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Pesquisa : D08.811.913.696.620.682.700.125.350 [Categoria DeCS]
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[PMID]:28637792
[Au] Autor:Takata T; Ihara H; Hatano N; Tsuchiya Y; Akaike T; Watanabe Y
[Ad] Endereço:Department of Pharmacology, High Technology Research Center, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
[Ti] Título:Reactive sulfur species inactivate Ca /calmodulin-dependent protein kinase IV via S-polysulfidation of its active-site cysteine residue.
[So] Source:Biochem J;474(15):2547-2562, 2017 Jul 17.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Reactive sulfur species (RSS) modulate protein functions via S polysulfidation of reactive Cys residues. Here, we report that Ca /calmodulin (CaM)-dependent protein kinase IV (CaMKIV) was reversibly inactivated by RSS via polysulfidation of the active-site Cys residue. CaMKIV is phosphorylated at Thr by its upstream CaMK kinase (CaMKK), resulting in the induction of its full activity. incubation of CaMKIV with the exogenous RSS donors Na S ( = 2-4) resulted in dose-dependent inhibition of the CaMKK-induced phospho-Thr and consequent inactivation of the enzyme activity. Conversely, mutated CaMKIV (C198V) was refractory to the Na S -induced enzyme inhibition. A biotin-polyethylene glycol-conjugated maleimide capture assay revealed that Cys in CaMKIV represents a target for S-polysulfidation. Furthermore, phosho-Thr and CaMKIV activity were inhibited by incubation with cysteine hydropersulfide, a newly identified RSS that is generated from cystine by cystathionine-γ-lyase. In transfected cells expressing CaMKIV, ionomycin-induced CaMKIV phosphorylation at Thr was decreased upon treatment with either Na S or the endoplasmic reticulum (ER) stress inducer thapsigargin, whereas cells expressing mutant CaMKIV (C198V) were resistant to this treatment. In addition, the ionomycin-induced phospho-Thr of endogenous CaMKIV was also inhibited by treatment either with Na S or thapsigargin in Jurkat T lymphocytes. Taken together, these data define a novel signaling function for intracellular RSS in inhibiting CaMKIV activity via S polysulfidation of its Cys during the response to ER stress.
[Mh] Termos MeSH primário: Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo
Cisteína/metabolismo
Sulfetos/metabolismo
Enxofre/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/antagonistas & inibidores
Estresse do Retículo Endoplasmático/efeitos dos fármacos
Ativação Enzimática/efeitos dos fármacos
Células HEK293
Seres Humanos
Células Jurkat
Espectrometria de Massas
Proteínas Mutantes/metabolismo
Fosforilação/efeitos dos fármacos
Fosfotreonina/metabolismo
Ratos
Tapsigargina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Mutant Proteins); 0 (Sulfides); 1114-81-4 (Phosphothreonine); 67526-95-8 (Thapsigargin); 70FD1KFU70 (Sulfur); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 4); K848JZ4886 (Cysteine); YGR27ZW0Y7 (sodium sulfide)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170092


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[PMID]:28592691
[Au] Autor:Joseph A; Turrigiano GG
[Ad] Endereço:Department of Biology and Center for Behavioral Genomics, Brandeis University, Waltham, Massachusetts 02454.
[Ti] Título:All for One But Not One for All: Excitatory Synaptic Scaling and Intrinsic Excitability Are Coregulated by CaMKIV, Whereas Inhibitory Synaptic Scaling Is Under Independent Control.
