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[PMID]:28784611
[Au] Autor:Snider CE; Willet AH; Chen JS; Arpag G; Zanic M; Gould KL
[Ad] Endereço:Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN.
[Ti] Título:Phosphoinositide-mediated ring anchoring resists perpendicular forces to promote medial cytokinesis.
[So] Source:J Cell Biol;216(10):3041-3050, 2017 Oct 02.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Many eukaryotic cells divide by assembling and constricting an actin- and myosin-based contractile ring (CR) that is physically linked to the plasma membrane (PM). In this study, we report that cells lacking , which encodes a conserved PM scaffold for the phosphatidylinositol-4 kinase Stt4, build CRs that can slide away from the cell middle during anaphase in a myosin V-dependent manner. The Efr3-dependent CR-anchoring mechanism is distinct from previously reported pathways dependent on the Fes/CIP4 homology Bin-Amphiphysin-Rvs167 (F-BAR) protein Cdc15 and paxillin Pxl1. In , the concentrations of several membrane-binding proteins were reduced in the CR and/or on the PM. Our results suggest that proper PM lipid composition is important to stabilize the central position of the CR and resist myosin V-based forces to promote the fidelity of cell division.
[Mh] Termos MeSH primário: Citocinese/fisiologia
Glicosilfosfatidilinositóis/metabolismo
Schizosaccharomyces/metabolismo
[Mh] Termos MeSH secundário: 1-Fosfatidilinositol 4-Quinase/genética
1-Fosfatidilinositol 4-Quinase/metabolismo
Proteínas de Ciclo Celular/genética
Proteínas de Ciclo Celular/metabolismo
Proteínas de Ligação ao GTP/genética
Proteínas de Ligação ao GTP/metabolismo
Glicosilfosfatidilinositóis/genética
Miosina Tipo V/genética
Miosina Tipo V/metabolismo
Schizosaccharomyces/genética
Proteínas de Schizosaccharomyces pombe/genética
Proteínas de Schizosaccharomyces pombe/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CDC15 protein); 0 (Cell Cycle Proteins); 0 (Glycosylphosphatidylinositols); 0 (Schizosaccharomyces pombe Proteins); EC 2.7.1.67 (1-Phosphatidylinositol 4-Kinase); EC 3.6.1.- (GTP-Binding Proteins); EC 3.6.1.- (Myosin Type V)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171007
[Lr] Data última revisão:
171007
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201705070


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[PMID]:28566381
[Au] Autor:Wong MT; Chen SS
[Ad] Endereço:Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China.
[Ti] Título:Hepatitis C Virus Subverts Human Choline Kinase-α To Bridge Phosphatidylinositol-4-Kinase IIIα (PI4KIIIα) and NS5A and Upregulates PI4KIIIα Activation, Thereby Promoting the Translocation of the Ternary Complex to the Endoplasmic Reticulum for Viral Replication.
[So] Source:J Virol;91(16), 2017 Aug 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In this study, we elucidated the mechanism by which human choline kinase-α (hCKα) interacts with nonstructural protein 5A (NS5A) and phosphatidylinositol-4-kinase IIIα (PI4KIIIα), the lipid kinase crucial for maintaining the integrity of virus-induced membranous webs, and modulates hepatitis C virus (HCV) replication. hCKα activity positively modulated phosphatidylinositol-4-phosphate (PI4P) levels in HCV-expressing cells, and hCKα-mediated PI4P accumulation was abolished by AL-9, a PI4KIIIα-specific inhibitor. hCKα colocalized with NS5A and PI4KIIIα or PI4P; NS5A expression increased hCKα and PI4KIIIα colocalization; and hCKα formed a ternary complex with PI4KIIIα and NS5A, supporting the functional interplay of hCKα with PI4KIIIα and NS5A. PI4KIIIα inactivation by AL-9 or hCKα inactivation by CK37, a specific hCKα inhibitor, impaired the endoplasmic reticulum (ER) localization and colocalization of these three molecules. Interestingly, hCKα knockdown or inactivation inhibited PI4KIIIα-NS5A binding. In an PI4KIIIα activity assay, hCKα activity slightly increased PI4KIIIα basal activity but greatly augmented NS5A-induced PI4KIIIα activity, supporting the essential role of ternary complex formation in robust PI4KIIIα activation. Concurring with the upregulation of PI4P production and viral replication, overexpression of active hCKα-R (but not the D288A mutant) restored PI4KIIIα and NS5A translocation to the ER in hCKα stable knockdown cells. Furthermore, active PI4KIIIα overexpression restored PI4P production, PI4KIIIα and NS5A translocation to the ER, and viral replication in CK37-treated cells. Based on our results, hCKα functions as an indispensable regulator that bridges PI4KIIIα and NS5A and potentiates NS5A-stimulated PI4KIIIα activity, which then facilitates the targeting of the ternary complex to the ER for viral replication. The mechanisms by which hCKα activity modulates the transport of the hCKα-NS5A complex to the ER are not understood. In the present study, we investigated how hCKα interacts with PI4KIIIα (a key element that maintains the integrity of the "membranous web" structure) and NS5A to regulate viral replication. We demonstrated that HCV hijacks hCKα to bridge PI4KIIIα and NS5A, forming a ternary complex, which then stimulates PI4KIIIα activity to produce PI4P. Pronounced PI4P synthesis then redirects the translocation of the ternary complex to the ER-derived, PI4P-enriched membrane for assembly of the viral replication complex and viral replication. Our study provides novel insights into the indispensable modulatory role of hCKα in the recruitment of PI4KIIIα to NS5A and in NS5A-stimulated PI4P production and reveals a new perspective for understanding the impact of profound PI4KIIIα activation on the targeting of PI4KIIIα and NS5A to the PI4P-enriched membrane for viral replication complex formation.
