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[PMID]:26773602
[Au] Autor:Zhao CY; Greenstein JL; Winslow RL
[Ad] Endereço:Department of Biomedical Engineering and the Institute for Computational Medicine, The Johns Hopkins University School of Medicine and Whiting School of Engineering, 3400 N Charles Street, Baltimore, MD 21218, USA. Electronic address: czhao10@jhu.edu.
[Ti] Título:Roles of phosphodiesterases in the regulation of the cardiac cyclic nucleotide cross-talk signaling network.
[So] Source:J Mol Cell Cardiol;91:215-27, 2016 Feb.
[Is] ISSN:1095-8584
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The balanced signaling between the two cyclic nucleotides (cNs) cAMP and cGMP plays a critical role in regulating cardiac contractility. Their degradation is controlled by distinctly regulated phosphodiesterase isoenzymes (PDEs), which in turn are also regulated by these cNs. As a result, PDEs facilitate communication between the ß-adrenergic and Nitric Oxide (NO)/cGMP/Protein Kinase G (PKG) signaling pathways, which regulate the synthesis of cAMP and cGMP respectively. The phenomena in which the cAMP and cGMP pathways influence the dynamics of each other are collectively referred to as cN cross-talk. However, the cross-talk response and the individual roles of each PDE isoenzyme in shaping this response remain to be fully characterized. We have developed a computational model of the cN cross-talk network that mechanistically integrates the ß-adrenergic and NO/cGMP/PKG pathways via regulation of PDEs by both cNs. The individual model components and the integrated network model replicate experimentally observed activation-response relationships and temporal dynamics. The model predicts that, due to compensatory interactions between PDEs, NO stimulation in the presence of sub-maximal ß-adrenergic stimulation results in an increase in cytosolic cAMP accumulation and corresponding increases in PKA-I and PKA-II activation; however, the potentiation is small in magnitude compared to that of NO activation of the NO/cGMP/PKG pathway. In a reciprocal manner, ß-adrenergic stimulation in the presence of sub-maximal NO stimulation results in modest cGMP elevation and corresponding increase in PKG activation. In addition, we demonstrate that PDE2 hydrolyzes increasing amounts of cAMP with increasing levels of ß-adrenergic stimulation, and hydrolyzes increasing amounts of cGMP with decreasing levels of NO stimulation. Finally, we show that PDE2 compensates for inhibition of PDE5 both in terms of cGMP and cAMP dynamics, leading to cGMP elevation and increased PKG activation, while maintaining whole-cell ß-adrenergic responses similar to that prior to PDE5 inhibition. By defining and quantifying reactions comprising cN cross-talk, the model characterizes the cross-talk response and reveals the underlying mechanisms of PDEs in this non-linear, tightly-coupled reaction system.
[Mh] Termos MeSH primário: AMP Cíclico/metabolismo
GMP Cíclico/metabolismo
Redes Reguladoras de Genes
Modelos Cardiovasculares
Miocárdio/enzimologia
Miócitos Cardíacos/enzimologia
Diester Fosfórico Hidrolases/genética
[Mh] Termos MeSH secundário: Animais
Simulação por Computador
Proteína Quinase Tipo I Dependente de AMP Cíclico/genética
Proteína Quinase Tipo I Dependente de AMP Cíclico/metabolismo
Proteína Quinase Tipo II Dependente de AMP Cíclico/genética
Proteína Quinase Tipo II Dependente de AMP Cíclico/metabolismo
Proteínas Quinases Dependentes de GMP Cíclico/genética
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo
Regulação da Expressão Gênica
Isoenzimas/genética
Isoenzimas/metabolismo
Contração Miocárdica
Miocárdio/citologia
Miócitos Cardíacos/citologia
Óxido Nítrico/metabolismo
Diester Fosfórico Hidrolases/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Isoenzymes); 31C4KY9ESH (Nitric Oxide); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type I); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type II); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases); EC 3.1.4.- (Phosphoric Diester Hydrolases); H2D2X058MU (Cyclic GMP)
[Em] Mês de entrada:1611
[Cu] Atualização por classe:170228
[Lr] Data última revisão:
170228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160117
[St] Status:MEDLINE


  2 / 439 MEDLINE  
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[PMID]:26468277
[Au] Autor:Bockus LB; Humphries KM
[Ad] Endereço:From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 and the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
[Ti] Título:cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart.