[So] Source:J Neurosci;37(28):6778-6785, 2017 Jul 12.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neocortical circuits use a family of homeostatic plasticity mechanisms to stabilize firing, including excitatory and inhibitory synaptic scaling and homeostatic intrinsic plasticity (Turrigiano and Nelson, 2004). All three mechanisms can be induced in tandem in cultured rat neocortical pyramidal neurons by chronic manipulations of firing, but it is unknown whether they are coinduced by the same activity-sensors and signaling pathways, or whether they are under independent control. Calcium/calmodulin-dependent protein kinase type IV (CaMKIV) is a key sensory/effector in excitatory synaptic scaling that senses perturbations in firing through changes in calcium influx, and translates this into compensatory changes in excitatory quantal amplitude (Ibata et al., 2008; Goold and Nicoll, 2010). Whether CaMKIV also controls inhibitory synaptic scaling and intrinsic homeostatic plasticity was unknown. To test this we manipulated CaMKIV signaling in individual neurons using dominant-negative (dn) or constitutively-active (ca) forms of nuclear-localized CaMKIV and measured the induction of all three forms of homeostatic plasticity. We found that excitatory synaptic scaling and intrinsic plasticity were bidirectionally coinduced by these manipulations. In contrast, these cell-autonomous manipulations had no impact on inhibitory quantal amplitude. Finally, we found that spontaneous firing rates were shifted up or down by dnCaMKIV or caCaMKIV, respectively, suggesting that uncoupling CaMKIV activation from activity generates an error signal in the negative feedback mechanism that controls firing rates. Together, our data show that excitatory synaptic scaling and intrinsic excitability are tightly coordinated through bidirectional changes in the same signaling pathway, whereas inhibitory synaptic scaling is sensed and regulated through an independent control mechanism. Maintaining stable function in highly interconnected neural circuits is essential for preventing circuit disorders, and is accomplished through a set of negative feedback mechanisms that sense and compensate for perturbations in activity. These "homeostatic" mechanisms can target synaptic excitation, synaptic inhibition, and intrinsic excitability, but whether they are independently controlled is not known. We find that synaptic excitation and intrinsic excitability are coregulated in individual neurons through CaMKIV signaling, which is tightly controlled by neuronal activity. In contrast, synaptic inhibition is unaffected by changes in firing or CaMKIV signaling in individual neurons. These results show that circuit stability is controlled both through cell-autonomous mechanisms that regulate some aspects of excitability, as well as circuit-level mechanisms that adjust inhibition.
[Mh] Termos MeSH primário: Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo
Potenciais Pós-Sinápticos Excitadores/fisiologia
Inibição Neural/fisiologia
Plasticidade Neuronal/fisiologia
Células Piramidais/fisiologia
Transmissão Sináptica/fisiologia
[Mh] Termos MeSH secundário: Potenciais de Ação/fisiologia
Animais
Animais Recém-Nascidos
Células Cultivadas
Feminino
Masculino
Ratos
Ratos Long-Evans
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 4); EC 2.7.11.17 (Camk4 protein, rat)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170609
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0618-17.2017


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[PMID]:28216372
[Au] Autor:Chen S; Dong Z; Yang P; Wang X; Jin G; Yu H; Chen L; Li L; Tang L; Bai S; Yan H; Shen F; Cong W; Wen W; Wang H
[Ad] Endereço:National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
[Ti] Título:Hepatitis B virus X protein stimulates high mobility group box 1 secretion and enhances hepatocellular carcinoma metastasis.
[So] Source:Cancer Lett;394:22-32, 2017 May 28.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Hepatitis B virus X protein (HBx) plays an important role in the progression of hepatocellular carcinoma. Here we reported that overexpression of HBx in hepatocellular carcinoma (HCC) cells could induce the secretion of high-mobility group box 1 (HMGB1) to promote invasion and metastasis of HCC in an autocrine/paracrine manner. HBx triggered an increase of cytoplasmic calcium and activated CAMKK/CAMKIV pathway, leading to subsequent translocation and release of HMGB1. HMGB1 neutralizing antibody, as well as calcium chelator or inhibitors of CAMKK/CAMKIV, could remarkably reduce invasion and metastasis of HCC cells in vitro and in a murine HCC metastasis model in vivo. Furthermore, the level of HMGB1 in patient serum and tumor tissues was positively correlated with HBV DNA load. We demonstrate an inverse relationship between HMGB1 in tumor cytoplasm and overall prognosis of HCC patients. CONCLUSION: HBx promotes the progression of HCC through translocation and secretion of HMGB1 from tumor cells via calcium dependent cascades. These data indicates that HMGB1 could serve as a novel prognostic biomarker and potential therapeutic target for HBV-related HCC.