[Mh] Termos MeSH primário: 1-Fosfatidilinositol 4-Quinase/metabolismo
Colina Quinase/metabolismo
Retículo Endoplasmático/metabolismo
Hepacivirus/fisiologia
Interações Hospedeiro-Patógeno
Proteínas não Estruturais Virais/metabolismo
Replicação Viral
[Mh] Termos MeSH secundário: Linhagem Celular
Hepatócitos/virologia
Seres Humanos
Transporte Proteico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NS-5 protein, hepatitis C virus); 0 (Viral Nonstructural Proteins); EC 2.7.1.32 (CHKA protein, human); EC 2.7.1.32 (Choline Kinase); EC 2.7.1.67 (1-Phosphatidylinositol 4-Kinase); EC 2.7.1.67 (PI4KIIIalpha protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170809
[Lr] Data última revisão:
170809
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170602
[St] Status:MEDLINE


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[PMID]:28562588
[Au] Autor:Manjunatha UH; Vinayak S; Zambriski JA; Chao AT; Sy T; Noble CG; Bonamy GMC; Kondreddi RR; Zou B; Gedeck P; Brooks CF; Herbert GT; Sateriale A; Tandel J; Noh S; Lakshminarayana SB; Lim SH; Goodman LB; Bodenreider C; Feng G; Zhang L; Blasco F; Wagner J; Leong FJ; Striepen B; Diagana TT
[Ad] Endereço:Novartis Institute for Tropical Diseases, Singapore 138670.
[Ti] Título:A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis.
[So] Source:Nature;546(7658):376-380, 2017 06 15.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Diarrhoeal disease is responsible for 8.6% of global child mortality. Recent epidemiological studies found the protozoan parasite Cryptosporidium to be a leading cause of paediatric diarrhoea, with particularly grave impact on infants and immunocompromised individuals. There is neither a vaccine nor an effective treatment. Here we establish a drug discovery process built on scalable phenotypic assays and mouse models that take advantage of transgenic parasites. Screening a library of compounds with anti-parasitic activity, we identify pyrazolopyridines as inhibitors of Cryptosporidium parvum and Cryptosporidium hominis. Oral treatment with the pyrazolopyridine KDU731 results in a potent reduction in intestinal infection of immunocompromised mice. Treatment also leads to rapid resolution of diarrhoea and dehydration in neonatal calves, a clinical model of cryptosporidiosis that closely resembles human infection. Our results suggest that the Cryptosporidium lipid kinase PI(4)K (phosphatidylinositol-4-OH kinase) is a target for pyrazolopyridines and that KDU731 warrants further preclinical evaluation as a drug candidate for the treatment of cryptosporidiosis.
