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[PMID]: 29317655 [Au] Autor: Pawlowski AC; Stogios PJ; Koteva K; Skarina T; Evdokimova E; Savchenko A; Wright GD [Ad] Endereço: Michael G. DeGroote Institute for Infectious Disease Research and the Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, L8S 4L8, ON, Canada. [Ti] Título: The evolution of substrate discrimination in macrolide antibiotic resistance enzymes. [So] Source: Nat Commun;9(1):112, 2018 01 09. [Is] ISSN: 2041-1723 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The production of antibiotics by microbes in the environment and their use in medicine and agriculture select for existing and emerging resistance. To address this inevitability, prudent development of antibiotic drugs requires careful consideration of resistance evolution. Here, we identify the molecular basis for expanded substrate specificity in MphI, a macrolide kinase (Mph) that does not confer resistance to erythromycin, in contrast to other known Mphs. Using a combination of phylogenetics, drug-resistance phenotypes, and in vitro enzyme assays, we find that MphI and MphK phosphorylate erythromycin poorly resulting in an antibiotic-sensitive phenotype. Using likelihood reconstruction of ancestral sequences and site-saturation combinatorial mutagenesis, supported by Mph crystal structures, we determine that two non-obvious mutations in combination expand the substrate range. This approach should be applicable for studying the functional evolution of any antibiotic resistance enzyme and for evaluating the evolvability of resistance enzymes to new generations of antibiotic scaffolds. [Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo Farmacorresistência Bacteriana Macrolídeos/metabolismo Fosfotransferases/metabolismo [Mh] Termos MeSH secundário: Antibacterianos/química Antibacterianos/metabolismo Antibacterianos/farmacologia Proteínas de Bactérias/química Proteínas de Bactérias/genética Eritromicina/química Eritromicina/metabolismo Eritromicina/farmacologia Escherichia coli/efeitos dos fármacos Escherichia coli/genética Macrolídeos/química Macrolídeos/farmacologia Modelos Moleculares Estrutura Molecular Fosfotransferases/classificação Fosfotransferases/genética Filogenia Domínios Proteicos Especificidade por Substrato [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Macrolides); 63937KV33D (Erythromycin); EC 2.7.- (Phosphotransferases) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180111 [St] Status: MEDLINE [do] DOI: 10.1038/s41467-017-02680-0

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[PMID]: 29287086 [Au] Autor: Liao KL; Melvin CE; Sozzani R; Jones RD; Elston TC; Jones AM [Ad] Endereço: Departments of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America. [Ti] Título: Dose-Duration Reciprocity for G protein activation: Modulation of kinase to substrate ratio alters cell signaling. [So] Source: PLoS One;12(12):e0190000, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: In animal cells, activation of heterotrimeric G protein signaling generally occurs when the system's cognate signal exceeds a threshold, whereas in plant cells, both the amount and the exposure time of at least one signal, D-glucose, are used toward activation. This unusual signaling property called Dose-Duration Reciprocity, first elucidated in the genetic model Arabidopsis thaliana, is achieved by a complex that is comprised of a 7-transmembrane REGULATOR OF G SIGNALING (RGS) protein (AtRGS1), a Gα subunit that binds and hydrolyzes nucleotide, a Gßγ dimer, and three WITH NO LYSINE (WNK) kinases. D-glucose is one of several signals such as salt and pathogen-derived molecular patterns that operates through this protein complex to activate G protein signaling by WNK kinase transphosphorylation of AtRGS1. Because WNK kinases compete for the same substrate, AtRGS1, we hypothesize that activation is sensitive to the AtRGS1 amount and that modulation of the AtRGS1 pool affects the response to the stimulant. Mathematical simulation revealed that the ratio of AtRGS1 to the kinase affects system sensitivity to D-glucose, and therefore illustrates how modulation of the cellular AtRGS1 level is a means to change signal-induced activation. AtRGS1 levels change under tested conditions that mimic physiological conditions therefore, we propose a previously-unknown mechanism by which plants react to changes in their environment. [Mh] Termos MeSH primário: Proteínas de Arabidopsis/metabolismo Arabidopsis/metabolismo Proteínas de Ligação ao GTP/metabolismo Fosfotransferases/metabolismo Transdução de Sinais [Mh] Termos MeSH secundário: Arabidopsis/enzimologia Arabidopsis/genética Arabidopsis/crescimento & desenvolvimento Genótipo Fosforilação Especificidade por Substrato [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Arabidopsis Proteins); EC 2.7.- (Phosphotransferases); EC 3.6.1.- (GTP-Binding Proteins) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180207 [Lr] Data última revisão: 180207 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171230 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0190000