[So] Source:J Biol Chem;290(49):29250-8, 2015 Dec 04.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Diabetes mellitus causes cardiac dysfunction and heart failure that is associated with metabolic abnormalities and autonomic impairment. Autonomic control of ventricular function occurs through regulation of cAMP-dependent protein kinase (PKA). The diabetic heart has suppressed ß-adrenergic responsiveness, partly attributable to receptor changes, yet little is known about how PKA signaling is directly affected. Control and streptozotocin-induced diabetic mice were therefore administered 8-bromo-cAMP (8Br-cAMP) acutely to activate PKA in a receptor-independent manner, and cardiac hemodynamic function and PKA signaling were evaluated. In response to 8Br-cAMP treatment, diabetic mice had impaired inotropic and lusitropic responses, thus demonstrating postreceptor defects. This impaired signaling was mediated by reduced PKA activity and PKA catalytic subunit content in the cytoplasm and myofilaments. Compartment-specific loss of PKA was reflected by reduced phosphorylation of discrete substrates. In response to 8Br-cAMP treatment, the glycolytic activator PFK-2 was robustly phosphorylated in control animals but not diabetics. Control adult cardiomyocytes cultured in lipid-supplemented media developed similar changes in PKA signaling, suggesting that lipotoxicity is a contributor to diabetes-induced ß-adrenergic signaling dysfunction. This work demonstrates that PKA signaling is impaired in diabetes and suggests that treating hyperlipidemia is vital for proper cardiac signaling and function.
[Mh] Termos MeSH primário: Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismo
Diabetes Mellitus Experimental/metabolismo
Miocárdio/enzimologia
[Mh] Termos MeSH secundário: 8-Bromo Monofosfato de Adenosina Cíclica/metabolismo
Animais
Domínio Catalítico
AMP Cíclico/metabolismo
Proteína Quinase Tipo II Dependente de AMP Cíclico/metabolismo
Citoplasma/metabolismo
Modelos Animais de Doenças
Insuficiência Cardíaca/fisiopatologia
Ventrículos do Coração/patologia
Hemodinâmica
Lactatos/metabolismo
Lipídeos/química
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Contração Miocárdica
Miócitos Cardíacos/metabolismo
Fosfofrutoquinase-2/metabolismo
Fosforilação
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Lactates); 0 (Lipids); 23583-48-4 (8-Bromo Cyclic Adenosine Monophosphate); E0399OZS9N (Cyclic AMP); EC 2.7.1.105 (Phosphofructokinase-2); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Catalytic Subunits); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type II)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151016
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M115.681767


  3 / 439 MEDLINE  
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[PMID]:25903037
[Au] Autor:Zinn VZ; Khatri A; Mednieks MI; Hand AR
[Ad] Endereço:University of Connecticut School of Dental Medicine, Farmington, CT, USA.
[Ti] Título:Localization of cystic fibrosis transmembrane conductance regulator signaling complexes in human salivary gland striated duct cells.
[So] Source:Eur J Oral Sci;123(3):140-8, 2015 Jun.