[Mh] Termos MeSH primário: Carcinoma Hepatocelular/metabolismo
Movimento Celular
Proteína HMGB1/metabolismo
Vírus da Hepatite B/metabolismo
Hepatite B/metabolismo
Neoplasias Hepáticas/metabolismo
Neoplasias Pulmonares/metabolismo
Transativadores/metabolismo
[Mh] Termos MeSH secundário: Animais
Anticorpos/farmacologia
Antineoplásicos/uso terapêutico
Quelantes de Cálcio/farmacologia
Sinalização do Cálcio
Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/antagonistas & inibidores
Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/antagonistas & inibidores
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo
Carcinoma Hepatocelular/secundário
Carcinoma Hepatocelular/terapia
Carcinoma Hepatocelular/virologia
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
DNA Viral/genética
Feminino
Regulação Viral da Expressão Gênica
Proteína HMGB1/antagonistas & inibidores
Hepatite B/complicações
Hepatite B/genética
Hepatite B/virologia
Vírus da Hepatite B/genética
Interações Hospedeiro-Patógeno
Seres Humanos
Neoplasias Hepáticas/patologia
Neoplasias Hepáticas/terapia
Neoplasias Hepáticas/virologia
Neoplasias Pulmonares/prevenção & controle
Neoplasias Pulmonares/secundário
Neoplasias Pulmonares/virologia
Masculino
Camundongos Endogâmicos NOD
Camundongos SCID
Meia-Idade
Prognóstico
Modelos de Riscos Proporcionais
Inibidores de Proteínas Quinases/farmacologia
Fatores de Tempo
Transativadores/genética
Transfecção
Carga Viral
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies); 0 (Antineoplastic Agents); 0 (Calcium Chelating Agents); 0 (DNA, Viral); 0 (HMGB1 Protein); 0 (HMGB1 protein, human); 0 (Protein Kinase Inhibitors); 0 (Trans-Activators); 0 (hepatitis B virus X protein); EC 2.7.11.17 (CAMK4 protein, human); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Kinase); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 4)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170221
[St] Status:MEDLINE


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[PMID]:28076846
[Au] Autor:Baburamani AA; Sobotka KS; Vontell R; Mallard C; Supramaniam VG; Thornton C; Hagberg H
[Ad] Endereço:Perinatal Brain Injury Group, Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, United Kingdom.
[Ti] Título:Effect of Trp53 gene deficiency on brain injury after neonatal hypoxia-ischemia.
[So] Source:Oncotarget;8(7):12081-12092, 2017 Feb 14.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hypoxia-ischemia (HI) can result in permanent life-long injuries such as motor and cognitive deficits. In response to cellular stressors such as hypoxia, tumor suppressor protein p53 is activated, potently initiating apoptosis and promoting Bax-dependent mitochondrial outer membrane permeabilization. The aim of this study was to investigate the effect of Trp53 genetic inhibition on injury development in the immature brain following HI. HI (50 min or 60 min) was induced at postnatal day 9 (PND9) in Trp53 heterozygote (het) and wild type (WT) mice. Utilizing Cre-LoxP technology, CaMK2α-Cre mice were bred with Trp53-Lox mice, resulting in knockdown of Trp53 in CaMK2α neurons. HI was induced at PND12 (50 min) and PND28 (40 min). Extent of brain injury was assessed 7 days following HI. Following 50 min HI at PND9, Trp53 het mice showed protection in the posterior hippocampus and thalamus. No difference was seen between WT or Trp53 het mice following a severe, 60 min HI. Cre-Lox mice that were subjected to HI at PND12 showed no difference in injury, however we determined that neuronal specific CaMK2α-Cre recombinase activity was strongly expressed by PND28. Concomitantly, Trp53 was reduced at 6 weeks of age in KO-Lox Trp53 mice. Cre-Lox mice subjected to HI at PND28 showed no significant difference in brain injury. These data suggest that p53 has a limited contribution to the development of injury in the immature/juvenile brain following HI. Further studies are required to determine the effect of p53 on downstream targets.
[Mh] Termos MeSH primário: Lesões Encefálicas/genética
Encéfalo/metabolismo
Hipóxia-Isquemia Encefálica/genética
Proteína Supressora de Tumor p53/genética
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Encéfalo/patologia
Lesões Encefálicas/etiologia
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/genética
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo
Modelos Animais de Doenças
Heterozigoto
Seres Humanos
Hipóxia-Isquemia Encefálica/complicações
Hibridização In Situ
Camundongos Knockout
Camundongos Transgênicos
Fatores de Tempo
Proteína Supressora de Tumor p53/deficiência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Tumor Suppressor Protein p53); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 4); EC 2.7.11.17 (Camk4 protein, mouse)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170112
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.14518


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[PMID]:27956097
[Au] Autor:Naz H; Khan P; Tarique M; Rahman S; Meena A; Ahamad S; Luqman S; Islam A; Ahmad F; Hassan MI
[Ad] Endereço:Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India.