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[PMID]: 27775685 [Au] Autor: Broder UN; Jaeger T; Jenal U [Ad] Endereço: Focal Area of Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland. [Ti] Título: LadS is a calcium-responsive kinase that induces acute-to-chronic virulence switch in Pseudomonas aeruginosa. [So] Source: Nat Microbiol;2:16184, 2016 Oct 24. [Is] ISSN: 2058-5276 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Virulence of pathogenic bacteria is a tightly controlled process to facilitate invasion and survival in host tissues. Although pathways controlling virulence have been defined in detail, signals modulating these processes are poorly understood. The opportunistic pathogen Pseudomonas aeruginosa causes acute and chronic infections in humans. Disease progression is typically associated with a loss of acute virulence and the emergence of biofilms and chronic behaviour. The acute-to-chronic switch is governed by the global Gac/Rsm pathway. Using a newly developed acute-chronic dual reporter system we show that calcium stimulates the Gac/Rsm pathway via the Gac-associated hybrid histidine kinase LadS. We show that calcium binds to the periplasmic DISMED2 sensor domain of LadS to activate its kinase activity. Activation of the Gac/Rsm pathway by calcium leads to a switch to the chronic program and confers drug tolerance by reducing P. aeruginosa growth rate. Clinical isolates from cystic fibrosis airways retain their calcium response during chronic infections. Our data imply that calcium sensing evolved as an adaptation to the opportunistic lifestyle of P. aeruginosa and that calcium serves as a host signal to balance acute-to-chronic behaviour during infections. Establishing calcium signalling in host-pathogen interaction adds to growing evidence indicating key roles for calcium in bacterial signalling. [Mh] Termos MeSH primário: Cálcio/metabolismo Regulação Bacteriana da Expressão Gênica Fosfotransferases/metabolismo Pseudomonas aeruginosa/patogenicidade [Mh] Termos MeSH secundário: Sinalização do Cálcio Fibrose Cística/complicações Interações Hospedeiro-Patógeno Seres Humanos Infecções por Pseudomonas/microbiologia Infecções por Pseudomonas/patologia Virulência [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: EC 2.7.- (Phosphotransferases); SY7Q814VUP (Calcium) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180126 [Lr] Data última revisão: 180126 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161025 [St] Status: MEDLINE [do] DOI: 10.1038/nmicrobiol.2016.184

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[PMID]: 28464395 [Au] Autor: Bayer CD; van Loo B; Hollfelder F [Ad] Endereço: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, CB2 1GA, Cambridge, UK. [Ti] Título: Specificity Effects of Amino Acid Substitutions in Promiscuous Hydrolases: Context-Dependence of Catalytic Residue Contributions to Local Fitness Landscapes in Nearby Sequence Space. [So] Source: Chembiochem;18(11):1001-1015, 2017 06 01. [Is] ISSN: 1439-7633 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Catalytic promiscuity can facilitate evolution of enzyme functions-a multifunctional catalyst may act as a springboard for efficient functional adaptation. We test the effect of single mutations on multiple activities in two groups of promiscuous AP superfamily members to probe this hypothesis. We quantify the effect of site-saturating mutagenesis of an analogous, nucleophile-flanking residue in two superfamily members: an arylsulfatase (AS) and a phosphonate monoester hydrolase (PMH). Statistical analysis suggests that no one physicochemical characteristic alone explains the mutational effects. Instead, these effects appear to be dominated by their structural context. Likewise, the effect of changing the catalytic nucleophile itself is not reaction-type-specific. Mapping of "fitness landscapes" of four activities onto the possible variation of a chosen sequence position revealed tremendous potential for respecialization of AP superfamily members through single-point mutations, highlighting catalytic promiscuity as a powerful predictor of adaptive potential. [Mh] Termos MeSH primário: Substituição de Aminoácidos/genética Evolução Molecular Direcionada Hidrolases/genética [Mh] Termos MeSH secundário: Fosfatase Alcalina/genética Bactérias/enzimologia Bactérias/genética Catálise Domínio Catalítico Mutagênese Sítio-Dirigida Fosfotransferases/genética Especificidade por Substrato Sulfatases/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: EC 2.7.- (Phosphotransferases); EC 3.- (Hydrolases); EC 3.1.3.1 (Alkaline Phosphatase); EC 3.1.6.- (Sulfatases) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 180122 [Lr] Data última revisão: 180122 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170503 [St] Status: MEDLINE [do] DOI: 10.1002/cbic.201600657

