição Genética
Ubiquitinação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (14-3-3 Proteins); 0 (Arrestin); 0 (BMH1 protein, S cerevisiae); 0 (BMH2 protein, S cerevisiae); 0 (Csr2 protein, S cerevisiae); 0 (HXT7 protein, S cerevisiae); 0 (Hxt6 protein, S cerevisiae); 0 (MIG1 protein, S cerevisiae); 0 (Mig2 protein, S cerevisiae); 0 (Monosaccharide Transport Proteins); 0 (Nuclear Proteins); 0 (Repressor Proteins); 0 (Saccharomyces cerevisiae Proteins); EC 2.7.1.- (SNF1-related protein kinases); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 3.1.3.16 (Protein Phosphatase 1); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171205
[Lr] Data última revisão:
171205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201610094


  7 / 3091 MEDLINE  
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[PMID]:28985363
[Au] Autor:Zhu S; Fisher LA; Bessho T; Peng A
[Ad] Endereço:Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583, USA.
[Ti] Título:Protein phosphatase 1 and phosphatase 1 nuclear targeting subunit-dependent regulation of DNA-dependent protein kinase and non-homologous end joining.
[So] Source:Nucleic Acids Res;45(18):10583-10594, 2017 Oct 13.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a key role in mediating non-homologous end joining (NHEJ), a major repair pathway for DNA double-strand breaks (DSBs). The activation, function and dynamics of DNA-PKcs is regulated largely by its reversible phosphorylation at numerous residues, many of which are targeted by DNA-PKcs itself. Interestingly, these DNA-PKcs phosphorylation sites function in a distinct, and sometimes opposing manner, suggesting that they are differentially regulated via complex actions of both kinases and phosphatases. In this study we identified several phosphatase subunits as potential DSB-associated proteins. In particular, protein phosphatase 1 (PP1) is recruited to a DSB-mimicking substrate in Xenopus egg extracts and sites of laser microirradiation in human cells. Depletion of PP1 impairs NHEJ in both Xenopus egg extracts and human cells. PP1 binds multiple motifs of DNA-PKcs, regulates DNA-PKcs phosphorylation, and is required for DNA-PKcs activation after DNA damage. Interestingly, phosphatase 1 nuclear targeting subunit (PNUTS), an inhibitory regulator of PP1, is also recruited to DNA damage sites to promote NHEJ. PNUTS associates with the DNA-PK complex and is required for DNA-PKcs phosphorylation at Ser-2056 and Thr-2609. Thus, PNUTS and PP1 together fine-tune the dynamic phosphorylation of DNA-PKcs after DNA damage to mediate NHEJ.
[Mh] Termos MeSH primário: Quebras de DNA de Cadeia Dupla
Reparo do DNA por Junção de Extremidades
Proteína Quinase Ativada por DNA/metabolismo
Proteínas de Ligação a DNA/metabolismo
Proteínas Nucleares/metabolismo
Proteína Fosfatase 1/metabolismo
Proteínas de Ligação a RNA/metabolismo
[Mh] Termos MeSH secundário: Animais
Células HeLa
Seres Humanos
Autoantígeno Ku/metabolismo
Fosforilação
Xenopus
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (Nuclear Proteins); 0 (PPP1R10 protein, human); 0 (RNA-Binding Proteins); EC 2.7.11.1 (DNA-Activated Protein Kinase); EC 3.1.3.16 (Protein Phosphatase 1); EC 4.2.99.- (Ku Autoantigen)
[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:171007
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx686