[Ti] Título:Binding studies and biological evaluation of ß-carotene as a potential inhibitor of human calcium/calmodulin-dependent protein kinase IV.
[So] Source:Int J Biol Macromol;96:161-170, 2017 Mar.
[Is] ISSN:1879-0003
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Human calcium/calmodulin-dependent protein kinase IV (CAMKIV), a member of Ser/Thr kinase family, is associated with cancer, cerebral hypoxia and neurodegenerative diseases. ß-carotene is a colored organic compound, abundant in plants and fruits and is used in cancer prevention. Here, we report a strong binding affinity of ß-carotene with CAMKIV using molecular docking, fluorescence binding and isothermal titration calorimetry methods. Furthermore, ß-carotene also reduces the enzyme activity of CAMKIV moderately as observed during ATPase assay. To see the role of ß-carotene on cell proliferation and apoptosis, cancerous cells (HeLa, HuH7and MCF-7) and normal (HEK-293-T) cell lines were used. Admirable anticancer activity of ß-carotene was observed. We further performed propidium iodide and DAPI (4',6-diamidino-2-phenylindole) assays to understand the mechanism of anticancer activity of ß-carotene at molecular level. Our findings provide a newer insight into the use of ß-carotene in cancer prevention and protection via inhibition of CAMKIV by regulating the signaling pathways.
[Mh] Termos MeSH primário: Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/antagonistas & inibidores
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo
Inibidores de Proteínas Quinases/metabolismo
Inibidores de Proteínas Quinases/farmacologia
beta Caroteno/metabolismo
beta Caroteno/farmacologia
[Mh] Termos MeSH secundário: Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Seres Humanos
Simulação de Acoplamento Molecular
Conformação Proteica
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Kinase Inhibitors); 01YAE03M7J (beta Carotene); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 4)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170410
[Lr] Data última revisão:
170410
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161214
[St] Status:MEDLINE


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[PMID]:27939430
[Au] Autor:Krebs J
[Ad] Endereço:NMR-based Structural Biology, MPI for Biophysical Chemistry, Göttingen, Germany.
[Ti] Título:Implications of the thyroid hormone on neuronal development with special emphasis on the calmodulin-kinase IV pathway.
[So] Source:Biochim Biophys Acta;1864(6):877-882, 2017 06.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Thyroid hormones influence brain development through regulation of gene expression. This is especially true for Ca -dependent regulation since a major pathway is controlled by the Ca /calmodulin-dependent protein kinase IV (CaMKIV) which in turn is induced by the thyroid hormone T . In addition, CaMKIV is involved in regulation of alternative splicing of a number of protein isoforms, among them PMCA1a, the neuronal specific isoform of the plasma membrane calcium pump. On the other hand, hypothyroidism or CaMKIV deficiency can have a severe influence on brain development. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.
[Mh] Termos MeSH primário: Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo
Neurônios/citologia
Hormônios Tireóideos/fisiologia
[Mh] Termos MeSH secundário: Processamento Alternativo
Animais
Encéfalo/enzimologia
Expressão Gênica
Seres Humanos
Neurônios/enzimologia
ATPases Transportadoras de Cálcio da Membrana Plasmática/genética
ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Thyroid Hormones); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 4); EC 3.6.3.8 (Plasma Membrane Calcium-Transporting ATPases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161213
[St] Status:MEDLINE


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[PMID]:27935279
[Au] Autor:Shen DL; Liu TW; Zandberg W; Clark T; Eskandari R; Alteen MG; Tan HY; Zhu Y; Cecioni S; Vocadlo D
[Ad] Endereço:Department of Chemistry, Simon Fraser University , Burnaby, British Columbia V5A 1S6, Canada.
[Ti] Título:Catalytic Promiscuity of O-GlcNAc Transferase Enables Unexpected Metabolic Engineering of Cytoplasmic Proteins with 2-Azido-2-deoxy-glucose.
