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[PMID]:28670762
[Au] Autor:Kritsch D; Hoffmann F; Steinbach D; Jansen L; Mary Photini S; Gajda M; Mosig AS; Sonnemann J; Peters S; Melnikova M; Thomale J; Dürst M; Runnebaum IB; Häfner N
[Ad] Endereço:Department of Gynecology and Reproductive Medicine, Jena University Hospital, Friedrich-Schiller University, Jena, Germany.
[Ti] Título:Tribbles 2 mediates cisplatin sensitivity and DNA damage response in epithelial ovarian cancer.
[So] Source:Int J Cancer;141(8):1600-1614, 2017 Oct 15.
[Is] ISSN:1097-0215
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aim was to identify methylated genes with functional involvement in cisplatin-resistance development of epithelial ovarian cancer (EOC). Genome-wide analyses of hypermethylated CpG-islands in resistant cell lines in combination with qRT-PCR analyses were used to identify epigenetically silenced genes. EOC-Type-II tumors were analyzed for gene methylation and expression and TCGA data were interrogated in-silico. Experiments revealed 37 commonly hypermethylated genes in resistant cells of which Tribbles 2 (TRIB2) showed the most pronounced downregulation on mRNA level and was characterized further. TRIB2 showed a reactivation after 5'-Aza-Cytidine treatment in resistant cells but a cisplatin-dependent, prominent upregulation on mRNA level in sensitive cells, only. Re-expression in resistant A2780 cells increased the sensitivity to cisplatin and other DNA-damaging agents, but not taxanes. Contrary, knockdown of TRIB2 increased resistance to cisplatin in sensitive cells. TRIB2 was involved in the induction of a cisplatin-dependent cell cycle arrest and apoptosis by influencing p21 and survivin expression. An increased Pt-DNA-adduct formation in TRIB2 re-expressing cells did not translate in higher levels of dsDNA damage (yH2AX-foci). Thus, TRIB2 is potentially involved in the signal transduction from nucleotide excision repair of intrastrand cross links. Importantly, patient stratification of two homogenous cohorts of EOC-Type-II patients from Jena (n = 38) and the TCGA (n = 149) by TRIB2 mRNA expression consistently revealed a significantly decreased PFS for patients with low TRIB2 levels (log-rank p < 0.05). Tumors from resistant patients expressed the lowest levels of TRIB2. Downregulation of TRIB2 contributes to platin-resistance and TRIB2 expression should be validated as prognostic and predictive marker for EOC.
[Mh] Termos MeSH primário: Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo
Cisplatino/farmacologia
Dano ao DNA
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Neoplasias Epiteliais e Glandulares/tratamento farmacológico
Neoplasias Epiteliais e Glandulares/genética
Neoplasias Ovarianas/tratamento farmacológico
Neoplasias Ovarianas/genética
[Mh] Termos MeSH secundário: Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Proteínas Quinases Dependentes de Cálcio-Calmodulina/biossíntese
Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética
Linhagem Celular Tumoral
Inibidor de Quinase Dependente de Ciclina p21/biossíntese
Adutos de DNA/biossíntese
Metilação de DNA
Resistência a Medicamentos Antineoplásicos/genética
Feminino
Fase G2
Seres Humanos
Peptídeos e Proteínas de Sinalização Intracelular/biossíntese
Peptídeos e Proteínas de Sinalização Intracelular/genética
Pontos de Checagem da Fase M do Ciclo Celular
Neoplasias Epiteliais e Glandulares/metabolismo
Neoplasias Ovarianas/metabolismo
Proteoma/metabolismo
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (CDKN1A protein, human); 0 (Cyclin-Dependent Kinase Inhibitor p21); 0 (DNA Adducts); 0 (Intracellular Signaling Peptides and Proteins); 0 (Proteome); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases); EC 2.7.11.17 (TRIB2 protein, human); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE
[do] DOI:10.1002/ijc.30860


  2 / 11840 MEDLINE  
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[PMID]:28623136
[Au] Autor:Wang P; Yang Q; Sang S; Chen Y; Zhong Y; Wei Z
[Ad] Endereço:State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address: wangpeng0129@whu.edu.cn.