[Is] ISSN:1600-0722
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic AMP-dependent protein kinase (PKA)-regulated Cl(-) channel, crucial for epithelial cell regulation of salt and water transport. Previous studies showed that ezrin, an actin binding and A-kinase anchoring protein (AKAP), facilitates association of PKA with CFTR. We used immunohistochemistry and immunogold transmission electron microscopy to localize CFTR, ezrin, and PKA type II regulatory (RII) and catalytic (C) subunits in striated duct cells of human parotid and submandibular glands. Immunohistochemistry localized the four proteins mainly to the apical membrane and the apical cytoplasm of striated duct cells. In acinar cells, ezrin localized to the luminal membrane, and PKA RII subunits were present in secretory granules, as previously described. Immunogold labeling showed that CFTR and PKA RII and C subunits were localized to the luminal membrane and associated with apical granules and vesicles of striated duct cells. Ezrin was present along the luminal membrane, on microvilli and along the junctional complexes between cells. Double labeling showed specific protein associations with apical granules and vesicles and along the luminal membrane. Ezrin, CFTR, and PKA RII and C subunits are co-localized in striated duct cells, suggesting the presence of signaling complexes that serve to regulate CFTR activity.
[Mh] Termos MeSH primário: Proteínas Quinases Dependentes de AMP Cíclico/análise
Regulador de Condutância Transmembrana em Fibrose Cística/análise
Proteínas do Citoesqueleto/análise
Glândula Parótida/química
Ductos Salivares/química
Glândula Submandibular/química
[Mh] Termos MeSH secundário: Proteínas de Ancoragem à Quinase A/análise
Membrana Celular/química
Membrana Celular/ultraestrutura
Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/análise
Proteína Quinase Tipo II Dependente de AMP Cíclico/análise
Citoplasma/química
Citoplasma/ultraestrutura
Seres Humanos
Imuno-Histoquímica
Junções Intercelulares/química
Junções Intercelulares/ultraestrutura
Microscopia Eletrônica de Transmissão
Microvilosidades/química
Microvilosidades/ultraestrutura
Glândula Parótida/citologia
Ductos Salivares/citologia
Vesículas Secretórias/química
Vesículas Secretórias/ultraestrutura
Glândula Submandibular/citologia
Vacúolos/química
Vacúolos/ultraestrutura
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (A Kinase Anchor Proteins); 0 (CFTR protein, human); 0 (Cytoskeletal Proteins); 0 (ezrin); 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Catalytic Subunits); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type II); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
[Em] Mês de entrada:1611
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:D; IM
[Da] Data de entrada para processamento:150424
[St] Status:MEDLINE
[do] DOI:10.1111/eos.12184


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[PMID]:25765284
[Au] Autor:Wang Y; Ho TG; Franz E; Hermann JS; Smith FD; Hehnly H; Esseltine JL; Hanold LE; Murph MM; Bertinetti D; Scott JD; Herberg FW; Kennedy EJ
[Ad] Endereço:†Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602, United States.
[Ti] Título:PKA-type I selective constrained peptide disruptors of AKAP complexes.
[So] Source:ACS Chem Biol;10(6):1502-10, 2015 Jun 19.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A-Kinase Anchoring Proteins (AKAPs) coordinate complex signaling events by serving as spatiotemporal modulators of cAMP-dependent protein kinase activity in cells. Although AKAPs organize a plethora of diverse pathways, their cellular roles are often elusive due to the dynamic nature of these signaling complexes. AKAPs can interact with the type I or type II PKA holoenzymes by virtue of high-affinity interactions with the R-subunits. As a means to delineate AKAP-mediated PKA signaling in cells, we sought to develop isoform-selective disruptors of AKAP signaling. Here, we report the development of conformationally constrained peptides named RI-STapled Anchoring Disruptors (RI-STADs) that target the docking/dimerization domain of the type 1 regulatory subunit of PKA. These high-affinity peptides are isoform-selective for the RI isoforms, can outcompete binding by the classical AKAP disruptor Ht31, and can selectively displace RIα, but not RIIα, from binding the dual-specific AKAP149 complex. Importantly, these peptides are cell-permeable and disrupt Type I PKA-mediated phosphorylation events in the context of live cells. Hence, RI-STAD peptides are versatile cellular tools to selectively probe anchored type I PKA signaling events.