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[PMID]: 29183754 [Au] Autor: Santos GB; Ribeiro ACG; Lima SNP; Trostchansky A; Cerdeira CD; Brigagão MRPL [Ad] Endereço: Departamento de Bioquímica, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, MG, Brazil. [Ti] Título: Nitroxide Tempol down-regulates kinase activities associated with NADPH oxidase function in phagocytic cells and potentially decreases their fungicidal response. [So] Source: Chem Biol Interact;279:203-209, 2018 Jan 05. [Is] ISSN: 1872-7786 [Cp] País de publicação: Ireland [La] Idioma: eng [Ab] Resumo: AIMS: The identification of novel targets to control inflammation in humans is probably the primary challenge that impairs the development of new anti-inflammatory drugs. Therefore, the modulation of intracellular signaling pathways in phagocytes may be an interesting means of achieving this goal. However, this change to signaling can compromise the host's susceptibility to invading pathogens. We investigated whether the antioxidant nitroxide Tempol regulates the activity of kinases associated with the production of oxidants in neutrophils, which affects the fungicidal capability of these cells. MAIN METHODS: The effects of Tempol on PMA- or fMLP-activated neutrophils were examined by oxygen consumption as an index of the oxidative burst, a release of extracellular and total Reactive Oxygen Species (ROS) by chemiluminescence, kinase activities through analysis of ATP consumption during enzyme activities and the dot blot immunoassay and, finally, by neutrophil capacity of killing Candida albicans. KEY FINDINGS: Tempol significantly inhibited the neutrophil oxidative burst in a concentration-dependent manner and decreased oxygen consumption (IC50 = 45 µM) and extracellular/total ROS formation with an increase on the lag period response. In addition, Tempol inhibited neutrophil kinase activities (i.e., a decrease in protein phosphorylation) elicited through different biochemical pathways and consequently impaired the fungicidal activity of these cells. SIGNIFICANCE: Although Tempol has potential anti-inflammatory activity that acts on different intracellular pathways (such as those involving kinases), researchers should be cautious, since this nitroxide down-regulated oxidants production and the fungicidal response of neutrophils. [Mh] Termos MeSH primário: Candida albicans/fisiologia Óxidos N-Cíclicos/farmacologia Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos NADPH Oxidases/metabolismo Fagócitos/efeitos dos fármacos [Mh] Termos MeSH secundário: Animais Óxidos N-Cíclicos/química Regulação para Baixo/efeitos dos fármacos Inflamação Masculino Camundongos Estrutura Molecular Neutrófilos/enzimologia Consumo de Oxigênio Fosfotransferases/genética Fosfotransferases/metabolismo Marcadores de Spin [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cyclic N-Oxides); 0 (Spin Labels); EC 1.6.3.- (NADPH Oxidases); EC 2.7.- (Phosphotransferases); U78ZX2F65X (tempol) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180103 [Lr] Data última revisão: 180103 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171130 [St] Status: MEDLINE