[Ti] Título:Arabidopsis inositol polyphosphate kinase AtIpk2ß is phosphorylated by CPK4 and positively modulates ABA signaling.
[So] Source:Biochem Biophys Res Commun;490(2):441-446, 2017 Aug 19.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Arabidopsis inositol polyphosphate kinase 2ß (AtIpk2ß) has multiple functions in plant development and in responding to abiotic stress. Although some related clues suggested a potential role of AtIpk2ß in ABA signaling, the defined evidence was still lack. Here we discovered that a key ABA signaling component calcium-dependent protein kinase 4 (CPK4) can interact with AtIpk2ß under ABA treated conditions through affinity purification and mass spectrometry detection. The interaction between CPK4 and AtIpk2ß were further confirmed by yeast two hybrid and bimolecular fluorescence complementation assays. Expression of AtIpk2ß also can be rapidly induced by ABA. In addition, we found that CPK4 can phosphorylate AtIpk2ß in vitro and identified five novel phosphorylation sites of AtIpk2ß by CPK4 kinase, including Tyr46, Ser48, Ser51, Thr128, Ser147. Overexpression of AtIpk2ß in Arabidopsis was more sensitive to ABA in seed germination, primary root inhibition, ABA-responsive gene expression than wild type plants, whereas knockout mutant atipk2ß exhibited no significant difference. The AtIpk2ß variants containing Tyr46, Thr128, Ser147 mutated to Ala cannot complement the yeast mutant ipk2 growth in high temperature, suggesting that those three amino acid residues are critical for AtIpk2ß. These findings provide insight into the modulation of ABA signaling by AtIpk2ß.
[Mh] Termos MeSH primário: Ácido Abscísico/metabolismo
Proteínas de Arabidopsis/metabolismo
Arabidopsis/metabolismo
Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo
Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Arabidopsis/química
Arabidopsis/genética
Proteínas de Arabidopsis/química
Proteínas de Arabidopsis/genética
Proteínas Quinases Dependentes de Cálcio-Calmodulina/química
Regulação da Expressão Gênica de Plantas
Fosforilação
Fosfotransferases (Aceptor do Grupo Álcool)/química
Fosfotransferases (Aceptor do Grupo Álcool)/genética
Mapas de Interação de Proteínas
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arabidopsis Proteins); 72S9A8J5GW (Abscisic Acid); EC 2.7.1.- (IPK2beta protein, Arabidopsis); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 2.7.11.17 (CPK4 protein, Arabidopsis); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170731
[Lr] Data última revisão:
170731
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170618
[St] Status:MEDLINE


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[PMID]:28615325
[Au] Autor:Zhang X; Yuan D; Sun Q; Xu L; Lee E; Lewis AJ; Zuckerbraun BS; Rosengart MR
[Ad] Endereço:Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
[Ti] Título:Calcium/calmodulin-dependent protein kinase regulates the PINK1/Parkin and DJ-1 pathways of mitophagy during sepsis.
[So] Source:FASEB J;31(10):4382-4395, 2017 Oct.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:During sepsis and shock states, mitochondrial dysfunction occurs. Consequently, adaptive mechanisms, such as fission, fusion, and mitophagy, are induced to eliminate damaged portions or entire dysfunctional mitochondria. The regulatory PINK1/Parkin and DJ-1 pathways are strongly induced by mitochondrial depolarization, although a direct link between loss of mitochondrial membrane potential (Δ ) and mitophagy has not been identified. Mitochondria also buffer Ca , and their buffering capacity is dependent on Δ Here, we characterize a role for calcium/calmodulin-dependent protein kinase (CaMK) I in the regulation of these mechanisms. Loss of Δ with either pharmacologic depolarization or LPS leads to Ca -dependent mitochondrial recruitment and activation of CaMKI that precedes the colocalization of PINK1/Parkin and DJ-1. CaMKI is required and serves as both a PINK1 and Parkin kinase. The mechanisms operate in both immune and nonimmune cells and are induced in models of endotoxemia, sepsis, and hemorrhagic shock. These data support the idea that CaMKI links mitochondrial stress with the PINK1/Parkin and DJ-1 mechanisms of mitophagy.-Zhang, X., Yuan, D., Sun, Q., Xu, L., Lee, E., Lewis, A. J., Zuckerbraun, B. S., Rosengart, M. R. Calcium/calmodulin-dependent protein kinase regulates the PINK1/Parkin and DJ-1 pathways of mitophagy during sepsis.