[Mh] Termos MeSH primário: Proteínas de Ancoragem à Quinase A/antagonistas & inibidores
Proteína Quinase Tipo II Dependente de AMP Cíclico/antagonistas & inibidores
Proteína Quinase Tipo I Dependente de AMP Cíclico/antagonistas & inibidores
Peptídeos/química
Inibidores de Proteínas Quinases/química
Subunidades Proteicas/antagonistas & inibidores
[Mh] Termos MeSH secundário: Proteínas de Ancoragem à Quinase A/química
Proteínas de Ancoragem à Quinase A/metabolismo
Sequência de Aminoácidos
Sítios de Ligação/efeitos dos fármacos
Linhagem Celular Tumoral
Permeabilidade da Membrana Celular
Proteína Quinase Tipo I Dependente de AMP Cíclico/química
Proteína Quinase Tipo I Dependente de AMP Cíclico/metabolismo
Proteína Quinase Tipo II Dependente de AMP Cíclico/química
Proteína Quinase Tipo II Dependente de AMP Cíclico/metabolismo
Seres Humanos
Cinética
Dados de Sequência Molecular
Peptídeos/farmacologia
Fosforilação
Ligação Proteica/efeitos dos fármacos
Conformação Proteica
Inibidores de Proteínas Quinases/farmacologia
Subunidades Proteicas/química
Subunidades Proteicas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (A Kinase Anchor Proteins); 0 (AKAP1 protein, human); 0 (Peptides); 0 (Protein Kinase Inhibitors); 0 (Protein Subunits); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type I); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type II)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150314
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.5b00009


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[PMID]:25451551
[Au] Autor:Narenji SA; Naghdi N; Azadmanesh K; Edalat R
[Ad] Endereço:Department of Biology, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran. Electronic address: S_asadian@toniau.ac.ir.
[Ti] Título:3α-diol administration decreases hippocampal PKA (II) mRNA expression and impairs Morris water maze performance in adult male rats.
[So] Source:Behav Brain Res;280:149-59, 2015 Mar 01.
[Is] ISSN:1872-7549
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The effect of testosterone and its metabolites on learning and memory has been the subject of many studies. This study used the Morris water maze task to investigate the effect of intra-hippocampal injection of 3α-diol (one of the metabolites of testosterone) on acquisition stage of spatial memory in adult male rats. During the experiment we observed that 3α-diol, significantly impaired Morris water maze performance in treated rat's compared with controls. Because signaling event mediated by protein kinase A (PKA) especially PKA (II) are critical for many neuronal functions such as learning and memory, the hippocampus was analyzed for mRNA expression of PKA (II) using TaqMan real time RT-PCR. The results indicated that the transcription levels of PKA (II) were significantly decreased in animals treated with 3α-diol compared with controls. Thus, the findings suggest that administration of 3α-diol in hippocampus of adult male rats impairs memory function, possibly via down-regulation of PKA.
[Mh] Termos MeSH primário: Proteína Quinase Tipo II Dependente de AMP Cíclico/metabolismo
Hipocampo/fisiologia
Aprendizagem em Labirinto/fisiologia
Testosterona/metabolismo
[Mh] Termos MeSH secundário: Animais
Hipocampo/efeitos dos fármacos
Masculino
Aprendizagem em Labirinto/efeitos dos fármacos
RNA Mensageiro/metabolismo
Ratos Wistar
Reação em Cadeia da Polimerase em Tempo Real
Memória Espacial/efeitos dos fármacos
Memória Espacial/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Messenger); 3XMK78S47O (Testosterone); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type II)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:141227
[Lr] Data última revisão:
141227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141203
[St] Status:MEDLINE


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[PMID]:23967353
[Au] Autor:Huang YA; Kao JW; Tseng DT; Chen WS; Chiang MH; Hwang E
[Ad] Endereço:Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.
[Ti] Título:Microtubule-associated type II protein kinase A is important for neurite elongation.