[Mh] Termos MeSH primário: 1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores
Criptosporidiose/tratamento farmacológico
Criptosporidiose/parasitologia
Cryptosporidium/efeitos dos fármacos
Cryptosporidium/enzimologia
Pirazóis/farmacologia
Piridinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Bovinos
Linhagem Celular Tumoral
Modelos Animais de Doenças
Feminino
Seres Humanos
Hospedeiro Imunocomprometido
Interferon gama/deficiência
Interferon gama/genética
Masculino
Camundongos
Camundongos Knockout
Pirazóis/química
Pirazóis/farmacocinética
Piridinas/química
Piridinas/farmacocinética
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (KDU731); 0 (Pyrazoles); 0 (Pyridines); 0 (pyrazolopyridine); 82115-62-6 (Interferon-gamma); EC 2.7.1.67 (1-Phosphatidylinositol 4-Kinase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170601
[St] Status:MEDLINE
[do] DOI:10.1038/nature22337


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[PMID]:28035045
[Au] Autor:Levin R; Hammond GR; Balla T; De Camilli P; Fairn GD; Grinstein S
[Ad] Endereço:Division of Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
[Ti] Título:Multiphasic dynamics of phosphatidylinositol 4-phosphate during phagocytosis.
[So] Source:Mol Biol Cell;28(1):128-140, 2017 Jan 01.
[Is] ISSN:1939-4586
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We analyzed the distribution, fate, and functional role of phosphatidylinositol 4-phosphate (PtdIns4P) during phagosome formation and maturation. To this end, we used genetically encoded probes consisting of the PtdIns4P-binding domain of the bacterial effector SidM. PtdIns4P was found to undergo complex, multiphasic changes during phagocytosis. The phosphoinositide, which is present in the plasmalemma before engagement of the target particle, is transiently enriched in the phagosomal cup. Soon after the phagosome seals, PtdIns4P levels drop precipitously due to the hydrolytic activity of Sac2 and phospholipase C, becoming undetectable for ∼10 min. PtdIns4P disappearance coincides with the emergence of phagosomal PtdIns3P. Conversely, the disappearance of PtdIns3P that signals the transition from early to late phagosomes is accompanied by resurgence of PtdIns4P, which is associated with the recruitment of phosphatidylinositol 4-kinase 2A. The reacquisition of PtdIns4P can be prevented by silencing expression of the kinase and can be counteracted by recruitment of a 4-phosphatase with a heterodimerization system. Using these approaches, we found that the secondary accumulation of PtdIns4P is required for proper phagosomal acidification. Defective acidification may be caused by impaired recruitment of Rab7 effectors, including RILP, which were shown earlier to displace phagosomes toward perinuclear lysosomes. Our results show multimodal dynamics of PtdIns4P during phagocytosis and suggest that the phosphoinositide plays important roles during the maturation of the phagosome.
[Mh] Termos MeSH primário: Fagossomos/metabolismo
Fosfatos de Fosfatidilinositol/metabolismo
Fosfatos de Fosfatidilinositol/fisiologia
[Mh] Termos MeSH secundário: 1-Fosfatidilinositol 4-Quinase/metabolismo
Animais
Endossomos/metabolismo
Lisossomos/metabolismo
Macrófagos/metabolismo
Camundongos
Antígenos de Histocompatibilidade Menor/metabolismo
Fagocitose/fisiologia
Fagossomos/fisiologia
Fosfatidilinositol 3-Quinases/metabolismo
Fosfatos de Fosfatidilinositol/genética
Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
Células RAW 264.7
Proteínas rab de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Minor Histocompatibility Antigens); 0 (Phosphatidylinositol Phosphates); 0 (phosphatidylinositol 3-phosphate); 0 (phosphatidylinositol 4-phosphate); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 2.7.1.67 (1-Phosphatidylinositol 4-Kinase); EC 2.7.1.67 (PI4KIIIalpha protein, human); EC 2.7.1.67 (phosphatidylinositol phosphate 4-kinase); EC 3.6.5.2 (rab GTP-Binding Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170921
[Lr] Data última revisão:
170921
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161231
[St] Status:MEDLINE
[do] DOI:10.1091/mbc.E16-06-0451


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[PMID]:28004945
[Au] Autor:Mejdrová I; Chalupská D; Placková P; Müller C; Sála M; Klíma M; Baumlová A; Hrebabecký H; Procházková E; Dejmek M; Strunin D; Weber J; Lee G; Matousová M; Mertlíková-Kaiserová H; Ziebuhr J; Birkus G; Boura E; Nencka R
[Ad] Endereço:Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
[Ti] Título:Rational Design of Novel Highly Potent and Selective Phosphatidylinositol 4-Kinase IIIß (PI4KB) Inhibitors as Broad-Spectrum Antiviral Agents and Tools for Chemical Biology.