[Mh] Termos MeSH primário: Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo
Mitocôndrias/metabolismo
Proteína Desglicase DJ-1/metabolismo
Proteínas Quinases/metabolismo
Sepse/metabolismo
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Lipopolissacarídeos/farmacologia
Masculino
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Camundongos Endogâmicos C57BL
Degradação Mitocondrial/efeitos dos fármacos
Transporte Proteico/efeitos dos fármacos
Proteínas Serina-Treonina Quinases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lipopolysaccharides); EC 2.7.- (Protein Kinases); EC 2.7.11.1 (PTEN-induced putative kinase); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases); EC 3.1.2.- (Protein Deglycase DJ-1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170616
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201601096RRR


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[PMID]:28489820
[Au] Autor:Liu KH; Niu Y; Konishi M; Wu Y; Du H; Sun Chung H; Li L; Boudsocq M; McCormack M; Maekawa S; Ishida T; Zhang C; Shokat K; Yanagisawa S; Sheen J
[Ad] Endereço:Department of Molecular Biology and Centre for Computational and Integrative Biology, Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA.
[Ti] Título:Discovery of nitrate-CPK-NLP signalling in central nutrient-growth networks.
[So] Source:Nature;545(7654):311-316, 2017 05 18.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nutrient signalling integrates and coordinates gene expression, metabolism and growth. However, its primary molecular mechanisms remain incompletely understood in plants and animals. Here we report unique Ca signalling triggered by nitrate with live imaging of an ultrasensitive biosensor in Arabidopsis leaves and roots. A nitrate-sensitized and targeted functional genomic screen identifies subgroup III Ca -sensor protein kinases (CPKs) as master regulators that orchestrate primary nitrate responses. A chemical switch with the engineered mutant CPK10(M141G) circumvents embryo lethality and enables conditional analyses of cpk10 cpk30 cpk32 triple mutants to define comprehensive nitrate-associated regulatory and developmental programs. Nitrate-coupled CPK signalling phosphorylates conserved NIN-LIKE PROTEIN (NLP) transcription factors to specify the reprogramming of gene sets for downstream transcription factors, transporters, nitrogen assimilation, carbon/nitrogen metabolism, redox, signalling, hormones and proliferation. Conditional cpk10 cpk30 cpk32 and nlp7 mutants similarly impair nitrate-stimulated system-wide shoot growth and root establishment. The nutrient-coupled Ca signalling network integrates transcriptome and cellular metabolism with shoot-root coordination and developmental plasticity in shaping organ biomass and architecture.
[Mh] Termos MeSH primário: Amidoidrolases/metabolismo
Arabidopsis/crescimento & desenvolvimento
Arabidopsis/metabolismo
Cálcio/metabolismo
Nitratos/metabolismo
Proteínas Quinases/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Amidoidrolases/genética
Sequência de Aminoácidos
Arabidopsis/genética
Proteínas de Arabidopsis/química
Proteínas de Arabidopsis/genética
Proteínas de Arabidopsis/metabolismo
Biomassa
Sinalização do Cálcio
Proteínas de Ligação ao Cálcio/química
Proteínas de Ligação ao Cálcio/genética
Proteínas de Ligação ao Cálcio/metabolismo
Proteínas Quinases Dependentes de Cálcio-Calmodulina/química
Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética
Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo
Carbono/metabolismo
Reprogramação Celular
Alimentos
Regulação da Expressão Gênica de Plantas
Nitrogênio/metabolismo
Oxirredução
Fosforilação
Raízes de Plantas/crescimento & desenvolvimento
Raízes de Plantas/metabolismo
Brotos de Planta/crescimento & desenvolvimento
Brotos de Planta/metabolismo
Plantas Geneticamente Modificadas
Proteínas Quinases/química
Proteínas Quinases/genética
Transcrição Genética
Transcriptoma
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (ATCDPK1 protein, Arabidopsis); 0 (Arabidopsis Proteins); 0 (Calcium-Binding Proteins); 0 (Nitrates); 7440-44-0 (Carbon); EC 2.7.- (CPK32 protein, Arabidopsis); EC 2.7.- (Protein Kinases); EC 2.7.11.17 (CPK30 protein, Arabidopsis); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases); EC 3.5.- (Amidohydrolases); N762921K75 (Nitrogen); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170908
[Lr] Data última revisão:
170908
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170511
[St] Status:MEDLINE
[do] DOI:10.1038/nature22077


  5 / 11840 MEDLINE  
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[PMID]:28364459
[Au] Autor:Tanaka S; Honda Y; Honda M; Yamada H; Honda K; Kodama T
[Ad] Endereço:Sleep Disorders Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Japan.