[So] Source:PLoS One;8(8):e73890, 2013.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neuritogenesis is a process through which neurons generate their widespread axon and dendrites. The microtubule cytoskeleton plays crucial roles throughout neuritogenesis. Our previous study indicated that the amount of type II protein kinase A (PKA) on microtubules significantly increased upon neuronal differentiation and neuritogenesis. While the overall pool of PKA has been shown to participate in various neuronal processes, the function of microtubule-associated PKA during neuritogenesis remains largely unknown. First, we showed that PKA localized to microtubule-based region in different neurons. Since PKA is essential for various cellular functions, globally inhibiting PKA activity will causes a wide variety of phenotypes in neurons. To examine the function of microtubule-associated PKA without changing the total PKA level, we utilized the neuron-specific PKA anchoring protein MAP2. Overexpressing the dominant negative MAP2 construct that binds to type II PKA but cannot bind to the microtubule cytoskeleton in dissociated hippocampal neurons removed PKA from microtubules and resulted in compromised neurite elongation. In addition, we demonstrated that the association of PKA with microtubules can also enhance cell protrusion using the non-neuronal P19 cells. Overexpressing a MAP2 deletion construct which does not target PKA to the microtubule cytoskeleton caused non-neuronal cells to generate shorter cell protrusions than control cells overexpressing wild-type MAP2 that anchors PKA to microtubules. Finally, we demonstrated that the ability of microtubule-associated PKA to promote protrusion elongation was independent of MAP2 phosphorylation. This suggests other proteins in close proximity to the microtubule cytoskeleton are involved in this process.
[Mh] Termos MeSH primário: Proteína Quinase Tipo II Dependente de AMP Cíclico/metabolismo
Microtúbulos/metabolismo
Neuritos/metabolismo
[Mh] Termos MeSH secundário: Animais
Hipocampo/citologia
Hipocampo/metabolismo
Camundongos
Proteínas Associadas aos Microtúbulos/metabolismo
Neurônios/citologia
Neurônios/metabolismo
Fosforilação
Ligação Proteica
Transporte Proteico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Microtubule-Associated Proteins); 0 (Mtap2 protein, mouse); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type II)
[Em] Mês de entrada:1405
[Cu] Atualização por classe:150423
[Lr] Data última revisão:
150423
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130823
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0073890


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[PMID]:23718778
[Au] Autor:Vázquez-Meza H; de Piña MZ; Pardo JP; Riveros-Rosas H; Villalobos-Molina R; Piña E
[Ad] Endereço:Departamento de Bioquímica, Universidad Nacional Autónoma de México, México, México. hvazquez@bq.unam.mx
[Ti] Título:Non-steroidal anti-inflammatory drugs activate NADPH oxidase in adipocytes and raise the H2O2 pool to prevent cAMP-stimulated protein kinase a activation and inhibit lipolysis.
[So] Source:BMC Biochem;14:13, 2013 May 30.
[Is] ISSN:1471-2091
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) -aspirin, naproxen, nimesulide, and piroxicam- lowered activation of type II cAMP-dependent protein kinase A (PKA-II) in isolated rat adipocytes, decreasing adrenaline- and dibutyryl cAMP (Bt2cAMP)-stimulated lipolysis. The molecular bases of insulin-like actions of NSAID were studied. RESULTS: Based on the reported inhibition of lipolysis by H2O2, catalase was successfully used to block NSAID inhibitory action on Bt2cAMP-stimulated lipolysis. NSAID, at (sub)micromolar range, induced an H2O2 burst in rat adipocyte plasma membranes and in whole adipocytes. NSAID-mediated rise of H2O2 was abrogated in adipocyte plasma membranes by: diphenyleneiodonium, an inhibitor of NADPH oxidase (NOX); the NOX4 antibody; and cytochrome c, trapping the NOX-formed superoxide. These three compounds prevented the inhibition of Bt2cAMP-stimulated lipolysis by NSAIDs. Inhibition of aquaporin-mediated H2O2 transport with AgNO3 in adipocytes allowed NOX activation but prevented the lipolysis inhibition promoted by NSAID: i.e., once synthesized, H2O2 must reach the lipolytic machinery. Since insulin inhibits adrenaline-stimulated lipolysis, the effect of aspirin on isoproterenol-stimulated lipolysis in rat adipocytes was studied. As expected, isoproterenol-mediated lipolysis was blunted by both insulin and aspirin. CONCLUSIONS: NSAIDs activate NOX4 in adipocytes to produce H2O2, which impairs cAMP-dependent PKA-II activation, thus preventing isoproterenol-activated lipolysis. H2O2 signaling in adipocytes is a novel and important cyclooxygenase-independent effect of NSAID.