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[PMID]: 29266096 [Au] Autor: Kudo T; Jeknic S; Macklin DN; Akhter S; Hughey JJ; Regot S; Covert MW [Ad] Endereço: Department of Chemical and Systems Biology, Stanford University, Stanford, California, USA. [Ti] Título: Live-cell measurements of kinase activity in single cells using translocation reporters. [So] Source: Nat Protoc;13(1):155-169, 2018 Jan. [Is] ISSN: 1750-2799 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Although kinases are important regulators of many cellular processes, measuring their activity in live cells remains challenging. We have developed kinase translocation reporters (KTRs), which enable multiplexed measurements of the dynamics of kinase activity at a single-cell level. These KTRs are composed of an engineered construct in which a kinase substrate is fused to a bipartite nuclear localization signal (bNLS) and nuclear export signal (NES), as well as to a fluorescent protein for microscopy-based detection of its localization. The negative charge introduced by phosphorylation of the substrate is used to directly modulate nuclear import and export, thereby regulating the reporter's distribution between the cytoplasm and nucleus. The relative cytoplasmic versus nuclear fluorescence of the KTR construct (the C/N ratio) is used as a proxy for the kinase activity in living, single cells. Multiple KTRs can be studied in the same cell by fusing them to different fluorescent proteins. Here, we present a protocol to execute and analyze live-cell microscopy experiments using KTRs. We describe strategies for development of new KTRs and procedures for lentiviral expression of KTRs in a cell line of choice. Cells are then plated in a 96-well plate, from which multichannel fluorescent images are acquired with automated time-lapse microscopy. We provide detailed guidance for a computational analysis and parameterization pipeline. The entire procedure, from virus production to data analysis, can be completed in ∼10 d. [Mh] Termos MeSH primário: Imagem Molecular/métodos Sinais de Localização Nuclear/metabolismo Fosfotransferases Proteínas Recombinantes de Fusão/metabolismo Análise de Célula Única/métodos [Mh] Termos MeSH secundário: Núcleo Celular/química Núcleo Celular/metabolismo Citoplasma/química Citoplasma/metabolismo Genes Reporter Células HEK293 Seres Humanos Processamento de Imagem Assistida por Computador Proteínas Luminescentes/química Proteínas Luminescentes/genética Proteínas Luminescentes/metabolismo Sinais de Localização Nuclear/genética Fosforilação Fosfotransferases/análise Fosfotransferases/metabolismo Proteínas Recombinantes de Fusão/química Proteínas Recombinantes de Fusão/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Luminescent Proteins); 0 (Nuclear Localization Signals); 0 (Recombinant Fusion Proteins); EC 2.7.- (Phosphotransferases) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180102 [Lr] Data última revisão: 180102 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171222 [St] Status: MEDLINE [do] DOI: 10.1038/nprot.2017.128

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[PMID]: 29202407 [Au] Autor: Ma X; Lv X; Zhang J [Ad] Endereço: Department of Medicinal Chemistry, School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China; Department of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei 230012, China. [Ti] Título: Exploiting polypharmacology for improving therapeutic outcome of kinase inhibitors (KIs): An update of recent medicinal chemistry efforts. [So] Source: Eur J Med Chem;143:449-463, 2018 Jan 01. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: Polypharmacology has been increasingly advocated for the therapeutic intervention in complex pathological conditions, exemplified by cancer. Although kinase inhibitors (KIs) have revolutionized the treatment for certain types of malignancies, some major medical needs remain unmet due to the relentless advance of drug resistance and insufficient efficacy of mono-target KIs. Hence, "multiple targets, multi-dimensional activities" represents an emerging paradigm for innovative anti-cancer drug discovery. Over recent years, considerable leaps have been made in pursuit of kinase-centric polypharmacological anti-cancer therapeutics, providing avenues to tackling the limitation of mono-target KIs. In the review, we summarize the clinically important mechanisms inducing KI resistance and depict a landscape of recent medicinal chemistry efforts on exploring kinase-centric polypharmacological anti-cancer agents that targeting multiple cancer-related processes. In parallel, some inevitable challenges are emphasized for the sake of more accurate and efficient drug discovery in the field. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Neoplasias/tratamento farmacológico Fosfotransferases/antagonistas & inibidores Polifarmacologia Inibidores de Proteínas Quinases/farmacologia [Mh] Termos MeSH secundário: Animais Antineoplásicos/síntese química Antineoplásicos/química Descoberta de Drogas Seres Humanos Neoplasias/metabolismo Fosfotransferases/metabolismo Inibidores de Proteínas Quinases/síntese química Inibidores de Proteínas Quinases/química [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Protein Kinase Inhibitors); EC 2.7.- (Phosphotransferases) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180101 [Lr] Data última revisão: 180101 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171205 [St] Status: MEDLINE