[So] Source:ACS Chem Biol;12(1):206-213, 2017 Jan 20.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:O-GlcNAc transferase (OGT) catalyzes the installation of N-acetylglucosamine (GlcNAc) O-linked to nucleocytoplasmic proteins (O-GlcNAc) within multicellular eukaryotes. OGT shows surprising tolerance for structural changes in the sugar component of its nucleotide sugar donor substrate, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). Here, we find that OGT uses UDP-glucose to install O-linked glucose (O-Glc) onto proteins only 25-fold less efficiently than O-GlcNAc. Spurred by this observation, we show that OGT transfers 2-azido-2-deoxy-d-glucose (GlcAz) in vitro from UDP-GlcAz to proteins. Further, feeding cells with per-O-acetyl GlcAz (AcGlcAz), in combination with inhibition or inducible knockout of OGT, shows OGT-dependent modification of nuclear and cytoplasmic proteins with O-GlcAz as detected using microscopy, immunoblot, and proteomics. We find that O-GlcAz is reversible within cells, and an unidentified cellular enzyme exists to cleave O-Glc that can also process O-GlcAz. We anticipate that AcGlcAz will prove to be a useful tool to study the O-GlcNAc modification. We also speculate that, given the high concentration of UDP-Glc within certain mammalian tissues, O-Glc may exist within mammals and serve as a physiologically relevant modification.
[Mh] Termos MeSH primário: Azidas/química
Desoxiglucose/análogos & derivados
Glucose/química
N-Acetilglucosaminiltransferases/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Animais
Azidas/metabolismo
Células COS
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo
Cercopithecus aethiops
Desoxiglucose/química
Glucose/análogos & derivados
Glucose/metabolismo
Glicosilação
Seres Humanos
Glicoproteínas de Membrana/metabolismo
Engenharia Metabólica
Camundongos
N-Acetilglucosaminiltransferases/genética
Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo
Especificidade por Substrato
Trítio
Uridina Difosfato Glucose/análogos & derivados
Uridina Difosfato Glucose/química
Uridina Difosfato Glucose/metabolismo
beta-N-Acetil-Hexosaminidases/química
Proteínas tau/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1,3,4,6-tetra-O-acetyl-5-thioglucopyranose); 0 (Adaptor Proteins, Signal Transducing); 0 (Azides); 0 (Membrane Glycoproteins); 0 (Nuclear Pore Complex Proteins); 0 (TAB1 protein, human); 0 (nuclear pore protein p62); 0 (tau Proteins); 0 (uridine diphospho-2-azido-2-deoxyglucopyranose); 10028-17-8 (Tritium); 80321-89-7 (1,3,4,6-tetra-O-acetyl-2-azido-2-deoxyglucopyranose); 9G2MP84A8W (Deoxyglucose); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.1.- (O-GlcNAc transferase); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 4); EC 3.2.1.50 (hexosaminidase C); EC 3.2.1.52 (beta-N-Acetylhexosaminidases); IY9XDZ35W2 (Glucose); V50K1D7P4Y (Uridine Diphosphate Glucose)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161210
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.6b00876


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[PMID]:27809417
[Au] Autor:Jameel E; Naz H; Khan P; Tarique M; Kumar J; Mumtazuddin S; Ahamad S; Islam A; Ahmad F; Hoda N; Hassan MI
[Ad] Endereço:Department of Chemistry, B.R. Ambedkar Bihar University, Muzaffarpur, Bihar, India.
[Ti] Título:Design, synthesis, and biological evaluation of pyrimidine derivatives as potential inhibitors of human calcium/calmodulin-dependent protein kinase IV.
[So] Source:Chem Biol Drug Des;89(5):741-754, 2017 May.
[Is] ISSN:1747-0285
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Calcium/calmodulin-dependent protein kinase IV (CAMKIV) is a multifunctional Ser/Thr kinase, associated with cerebral hypoxia, cancer, and neurodegenerative diseases. Here, we report design, synthesis, and biological evaluation of seven pyrimidine-substituted novel inhibitors of CAMKIV. We successfully synthesized and extensively characterized (ESI-MS, H NMR, and C NMR studies) seven compounds that are showing appreciable binding affinity to the CAMKIV. Molecular docking and fluorescence binding studies revealed that compound 1 is showing very high binding free energy (ΔG = -11.52 kcal/mol) and binding affinity (K = 9.2 × 10 m ) to the CAMKIV. We further performed MTT assay to check the cytotoxicity and anticancer activity of these compounds. An appreciable IC (39 µm) value of compound 1 was observed on human hepatoma cell line and nontoxic till the 400 µm on human embryonic kidney cells. To ensure anticancer activity of all these compounds, we further performed propidium iodide assay to evaluate cell viability and DNA content during the cell cycle. We found that compound 1 is again showing a better anticancer activity on both human hepatoma and human embryonic kidney cell lines.