[Mh] Termos MeSH primário: Adipócitos/enzimologia
Anti-Inflamatórios não Esteroides/farmacologia
Proteína Quinase Tipo II Dependente de AMP Cíclico/metabolismo
Peróxido de Hidrogênio/metabolismo
Lipólise/efeitos dos fármacos
NADPH Oxidases/metabolismo
[Mh] Termos MeSH secundário: Adipócitos/citologia
Adipócitos/metabolismo
Animais
Aquaporinas/farmacologia
Ativação Enzimática/efeitos dos fármacos
Masculino
NADPH Oxidases/antagonistas & inibidores
Ratos
Ratos Wistar
Nitrato de Prata/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Aquaporins); 95IT3W8JZE (Silver Nitrate); BBX060AN9V (Hydrogen Peroxide); EC 1.6.3.- (NADPH Oxidases); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type II)
[Em] Mês de entrada:1309
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130531
[St] Status:MEDLINE
[do] DOI:10.1186/1471-2091-14-13


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[PMID]:23455313
[Au] Autor:Nguyen E; Gausdal G; Varennes J; Pendino F; Lanotte M; Døskeland SO; Ségal-Bendirdjian E
[Ad] Endereço:Institut National de la Santé et de Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR)-S 1007, Homeostasis and Cancer, Paris, France.
[Ti] Título:Activation of both protein kinase A (PKA) type I and PKA type II isozymes is required for retinoid-induced maturation of acute promyelocytic leukemia cells.
[So] Source:Mol Pharmacol;83(5):1057-65, 2013 May.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Acute promyelocytic leukemia (APL) is characterized by granulopoietic differentiation arrest at the promyelocytic stage. In most cases, this defect can be overcome by treatment with all-trans-retinoic acid (ATRA), leading to complete clinical remission. Cyclic AMP signaling has a key role in retinoid treatment efficacy: it enhances ATRA-induced maturation in ATRA-sensitive APL cells (including NB4 cells) and restores it in some ATRA-resistant cells (including NB4-LR1 cells). We show that the two cell types express identical levels of the Cα catalytic subunit and comparable global cAMP-dependent protein kinase A (PKA) enzyme activity. However, the maturation-resistant NB4-LR1 cells have a PKA isozyme switch: compared with the NB4 cells, they have decreased content of the juxtanuclearly located PKA regulatory subunit IIα and PKA regulatory subunit IIß, and a compensatory increase of the generally cytoplasmically distributed PKA-RIα. Furthermore, the PKA regulatory subunit II exists mainly in the less cAMP-responsive nonautophosphorylated state in the NB4-LR1 cells. By the use of isozyme-specific cAMP analog pairs, we show that both PKA-I and PKA-II must be activated to achieve maturation in NB4-LR1 as well as NB4 cells. Therefore, special attention should be paid to activating not only PKA-I but also PKA-II in attempts to enhance ATRA-induced APL maturation in a clinical setting.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Proteína Quinase Tipo II Dependente de AMP Cíclico/metabolismo
Proteína Quinase Tipo I Dependente de AMP Cíclico/metabolismo
Leucemia Promielocítica Aguda/tratamento farmacológico
Leucemia Promielocítica Aguda/patologia
Tretinoína/farmacologia
[Mh] Termos MeSH secundário: Diferenciação Celular/efeitos dos fármacos
Linhagem Celular Tumoral
AMP Cíclico/metabolismo
Citoplasma/efeitos dos fármacos
Citoplasma/metabolismo
Seres Humanos
Isoenzimas/metabolismo
Leucemia Promielocítica Aguda/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Isoenzymes); 5688UTC01R (Tretinoin); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type I); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type II)
[Em] Mês de entrada:1309
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130305
[St] Status:MEDLINE
[do] DOI:10.1124/mol.112.081034


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[PMID]:23449452
[Au] Autor:Gausdal G; Wergeland A; Skavland J; Nguyen E; Pendino F; Rouhee N; McCormack E; Herfindal L; Kleppe R; Havemann U; Schwede F; Bruserud O; Gjertsen BT; Lanotte M; Ségal-Bendirdjian E; Døskeland SO
[Ad] Endereço:Department of Biomedicine, University of Bergen, Bergen, Norway.