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[PMID]: 28462919 [Au] Autor: Slinger E; Thijssen R; Kater AP; Eldering E [Ad] Endereço: Cancer Center Amsterdam, Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands. [Ti] Título: Targeting antigen-independent proliferation in chronic lymphocytic leukemia through differential kinase inhibition. [So] Source: Leukemia;31(12):2601-2607, 2017 Dec. [Is] ISSN: 1476-5551 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The clinical success of B-cell receptor (BCR) signaling pathway inhibitors in chronic lymphocytic leukemia (CLL) is attributed to inhibition of adhesion in and migration towards the lymph node. Proliferation of CLL cells is restricted to this protective niche, but the underlying mechanism(s) is/are not known. Treatment with BCR pathway inhibitors results in rapid reductions of total clone size, while CLL cell survival is not affected, which points towards inhibition of proliferation. In vitro, BCR stimulation does not induce proliferation of CLL, but triggering via Toll-like receptor, tumor necrosis factor or cytokine receptors does. Here, we investigated the effects of clinically applied inhibitors that target BCR signaling, in the context of proliferation triggered either via CD40L/IL-21 or after CpG stimulation. CD40L/IL-21-induced proliferation could be inhibited by idelalisib and ibrutinib. We demonstrate this was due to blockade of CD40L-induced ERK-signaling. Targeting JAKs, but not SYK, blocked CD40L/IL-21-induced proliferation. In contrast, PI3K, BTK as well as SYK inhibition prevented CpG-induced proliferation. Knockdown experiments showed that CD40L/IL-21 did not co-opt upstream BCR components such as CD79A, in contrast to CpG-induced proliferation. Our data indicate that currently applied BTK/PI3K inhibitors target antigen-independent proliferation in CLL, and suggest that targeting of JAK and/or SYK might be clinically useful. [Mh] Termos MeSH primário: Antígenos de Neoplasias/imunologia Leucemia Linfocítica Crônica de Células B/imunologia Leucemia Linfocítica Crônica de Células B/metabolismo Fosfotransferases/antagonistas & inibidores [Mh] Termos MeSH secundário: Biomarcadores Antígenos CD40/imunologia Antígenos CD40/metabolismo Linhagem Celular Tumoral Proliferação Celular Seres Humanos Interleucinas/metabolismo Janus Quinases/metabolismo Leucemia Linfocítica Crônica de Células B/genética NF-kappa B/metabolismo Fosfotransferases/metabolismo Inibidores de Proteínas Quinases/farmacologia Receptores de Antígenos de Linfócitos B/metabolismo Fatores de Transcrição STAT/metabolismo Transdução de Sinais/efeitos dos fármacos Células Tumorais Cultivadas [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antigens, Neoplasm); 0 (Biomarkers); 0 (CD40 Antigens); 0 (Interleukins); 0 (NF-kappa B); 0 (Protein Kinase Inhibitors); 0 (Receptors, Antigen, B-Cell); 0 (STAT Transcription Factors); 0 (interleukin-21); EC 2.7.- (Phosphotransferases); EC 2.7.10.2 (Janus Kinases) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171215 [Lr] Data última revisão: 171215 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170503 [St] Status: MEDLINE [do] DOI: 10.1038/leu.2017.129

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[PMID]: 28470426 [Au] Autor: Salas-Delgado G; Ongay-Larios L; Kawasaki-Watanabe L; López-Villaseñor I; Coria R [Ad] Endereço: Departamento de Genética Molecular, Instituto de FisiologíaCelular, Universidad Nacional Autónoma de México, 04510, Ciudad de México, México. [Ti] Título: The yeasts phosphorelay systems: a comparative view. [So] Source: World J Microbiol Biotechnol;33(6):111, 2017 Jun. [Is] ISSN: 1573-0972 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Cells contain signal transduction pathways that mediate communication between the extracellular environment and the cell interior. These pathways control transcriptional programs and posttranscriptional processes that modify cell metabolism in order to maintain homeostasis. One type of these signal transduction systems are the so-called Two Component Systems (TCS), which conduct the transfer of phosphate groups between specific and conserved histidine and aspartate residues present in at least two proteins; the first protein is a sensor kinase which autophosphorylates a histidine residue in response to a stimulus, this phosphate is then transferred to an aspartic residue located in a response regulator protein. There are classical and hybrid TCS, whose difference consists in the number of proteins and functional domains involved in the phosphorelay. The TCS are widespread in bacteria where the sensor and its response regulator are mostly specific for a given stimulus. In eukaryotic organisms such as fungi, slime molds, and plants, TCS are present as hybrid multistep phosphorelays, with a variety of arrangements (Stock et al. in Annu Rev Biochem 69:183-215, 2000; Wuichet et al. in Curr Opin Microbiol 292:1039-1050, 2010). In these multistep phosphorelay systems, several phosphotransfer events take place between different histidine and aspartate residues localized in specific domains present in more than two proteins (Thomason and Kay, in J Cell Sci 113:3141-3150, 2000; Robinson et al. in Nat Struct Biol 7:626-633, 2000). This review presents a brief and succinct description of the Two-component systems of model yeasts, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Candida albicans, Cryptococcus neoformans and Kluyveromyces lactis. We have focused on the comparison of domain organization and functions of each component present in these phosphorelay systems. [Mh] Termos MeSH primário: Fosfatos/metabolismo Transdução de Sinais/fisiologia Leveduras/metabolismo [Mh] Termos MeSH secundário: Ácido Aspártico/metabolismo Candida albicans/metabolismo Cryptococcus neoformans/metabolismo Proteínas Fúngicas Histidina/metabolismo Histidina Quinase Kluyveromyces/metabolismo Fosforilação/fisiologia Fosfotransferases/metabolismo Saccharomyces cerevisiae/metabolismo Schizosaccharomyces/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Fungal Proteins); 0 (Phosphates); 30KYC7MIAI (Aspartic Acid); 4QD397987E (Histidine); EC 2.7.- (Phosphotransferases); EC 2.7.13.1 (Histidine Kinase) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171201 [Lr] Data última revisão: 171201 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170505 [St] Status: MEDLINE [do] DOI: 10.1007/s11274-017-2272-z