[Ti] Título:Anti-Tribbles Pseudokinase 2 (TRIB2)-Immunization Modulates Hypocretin/Orexin Neuronal Functions.
[So] Source:Sleep;40(1), 2017 Jan 01.
[Is] ISSN:1550-9109
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Study Objectives: Recent findings showed that 16%-26% of narcolepsy patients were positive for anti-tribbles pseudokinase 2 (TRIB2) antibody, and the intracerebroventricular administration of immunoglobulin-G purified from anti-TRIB2 positive narcolepsy patients caused hypocretin/orexin neuron loss. We investigated the pathophysiological role of TRIB2 antibody using TRIB2-immunized rats and hypocretin/ataxin-3 transgenic (ataxin-3) mice. Methods: Plasma, cerebrospinal fluid (CSF), and hypothalamic tissues from TRIB2-immunized rats were collected. Anti-TRIB2 titers, hypocretin contents, mRNA expressions, the cell count of hypocretin neurons, and immunoreactivity of anti-TRIB2 antibodies on hypocretin neurons were investigated. The plasma from ataxin-3 mice was also used to determine the anti-TRIB2 antibody titer changes following the loss of hypocretin neurons. Results: TRIB2 antibody titers increased in the plasma and CSF of TRIB2-immunized rats. The hypothalamic tissue immunostained with the sera from TRIB2-immunized rats revealed positive signals in the cytoplasm of hypcretin neurons. While no changes were found regarding hypothalamic hypocretin contents or cell counts, but there were significant decreases of the hypocretin mRNA level and release into the CSF. The plasma from over 26-week-old ataxin-3 mice, at the advanced stage of hypocretin cell destruction, showed positive reactions against TRIB2 antigen, and positive plasma also reacted with murine hypothalamic hypocretin neurons. Conclusions: Our results suggest that the general activation of the immune system modulates the functions of hypocretin neurons. The absence of a change in hypocretin cell populations suggested that factors other than anti-TRIB2 antibody play a part in the loss of hypocretin neurons in narcolepsy. The increased anti-TRIB2 antibody after the destruction of hypocretin neurons suggest that anti-TRIB2 antibody in narcolepsy patients is the consequence rather than the inciting cause of hypocretin cell destruction.
[Mh] Termos MeSH primário: Autoanticorpos/metabolismo
Autoantígenos/metabolismo
Proteínas Quinases Dependentes de Cálcio-Calmodulina/imunologia
Peptídeos e Proteínas de Sinalização Intracelular/imunologia
Narcolepsia/imunologia
Neurônios/imunologia
Orexinas/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Ataxina-3/metabolismo
Biomarcadores/metabolismo
Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo
Feminino
Hipotálamo/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Masculino
Camundongos
Camundongos Transgênicos
Narcolepsia/metabolismo
Narcolepsia/fisiopatologia
Neurônios/metabolismo
Neuropeptídeos/metabolismo
Ratos
Ratos Sprague-Dawley
Vacinação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantibodies); 0 (Autoantigens); 0 (Biomarkers); 0 (Intracellular Signaling Peptides and Proteins); 0 (Neuropeptides); 0 (Orexins); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases); EC 3.4.19.12 (Ataxin-3)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170402
[St] Status:MEDLINE
[do] DOI:10.1093/sleep/zsw036


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[PMID]:28341239
[Au] Autor:Shoda W; Nomura N; Ando F; Mori Y; Mori T; Sohara E; Rai T; Uchida S
[Ad] Endereço:Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
[Ti] Título:Calcineurin inhibitors block sodium-chloride cotransporter dephosphorylation in response to high potassium intake.