[Ti] Título:Cyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosis.
[So] Source:Cell Death Dis;4:e516, 2013 Feb 28.
[Is] ISSN:2041-4889
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We show that cyclic AMP (cAMP) elevating agents protect blasts from patients with acute promyelocytic leukemia (APL) against death induced by first-line anti-leukemic anthracyclines like daunorubicin (DNR). The cAMP effect was reproduced in NB4 APL cells, and shown to depend on activation of the generally cytoplasmic cAMP-kinase type I (PKA-I) rather than the perinuclear PKA-II. The protection of both NB4 cells and APL blasts was associated with (inactivating) phosphorylation of PKA site Ser118 of pro-apoptotic Bad and (activating) phosphorylation of PKA site Ser133 of the AML oncogene CREB. Either event would be expected to protect broadly against cell death, and we found cAMP elevation to protect also against 2-deoxyglucose, rotenone, proteasome inhibitor and a BH3-only mimetic. The in vitro findings were mirrored by the findings in NSG mice with orthotopic NB4 cell leukemia. The mice showed more rapid disease progression when given cAMP-increasing agents (prostaglandin E2 analog and theophylline), both with and without DNR chemotherapy. The all-trans retinoic acid (ATRA)-induced terminal APL cell differentiation is a cornerstone in current APL treatment and is enhanced by cAMP. We show also that ATRA-resistant APL cells, believed to be responsible for treatment failure with current ATRA-based treatment protocols, were protected by cAMP against death. This suggests that the beneficial pro-differentiating and non-beneficial pro-survival APL cell effects of cAMP should be weighed against each other. The results suggest also general awareness toward drugs that can affect bone marrow cAMP levels in leukemia patients.
[Mh] Termos MeSH primário: Antibióticos Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
AMP Cíclico/metabolismo
Daunorrubicina/farmacologia
[Mh] Termos MeSH secundário: 1-Metil-3-Isobutilxantina/farmacologia
Animais
Antibióticos Antineoplásicos/uso terapêutico
Linhagem Celular Tumoral
AMP Cíclico/agonistas
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo
Proteína Quinase Tipo I Dependente de AMP Cíclico/metabolismo
Proteína Quinase Tipo II Dependente de AMP Cíclico/antagonistas & inibidores
Proteína Quinase Tipo II Dependente de AMP Cíclico/genética
Proteína Quinase Tipo II Dependente de AMP Cíclico/metabolismo
Daunorrubicina/uso terapêutico
Dinoprostona/análogos & derivados
Dinoprostona/farmacologia
Dinoprostona/uso terapêutico
Progressão da Doença
Células HL-60
Seres Humanos
Leucemia Promielocítica Aguda/tratamento farmacológico
Leucemia Promielocítica Aguda/metabolismo
Leucemia Promielocítica Aguda/patologia
Masculino
Camundongos
Camundongos Endogâmicos NOD
Camundongos SCID
Interferência de RNA
RNA Interferente Pequeno/metabolismo
Teofilina/farmacologia
Teofilina/uso terapêutico
Transplante Heterólogo
Tretinoína/farmacologia
Tretinoína/uso terapêutico
Proteína de Morte Celular Associada a bcl/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antibiotics, Antineoplastic); 0 (Cyclic AMP Response Element-Binding Protein); 0 (RNA, Small Interfering); 0 (bcl-Associated Death Protein); 5688UTC01R (Tretinoin); C137DTR5RG (Theophylline); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type I); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type II); K7Q1JQR04M (Dinoprostone); TBT296U68M (1-Methyl-3-isobutylxanthine); ZS7284E0ZP (Daunorubicin)
[Em] Mês de entrada:1306
[Cu] Atualização por classe:150218
[Lr] Data última revisão:
150218
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130302
[St] Status:MEDLINE
[do] DOI:10.1038/cddis.2013.39


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[PMID]:22317922
[Au] Autor:Serezani CH; Kane S; Medeiros AI; Cornett AM; Kim SH; Marques MM; Lee SP; Lewis C; Bourdonnay E; Ballinger MN; White ES; Peters-Golden M
[Ad] Endereço:Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
[Ti] Título:PTEN directly activates the actin depolymerization factor cofilin-1 during PGE2-mediated inhibition of phagocytosis of fungi.