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[PMID]: 29049311 [Au] Autor: Ryals M; Pak K; Jalota R; Kurabi A; Ryan AF [Ad] Endereço: Department of Surgery/Otolaryngology, University of California, San Diego, School of Medicine, La Jolla, California, United States of America. [Ti] Título: A kinase inhibitor library screen identifies novel enzymes involved in ototoxic damage to the murine organ of Corti. [So] Source: PLoS One;12(10):e0186001, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Ototoxicity is a significant side effect of a number of drugs, including the aminoglycoside antibiotics and platinum-based chemotherapeutic agents that are used to treat life-threatening illnesses. Although much progress has been made, the mechanisms that lead to ototoxic loss of inner ear sensory hair cells (HCs) remains incompletely understood. Given the critical role of protein phosphorylation in intracellular processes, including both damage and survival signaling, we screened a library of kinase inhibitors targeting members of all the major families in the kinome. Micro-explants from the organ of Corti of mice in which only the sensory cells express GFP were exposed to 200 µM of the ototoxic aminoglycoside gentamicin with or without three dosages of each kinase inhibitor. The loss of sensory cells was compared to that seen with gentamicin alone, or without treatment. Of the 160 inhibitors, 15 exhibited a statistically significant protective effect, while 3 significantly enhanced HC loss. The results confirm some previous studies of kinase involvement in HC damage and survival, and also highlight several novel potential kinase pathway contributions to ototoxicity. [Mh] Termos MeSH primário: Aminoglicosídeos/toxicidade Antibacterianos/toxicidade Antineoplásicos/toxicidade Inibidores Enzimáticos/farmacologia Órgão Espiral/efeitos dos fármacos Fosfotransferases/antagonistas & inibidores [Mh] Termos MeSH secundário: Animais Camundongos Camundongos Transgênicos Órgão Espiral/enzimologia [Pt] Tipo de publicação: JOURNAL ARTICLE; VALIDATION STUDIES [Nm] Nome de substância: 0 (Aminoglycosides); 0 (Anti-Bacterial Agents); 0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); EC 2.7.- (Phosphotransferases) [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: 171020 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0186001

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2	and or and not		PalavrasDescritor de assuntoDescritor de assunto primárioLimitesAutorPalavras do títuloPalavras do resumoIdiomaPaís de publicaçãoNome de substânciaNome de pessoa como assuntoRevistaAssunto de RevistaISSNTipo de publicaçãoIdentificador únicoMês de entradaAno de publicaçãoTexto completoAtualização por classeCategoria DeCSCategoria DeCS explodidaCategoria CID-10SubSetsPais de AfiliaçãoAfiliaçãoAfiliação 2
3	and or and not		PalavrasDescritor de assuntoDescritor de assunto primárioLimitesAutorPalavras do títuloPalavras do resumoIdiomaPaís de publicaçãoNome de substânciaNome de pessoa como assuntoRevistaAssunto de RevistaISSNTipo de publicaçãoIdentificador únicoMês de entradaAno de publicaçãoTexto completoAtualização por classeCategoria DeCSCategoria DeCS explodidaCategoria CID-10SubSetsPais de AfiliaçãoAfiliaçãoAfiliação 2

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