[Mh] Termos MeSH primário: Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/antagonistas & inibidores
Inibidores de Proteínas Quinases/síntese química
Pirimidinas/química
[Mh] Termos MeSH secundário: Sítios de Ligação
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Desenho de Drogas
Células HEK293
Seres Humanos
Simulação de Acoplamento Molecular
Ligação Proteica
Inibidores de Proteínas Quinases/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Estrutura Terciária de Proteína
Pirimidinas/metabolismo
Pirimidinas/farmacologia
Espectrometria de Fluorescência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Kinase Inhibitors); 0 (Pyrimidines); EC 2.7.11.17 (CAMK4 protein, human); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 4)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170509
[Lr] Data última revisão:
170509
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161104
[St] Status:MEDLINE
[do] DOI:10.1111/cbdd.12898


  9 / 403 MEDLINE  
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[PMID]:26835540
[Au] Autor:Naz H; Shahbaaz M; Haque MA; Bisetty K; Islam A; Ahmad F; Hassan MI
[Ad] Endereço:a Center for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia , Jamia Nagar, New Delhi 110025 , India.
[Ti] Título:Urea-induced denaturation of human calcium/calmodulin-dependent protein kinase IV: a combined spectroscopic and MD simulation studies.
[So] Source:J Biomol Struct Dyn;35(3):463-475, 2017 Feb.
[Is] ISSN:1538-0254
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Calcium/calmodulin-dependent protein kinase IV (CaMKIV) is a multifunctional enzyme which belongs to the Ser/Thr kinase family. CaMKIV plays important role in varieties of biological processes such as gene expression regulation, memory consolidation, bone growth, T-cell maturation, sperm motility, regulation of microtubule dynamics, cell-cycle progression, and apoptosis. To measure stability parameters, urea-induced denaturation of CaMKIV was carried out at pH 7.4 and 25°C, using three different probes, namely far-UV CD, near-UV absorption, and tryptophan fluorescence. A coincidence of normalized denaturation curves of these optical properties suggests that urea-induced denaturation is a two-state process. Analysis of these denaturation curves gave values of 4.20 ± 0.12 kcal mol , 2.95 ± 0.15 M, and 1.42 ± 0.06 kcal mol M for [Formula: see text] (Gibbs free energy change (ΔG ) in the absence of urea), C (molar urea concentration ([urea]) at the midpoint of the denaturation curve), and m (=∂ΔG /∂[urea]), respectively. All these experimental observations have been fully supported by 30 ns molecular dynamics simulation studies.
[Mh] Termos MeSH primário: Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/química
Simulação de Dinâmica Molecular
Conformação Proteica
Desnaturação Proteica
Análise Espectral
Ureia/química
[Mh] Termos MeSH secundário: Dicroísmo Circular
Seres Humanos
Desnaturação Proteica/efeitos dos fármacos
Relação Estrutura-Atividade
Ureia/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
8W8T17847W (Urea); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 4)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170302
[Lr] Data última revisão:
170302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160203
[St] Status:MEDLINE
[do] DOI:10.1080/07391102.2016.1150203


  10 / 403 MEDLINE  
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[PMID]:27659345
[Au] Autor:Lin R; Zhang Y; Yan D; Liao X; Fu Y; Cai W
[Ad] Endereço:Department of Biology, Hainan Medical College, Haikou 571199, Hainan, People's Republic of China.xianronglin@gmail.com.
[Ti] Título:Lack of association between rs10491334 in the CAMK4 gene and longevity in a Chinese population.
[So] Source:J Genet;95(3):729-32, 2016 Sep.
[Is] ISSN:0973-7731
[Cp] País de publicação:India
[La] Idioma:eng
[Mh] Termos MeSH primário: Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/genética
Longevidade/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Alelos
Grupo com Ancestrais do Continente Asiático
Feminino
Expressão Gênica
Estudo de Associação Genômica Ampla
Genótipo
Seres Humanos
Masculino
Meia-Idade
Modelos Genéticos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.11.17 (CAMK4 protein, human); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 4)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160924
[St] Status:MEDLINE



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