[So] Source:Kidney Int;91(2):402-411, 2017 Feb.
[Is] ISSN:1523-1755
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dietary potassium intake is inversely related to blood pressure and mortality. Moreover, the sodium-chloride cotransporter (NCC) plays an important role in blood pressure regulation and urinary potassium excretion in response to potassium intake. Previously, it was shown that NCC is activated by the WNK4-SPAK cascade and dephosphorylated by protein phosphatase. However, the mechanism of NCC regulation with acute potassium intake is still unclear. To identify the molecular mechanism of NCC regulation in response to potassium intake, we used adult C57BL/6 mice fed a 1.7% potassium solution by oral gavage. We confirmed that acute potassium load rapidly dephosphorylated NCC, which was not dependent on the accompanying anions. Mice were treated with tacrolimus (calcineurin inhibitor) and W7 (calmodulin inhibitor) before the oral potassium loads. Dephosphorylation of NCC induced by potassium was significantly inhibited by both tacrolimus and W7 treatment. There was no significant difference in WNK4, OSR1, and SPAK expression after high potassium intake, even after tacrolimus and W7 treatment. Another phosphatase, protein phosphatase 1, and its endogenous inhibitor I-1 did not show a significant change after potassium intake. Hyperkaliuria, induced by high potassium intake, was significantly suppressed by tacrolimus treatment. Thus, calcineurin is activated by an acute potassium load, which rapidly dephosphorylates NCC, leading to increased urinary potassium excretion.
[Mh] Termos MeSH primário: Inibidores de Calcineurina/farmacologia
Calcineurina/metabolismo
Rim/efeitos dos fármacos
Potássio na Dieta/metabolismo
Eliminação Renal/efeitos dos fármacos
Tacrolimo/farmacologia
[Mh] Termos MeSH secundário: Animais
Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores
Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo
Concentração de Íons de Hidrogênio
Rim/metabolismo
Masculino
Camundongos Endogâmicos C57BL
Fosforilação
Potássio na Dieta/sangue
Potássio na Dieta/urina
Inibidores de Proteínas Quinases/farmacologia
Proteína Fosfatase 1/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
Transdução de Sinais/efeitos dos fármacos
Membro 3 da Família 12 de Carreador de Soluto/efeitos dos fármacos
Membro 3 da Família 12 de Carreador de Soluto/metabolismo
Sulfonamidas/farmacologia
Fatores de Tempo
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcineurin Inhibitors); 0 (Osr1 protein, mouse); 0 (Potassium, Dietary); 0 (Protein Kinase Inhibitors); 0 (Slc12a3 protein, mouse); 0 (Solute Carrier Family 12, Member 3); 0 (Sulfonamides); 0 (Transcription Factors); 65595-90-6 (W 7); EC 2.7.1.- (Prkwnk4 protein, mouse); EC 2.7.1.- (Stk39 protein, mouse); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases); EC 3.1.3.16 (Calcineurin); EC 3.1.3.16 (Protein Phosphatase 1); WM0HAQ4WNM (Tacrolimus)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170326
[St] Status:MEDLINE


  7 / 11840 MEDLINE  
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[PMID]:28295333
[Au] Autor:Takemoto-Kimura S; Suzuki K; Horigane SI; Kamijo S; Inoue M; Sakamoto M; Fujii H; Bito H
[Ad] Endereço:Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
[Ti] Título:Calmodulin kinases: essential regulators in health and disease.
[So] Source:J Neurochem;141(6):808-818, 2017 Jun.