  8 / 3091 MEDLINE  
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[PMID]:28958332
[Au] Autor:Watanabe S; Ishikawa K; Fish K; Oh JG; Motloch LJ; Kohlbrenner E; Lee P; Xie C; Lee A; Liang L; Kho C; Leonardson L; McIntyre M; Wilson S; Samulski RJ; Kranias EG; Weber T; Akar FG; Hajjar RJ
[Ad] Endereço:Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
[Ti] Título:Protein Phosphatase Inhibitor-1 Gene Therapy in a Swine Model of Nonischemic Heart Failure.
[So] Source:J Am Coll Cardiol;70(14):1744-1756, 2017 Oct 03.
[Is] ISSN:1558-3597
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Increased protein phosphatase-1 in heart failure (HF) induces molecular changes deleterious to the cardiac cell. Inhibiting protein phosphatase-1 through the overexpression of a constitutively active inhibitor-1 (I-1c) has been shown to reverse cardiac dysfunction in a model of ischemic HF. OBJECTIVES: This study sought to determine the therapeutic efficacy of a re-engineered adenoassociated viral vector carrying I-1c (BNP116.I-1c) in a preclinical model of nonischemic HF, and to assess thoroughly the safety of BNP116.I-1c gene therapy. METHODS: Volume-overload HF was created in Yorkshire swine by inducing severe mitral regurgitation. One month after mitral regurgitation induction, pigs were randomized to intracoronary delivery of either BNP116.I-1c (n = 6) or saline (n = 7). Therapeutic efficacy and safety were evaluated 2 months after gene delivery. Additionally, 24 naive pigs received different doses of BNP116.I-1c for safety evaluation. RESULTS: At 1 month after mitral regurgitation induction, pigs developed HF as evidenced by increased left ventricular end-diastolic pressure and left ventricular volume indexes. Treatment with BNP116.I-1c resulted in improved left ventricular ejection fraction (-5.9 ± 4.2% vs. 5.5 ± 4.0%; p < 0.001) and adjusted dP/dt maximum (-3.39 ± 2.44 s vs. 1.30 ± 2.39 s ; p = 0.007). Moreover, BNP116.I-1c-treated pigs also exhibited a significant increase in left atrial ejection fraction at 2 months after gene delivery (-4.3 ± 3.1% vs. 7.5 ± 3.1%; p = 0.02). In vitro I-1c gene transfer in isolated left atrial myocytes from both pigs and rats increased calcium transient amplitude, consistent with its positive impact on left atrial contraction. We found no evidence of adverse electrical remodeling, arrhythmogenicity, activation of a cellular immune response, or off-target organ damage by BNP116.I-1c gene therapy in pigs. CONCLUSIONS: Intracoronary delivery of BNP116.I-1c was safe and improved contractility of the left ventricle and atrium in a large animal model of nonischemic HF.
[Mh] Termos MeSH primário: Insuficiência Cardíaca/tratamento farmacológico
Insuficiência Cardíaca/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/farmacologia
Proteína Fosfatase 1
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Sistemas de Liberação de Medicamentos
Monitoramento de Medicamentos/métodos
Inibidores Enzimáticos/farmacologia
Terapia Genética/métodos
Vetores Genéticos/farmacologia
Insuficiência Cardíaca/etiologia
Insuficiência Cardíaca/fisiopatologia
Proteína Fosfatase 1/antagonistas & inibidores
Proteína Fosfatase 1/metabolismo
Suínos
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Intracellular Signaling Peptides and Proteins); 0 (protein phosphatase inhibitor-1); EC 3.1.3.16 (Protein Phosphatase 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170930
[St] Status:MEDLINE


  9 / 3091 MEDLINE  
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[PMID]:28759048
[Au] Autor:Carrara M; Sigurdardottir A; Bertolotti A
[Ad] Endereço:MRC Laboratory of Molecular Biology, Cambridge, UK.
[Ti] Título:Decoding the selectivity of eIF2α holophosphatases and PPP1R15A inhibitors.
[So] Source:Nat Struct Mol Biol;24(9):708-716, 2017 Sep.
[Is] ISSN:1545-9985
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The reversible phosphorylation of proteins controls most cellular functions. Protein kinases have been popular drug targets, unlike phosphatases, which remain a drug discovery challenge. Guanabenz and Sephin1 are selective inhibitors of the phosphatase regulatory subunit PPP1R15A (R15A) that prolong the benefit of eIF2α phosphorylation, thereby protecting cells from proteostatic defects. In mice, Sephin1 prevents two neurodegenerative diseases, Charcot-Marie-Tooth 1B (CMT-1B) and SOD1-mediated amyotrophic lateral sclerosis (ALS). However, the molecular basis for R15A inhibition is unknown. Here we reconstituted human recombinant eIF2α holophosphatases, R15A-PP1 and R15B-PP1, whose activity depends on both the catalytic subunit PP1 (protein phosphatase 1) and either R15A or R15B. This system enabled the functional characterization of these holophosphatases and revealed that Guanabenz and Sephin1 induced a selective conformational change in R15A, detected by resistance to limited proteolysis. This altered the recruitment of eIF2α, preventing its dephosphorylation. This work demonstrates that regulatory subunits of phosphatases are valid drug targets and provides the molecular rationale to expand this concept to other phosphatases.
[Mh] Termos MeSH primário: Fator de Iniciação 2 em Eucariotos/química
Fator de Iniciação 2 em Eucariotos/metabolismo
Proteínas de Membrana/química
Proteínas de Membrana/metabolismo
Proteína Fosfatase 1/química
Proteína Fosfatase 1/metabolismo
[Mh] Termos MeSH secundário: Guanabenzo/análogos & derivados
Guanabenzo/metabolismo
Seres Humanos
Ligação Proteica
Conformação Proteica/efeitos dos fármacos
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2); 0 (Membrane Proteins); 0 (PPP1R16B protein, human); 0 (Recombinant Proteins); 0 (sephin1); EC 3.1.3.16 (PPP1R15A protein, human); EC 3.1.3.16 (Protein Phosphatase 1); GGD30112WC (Guanabenz)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE
[do] DOI:10.1038/nsmb.3443