[So] Source:Sci Signal;5(210):ra12, 2012 Feb 07.
[Is] ISSN:1937-9145
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Macrophage ingestion of the yeast Candida albicans requires its recognition by multiple receptors and the activation of diverse signaling programs. Synthesis of the lipid mediator prostaglandin E(2) (PGE(2)) and generation of cyclic adenosine monophosphate (cAMP) also accompany this process. Here, we characterized the mechanisms underlying PGE(2)-mediated inhibition of phagocytosis and filamentous actin (F-actin) polymerization in response to ingestion of C. albicans by alveolar macrophages. PGE(2) suppressed phagocytosis and F-actin formation through the PGE(2) receptors EP2 and EP4, cAMP, and activation of types I and II protein kinase A. Dephosphorylation and activation of the actin depolymerizing factor cofilin-1 were necessary for these inhibitory effects of PGE(2). PGE(2)-dependent activation of cofilin-1 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated. Because enhanced production of PGE(2) accompanies many immunosuppressed states, the PTEN-dependent pathway described here may contribute to impaired antifungal defenses.
[Mh] Termos MeSH primário: Candida albicans/imunologia
Candidíase/imunologia
Cofilina 1/imunologia
Dinoprostona/imunologia
Tolerância Imunológica
Macrófagos Alveolares/imunologia
PTEN Fosfo-Hidrolase/imunologia
Fagocitose/imunologia
[Mh] Termos MeSH secundário: Actinas/imunologia
Actinas/metabolismo
Animais
Candida albicans/metabolismo
Candidíase/metabolismo
Células Cultivadas
Cofilina 1/metabolismo
AMP Cíclico/imunologia
AMP Cíclico/metabolismo
Proteína Quinase Tipo I Dependente de AMP Cíclico/imunologia
Proteína Quinase Tipo I Dependente de AMP Cíclico/metabolismo
Proteína Quinase Tipo II Dependente de AMP Cíclico/imunologia
Proteína Quinase Tipo II Dependente de AMP Cíclico/metabolismo
Dinoprostona/biossíntese
Feminino
Macrófagos Alveolares/metabolismo
Macrófagos Alveolares/microbiologia
PTEN Fosfo-Hidrolase/metabolismo
Fosforilação/imunologia
Ratos
Ratos Wistar
Receptores de Prostaglandina E Subtipo EP2/imunologia
Receptores de Prostaglandina E Subtipo EP2/metabolismo
Receptores de Prostaglandina E Subtipo EP4/imunologia
Receptores de Prostaglandina E Subtipo EP4/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Actins); 0 (Cfl1 protein, rat); 0 (Cofilin 1); 0 (Receptors, Prostaglandin E, EP2 Subtype); 0 (Receptors, Prostaglandin E, EP4 Subtype); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type I); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Type II); EC 3.1.3.67 (PTEN Phosphohydrolase); EC 3.1.3.67 (Pten protein, rat); K7Q1JQR04M (Dinoprostone)
[Em] Mês de entrada:1206
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120210
[St] Status:MEDLINE
[do] DOI:10.1126/scisignal.2002448



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