[Is] ISSN:1471-4159
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Neuronal activity induces intracellular Ca increase, which triggers activation of a series of Ca -dependent signaling cascades. Among these, the multifunctional Ca /calmodulin-dependent protein kinases (CaMKs, or calmodulin kinases) play key roles in neuronal transmission, synaptic plasticity, circuit development and cognition. The most investigated CaMKs for these roles in neuronal functions are CaMKI, CaMKII, CaMKIV and we will shed light on these neuronal CaMKs' functions in this review. Catalytically active members of CaMKs currently are CaMKI, CaMKII, CaMKIV and CaMKK. Although they all necessitate the binding of Ca and calmodulin complex (Ca /CaM) for releasing autoinhibition, each member of CaMK has distinct activation mechanisms-autophosphorylation mediated autonomy of multimeric CaMKII and CaMKK-dependent phosphoswitch-induced activation of CaMKI or CaMKIV. Furthermore, each CaMK shows distinct subcellular localization that underlies specific compartmentalized function in each activated neuron. In this review, we first summarize these molecular characteristics of each CaMK as to regulation and subcellular localization, and then describe each biological function. In the last section, we also focus on the emerging role of CaMKs in pathophysiological conditions by introducing the recent studies, especially focusing on drug addiction and depression, and discuss how dysfunctional CaMKs may contribute to the pathology of the neuropsychological disorders. This article is part of the mini review series "60th Anniversary of the Japanese Society for Neurochemistry".
[Mh] Termos MeSH primário: Sinalização do Cálcio/fisiologia
Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo
Calmodulina/metabolismo
Plasticidade Neuronal/fisiologia
Neurônios/metabolismo
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Fosforilação
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Calmodulin); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170810
[Lr] Data última revisão:
170810
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170316
[St] Status:MEDLINE
[do] DOI:10.1111/jnc.14020


  8 / 11840 MEDLINE  
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[PMID]:28255011
[Au] Autor:Coppini R; Mazzoni L; Ferrantini C; Gentile F; Pioner JM; Laurino A; Santini L; Bargelli V; Rotellini M; Bartolucci G; Crocini C; Sacconi L; Tesi C; Belardinelli L; Tardiff J; Mugelli A; Olivotto I; Cerbai E; Poggesi C
[Ad] Endereço:From the Department NeuroFarBa (R.C., L.M., T.L., L. Santini, V.B., G.B., A.M., E.C.) and Department of Experimental and Clinical Medicine (C.F., F.G., J.M.P., C.T., C.P.), University of Florence, Italy; European Laboratory for Non-linear Spectroscopy (LENS), University of Florence & National In
[Ti] Título:Ranolazine Prevents Phenotype Development in a Mouse Model of Hypertrophic Cardiomyopathy.
[So] Source:Circ Heart Fail;10(3), 2017 03.
[Is] ISSN:1941-3297
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Current therapies are ineffective in preventing the development of cardiac phenotype in young carriers of mutations associated with hypertrophic cardiomyopathy (HCM). Ranolazine, a late Na current blocker, reduced the electromechanical dysfunction of human HCM myocardium in vitro. METHODS AND RESULTS: To test whether long-term treatment prevents cardiomyopathy in vivo, transgenic mice harboring the R92Q troponin-T mutation and wild-type littermates received an oral lifelong treatment with ranolazine and were compared with age-matched vehicle-treated animals. In 12-months-old male R92Q mice, ranolazine at therapeutic plasma concentrations prevented the development of HCM-related cardiac phenotype, including thickening of the interventricular septum, left ventricular volume reduction, left ventricular hypercontractility, diastolic dysfunction, left-atrial enlargement and left ventricular fibrosis, as evaluated in vivo using echocardiography and magnetic resonance. Left ventricular cardiomyocytes from vehicle-treated R92Q mice showed marked excitation-contraction coupling abnormalities, including increased diastolic [Ca ] and Ca waves, whereas cells from treated mutants were undistinguishable from those from wild-type mice. Intact trabeculae from vehicle-treated mutants displayed inotropic insufficiency, increased diastolic tension, and premature contractions; ranolazine treatment counteracted the development of myocardial mechanical abnormalities. In mutant myocytes, ranolazine inhibited the enhanced late Na current and reduced intracellular [Na ] and diastolic [Ca ], ultimately preventing the pathological increase of calmodulin kinase activity in treated mice. CONCLUSIONS: Owing to the sustained reduction of intracellular Ca and calmodulin kinase activity, ranolazine prevented the development of morphological and functional cardiac phenotype in mice carrying a clinically relevant HCM-related mutation. Pharmacological inhibitors of late Na current are promising candidates for an early preventive therapy in young phenotype-negative subjects carrying high-risk HCM-related mutations.