  10 / 3091 MEDLINE  
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[PMID]:28751570
[Au] Autor:Ohyama K; Matsumoto Y; Amamizu H; Uzuka H; Nishimiya K; Morosawa S; Hirano M; Watabe H; Funaki Y; Miyata S; Takahashi J; Ito K; Shimokawa H
[Ad] Endereço:From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.O., Y.M., H.A., H.U., K.N., S. Morosawa, M.H., S. Miyata, J.T., K.I., H.S.); and Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan (H.W., Y.F.).
[Ti] Título:Association of Coronary Perivascular Adipose Tissue Inflammation and Drug-Eluting Stent-Induced Coronary Hyperconstricting Responses in Pigs: F-Fluorodeoxyglucose Positron Emission Tomography Imaging Study.
[So] Source:Arterioscler Thromb Vasc Biol;37(9):1757-1764, 2017 Sep.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Although coronary perivascular adipose tissue (PVAT) may play important roles as a source of inflammation, the association of coronary PVAT inflammation and coronary hyperconstricting responses remains to be examined. We addressed this important issue in a porcine model of coronary hyperconstricting responses after drug-eluting stent implantation with F-fluorodeoxyglucose ( F-FDG) positron emission tomographic imaging. APPROACH AND RESULTS: An everolimus-eluting stent (EES) was randomly implanted in pigs into the left anterior descending or the left circumflex coronary artery while nonstented coronary artery was used as a control. After 1 month, coronary vasoconstricting responses to intracoronary serotonin (10 and 100 µg/kg) were examined by coronary angiography in vivo, followed by in vivo and ex vivo F-FDG positron emission tomographic/computed tomographic imaging. Coronary vasoconstricting responses to serotonin were significantly enhanced at the EES edges compared with the control site ( <0.01; n=40). Notably, in vivo and ex vivo F-FDG positron emission tomographic/computed tomographic imaging and autoradiography showed enhanced F-FDG uptake and its accumulation in PVAT at the EES edges compared with the control site, respectively (both <0.05). Furthermore, histological and reverse transcription polymerase chain reaction analysis showed that inflammatory changes of coronary PVAT were significantly enhanced at the EES edges compared with the control site (all <0.01). Importantly, Rho-kinase expressions (ROCK1/ROCK2) and Rho-kinase activity (phosphorylated myosin phosphatase target subunit-1) at the EES edges were significantly enhanced compared with the control site. CONCLUSIONS: These results indicate for the first time that inflammatory changes of coronary PVAT are associated with drug-eluting stent-induced coronary hyperconstricting responses in pigs in vivo and that F-FDG positron emission tomographic imaging is useful for assessment of coronary PVAT inflammation.
[Mh] Termos MeSH primário: Tecido Adiposo/diagnóstico por imagem
Vasos Coronários/diagnóstico por imagem
Stents Farmacológicos/efeitos adversos
Fluordesoxiglucose F18/administração & dosagem
Inflamação/diagnóstico por imagem
Intervenção Coronária Percutânea/efeitos adversos
Intervenção Coronária Percutânea/instrumentação
Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
Compostos Radiofarmacêuticos/administração & dosagem
Vasoconstrição
[Mh] Termos MeSH secundário: Tecido Adiposo/metabolismo
Animais
Proliferação Celular
Vasos Coronários/efeitos dos fármacos
Vasos Coronários/metabolismo
Vasos Coronários/fisiopatologia
Modelos Animais de Doenças
Inflamação/etiologia
Inflamação/metabolismo
Inflamação/fisiopatologia
Masculino
Fosforilação
Valor Preditivo dos Testes
Proteína Fosfatase 1/metabolismo
Sus scrofa
Fatores de Tempo
Vasoconstrição/efeitos dos fármacos
Vasoconstritores/farmacologia
Quinases Associadas a rho/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Radiopharmaceuticals); 0 (Vasoconstrictor Agents); 0Z5B2CJX4D (Fluorodeoxyglucose F18); EC 2.7.11.1 (rho-Associated Kinases); EC 3.1.3.16 (Protein Phosphatase 1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170729
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309843



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