[Mh] Termos MeSH primário: Cardiomiopatia Hipertrófica/prevenção & controle
Miócitos Cardíacos/efeitos dos fármacos
Ranolazina/farmacologia
Bloqueadores dos Canais de Sódio/farmacologia
Sódio/metabolismo
[Mh] Termos MeSH secundário: Animais
Western Blotting
Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo
Cardiomiopatia Hipertrófica/genética
Cardiomiopatia Hipertrófica/metabolismo
Cardiomiopatia Hipertrófica/fisiopatologia
Modelos Animais de Doenças
Ecocardiografia Doppler
Acoplamento Excitação-Contração/efeitos dos fármacos
Predisposição Genética para Doença
Frequência Cardíaca
Hipertrofia Ventricular Esquerda/genética
Hipertrofia Ventricular Esquerda/metabolismo
Hipertrofia Ventricular Esquerda/prevenção & controle
Imagem por Ressonância Magnética
Masculino
Potenciais da Membrana
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Microscopia Confocal
Mutação
Contração Miocárdica/efeitos dos fármacos
Miócitos Cardíacos/metabolismo
Miócitos Cardíacos/patologia
Fenótipo
Fatores de Tempo
Troponina T/genética
Disfunção Ventricular Esquerda/genética
Disfunção Ventricular Esquerda/metabolismo
Disfunção Ventricular Esquerda/prevenção & controle
Função Ventricular Esquerda/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Sodium Channel Blockers); 0 (Troponin T); 9NEZ333N27 (Sodium); A6IEZ5M406 (Ranolazine); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170304
[St] Status:MEDLINE


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[PMID]:28212671
[Au] Autor:Nakayama K; Iwamoto S
[Ad] Endereço:Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, 329-0498, Japan. nakayama@jichi.ac.jp.
[Ti] Título:An adaptive variant of TRIB2, rs1057001, is associated with higher expression levels of thermogenic genes in human subcutaneous and visceral adipose tissues.
[So] Source:J Physiol Anthropol;36(1):16, 2017 Feb 17.
[Is] ISSN:1880-6805
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: An obesity-related single-nucleotide polymorphism (SNP) of the Tribbles pseudokinase 2 gene (TRIB2) was shown to have underwent adaptive evolution in the last glacial period, suggesting a selective advantage of this SNP in human populations in cold environments. In order to verify this hypothesis, the effect of the TRIB2 SNP on the expression of genes involved in adaptive thermogenesis was tested using messenger RNAs prepared from adipose tissues of Japanese adults. METHODS: Complementary DNA was prepared from subcutaneous adipose tissues (SAT) and visceral adipose tissues (VAT) obtained from 48 Japanese adults. Transcript levels of 15 selected genes, including five genes that are upregulated in development of thermogenic adipocytes, were measured by using real-time polymerase chain reaction. Differences in transcript levels between the TRIB2 SNP genotype groups (AA genotype versus AT + TT genotype) were assessed using t test. RESULTS: Of the five thermogenic genes, DIO2, CIDEA, PPARGC1A, and PRDM16 showed significantly higher transcript levels in SAT of individuals with the AA genotype relative to those with the AT + TT genotype (P < 0.05). However, only 2 out of the 10 non-thermogenic genes exhibited differences in transcript levels according to genotype. Additionally, in silico prediction indicated that this SNP likely affects the expression of nearby genes including TRIB2. CONCLUSION: The higher expression levels of thermogenic genes in individuals homozygous for the adaptive variant of TRIB2 SNP suggest a greater propensity for induction of thermogenesis in adipose tissues in cold environments.
[Mh] Termos MeSH primário: Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética
Gordura Intra-Abdominal/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/genética
Polimorfismo de Nucleotídeo Único/genética
Gordura Subcutânea/metabolismo
Termogênese/genética
[Mh] Termos MeSH secundário: Adulto
Grupo com Ancestrais do Continente Asiático
Feminino
Seres Humanos
Japão
Masculino
Obesidade/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Intracellular Signaling Peptides and Proteins); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases); EC 2.7.11.17 (TRIB2 protein, human)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170626
[Lr] Data última revisão:
170626
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170219
[St] Status:MEDLINE
[do] DOI:10.1186/s40101-017-0132-z


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[PMID]:28167260
[Au] Autor:Omoto Y; Higa-Nakamine S; Higa A; Yamamoto H
[Ad] Endereço:Department of Biochemistry, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan.
[Ti] Título:ErbB4 cleavage by gonadotropin-releasing hormone receptor stimulation in cultured gonadotroph cells.
[So] Source:Eur J Pharmacol;799:171-179, 2017 Mar 15.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The receptor for gonadotropin-releasing hormone (GnRH) belongs to the G-protein-coupled receptors, and its stimulation activates extracellular signal-regulated protein kinase (ERK). In the present study, we first examined the actions of GnRH on the ErbB family using two types of cultured gonadotroph cells. As reported previously, AG1478, an inhibitor of the ErbB family tyrosine kinase, inhibited GnRH-induced ERK activation in undifferentiated gonadotroph αT3-1 cells. However, AG1478 did not inhibit ERK activation in differentiated gonadotroph LßT2 cells, suggesting that transactivation of the ErbB family was not necessary for ERK activation in LßT2 cells. We found that ErbB4 was expressed in αT3-1 cells but not in LßT2 cells. GnRH induced the cleavage of ErbB4 and accumulation of an 80-kDa fragment in αT3-1 cells. Pharmacological experiments suggested that G and tumor necrosis factor-α-converting enzyme (TACE) were essential for GnRH-induced ErbB4 cleavage. GnRH increased the phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS), indicating that GnRH activated protein kinase C (PKC). Down-regulation of PKC and bisindolylmaleimide I, a PKC inhibitor, strongly inhibited the GnRH-induced cleavage of ErbB4. It was surprising that GnRH treatment of LßT2 cells after overexpression of ErbB4 induced ErbB4 cleavage in a TACE-dependent manner. ErbB4 cleavage was induced also by treatment of αT3-1 cells, ErbB4-overexpressing LßT2 cells, and immortalized GnRH neurons (GT1-7 cells) with leuprorelin acetate. These results may suggest that the pharmacological effects of leuprorelin acetate are conducted through TACE-mediated proteolysis of membrane proteins, including ErbB4, in gonadotroph cells and GnRH neurons.
[Mh] Termos MeSH primário: Gonadotrofos/metabolismo
Proteólise
Receptor ErbB-4/metabolismo
Receptores LHRH/metabolismo
[Mh] Termos MeSH secundário: Proteína ADAM17/metabolismo
Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo
Linhagem Celular
Ativação Enzimática/efeitos dos fármacos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Proteínas de Ligação ao GTP/metabolismo
Gonadotrofos/citologia
Gonadotrofos/efeitos dos fármacos
Hormônio Liberador de Gonadotropina/farmacologia
Leuprolida/farmacologia
Proteína Quinase C/metabolismo
Proteólise/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
Acetato de Tetradecanoilforbol/análogos & derivados
Acetato de Tetradecanoilforbol/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, LHRH); 33515-09-2 (Gonadotropin-Releasing Hormone); 56937-68-9 (phorbolol myristate acetate); EC 2.7.10.1 (Receptor, ErbB-4); EC 2.7.11.13 (Protein Kinase C); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.4.24.86 (ADAM17 Protein); EC 3.6.1.- (GTP-Binding Proteins); EFY6W0M8TG (Leuprolide); NI40JAQ945 (Tetradecanoylphorbol Acetate)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170428
[Lr] Data última revisão:
170428
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170208
[St] Status:MEDLINE



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