[So] Source:J Med Chem;60(1):100-118, 2017 Jan 12.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Phosphatidylinositol 4-kinase IIIß (PI4KB) is indispensable for the replication of various positive-sense single stranded RNA viruses, which hijack this cellular enzyme to remodel intracellular membranes of infected cells to set up the functional replication machinery. Therefore, the inhibition of this PI4K isoform leads to the arrest of viral replication. Here, we report on the synthesis of novel PI4KB inhibitors, which were rationally designed based on two distinct structural types of inhibitors that bind in the ATP binding side of PI4KB. These "hybrids" not only excel in outstanding inhibitory activity but also show high selectivity to PI4KB compared to other kinases. Thus, these compounds exert selective nanomolar or even subnanomolar activity against PI4KB as well as profound antiviral effect against hepatitis C virus, human rhinovirus, and coxsackievirus B3. Our crystallographic analysis unveiled the exact position of the side chains and explains their extensive contribution to the inhibitory activity.
[Mh] Termos MeSH primário: 1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores
Antivirais/química
Antivirais/farmacologia
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
[Mh] Termos MeSH secundário: Desenho de Drogas
Células HeLa
Seres Humanos
Estrutura Molecular
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Enzyme Inhibitors); EC 2.7.1.67 (1-Phosphatidylinositol 4-Kinase)
[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:161223
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b01465


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[PMID]:27870828
[Au] Autor:Choi S; Hedman AC; Sayedyahossein S; Thapa N; Sacks DB; Anderson RA
[Ad] Endereço:University of Wisconsin-Madison, School of Medicine and Public Health, 1300 University Avenue, Madison, Wisconsin 53706, USA.
[Ti] Título:Agonist-stimulated phosphatidylinositol-3,4,5-trisphosphate generation by scaffolded phosphoinositide kinases.
[So] Source:Nat Cell Biol;18(12):1324-1335, 2016 Dec.
[Is] ISSN:1476-4679
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Generation of the lipid messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P ) is crucial for development, cell growth and survival, and motility, and it becomes dysfunctional in many diseases including cancers. Here we reveal a mechanism for PtdIns(3,4,5)P generation by scaffolded phosphoinositide kinases. In this pathway, class I phosphatidylinositol-3-OH kinase (PI(3)K) is assembled by IQGAP1 with PI(4)KIIIα and PIPKIα, which sequentially generate PtdIns(3,4,5)P from phosphatidylinositol. By scaffolding these kinases into functional proximity, the PtdIns(4,5)P generated is selectively used by PI(3)K for PtdIns(3,4,5)P generation, which then signals to PDK1 and Akt that are also in the complex. Moreover, multiple receptor types stimulate the assembly of this IQGAP1-PI(3)K signalling complex. Blockade of IQGAP1 interaction with PIPKIα or PI(3)K inhibited PtdIns(3,4,5)P generation and signalling, and selectively diminished cancer cell survival, revealing a target for cancer chemotherapy.
[Mh] Termos MeSH primário: 1-Fosfatidilinositol 4-Quinase/metabolismo
Fosfatos de Fosfatidilinositol/metabolismo
[Mh] Termos MeSH secundário: Animais
Morte Celular
Linhagem Celular
Sobrevivência Celular
Seres Humanos
Imunoprecipitação
Insulina/metabolismo
Camundongos
Modelos Biológicos
Neoplasias/patologia
Peptídeos/metabolismo
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Receptores de Superfície Celular/metabolismo
Transdução de Sinais
Proteínas Ativadoras de ras GTPase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IQ motif containing GTPase activating protein 1); 0 (Insulin); 0 (Peptides); 0 (Phosphatidylinositol Phosphates); 0 (Receptors, Cell Surface); 0 (phosphatidylinositol 3,4,5-triphosphate); 0 (ras GTPase-Activating Proteins); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.67 (1-Phosphatidylinositol 4-Kinase); EC 2.7.1.67 (PI4KIIIalpha protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161122
[St] Status:MEDLINE
[do] DOI:10.1038/ncb3441


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[PMID]:27838849
[Au] Autor:Liu CH; Chang HK; Lee SP; Shieh RC
[Ad] Endereço:Institute of Biomedical Sciences, Academia Sinica, 128 Yen-Chiu Yuan Road, Section 2, 115, Taipei, Taiwan, Republic of China.
[Ti] Título:Activation of the Ca -sensing receptors increases currents through inward rectifier K channels via activation of phosphatidylinositol 4-kinase.
[So] Source:Pflugers Arch;468(11-12):1931-1943, 2016 Nov.
[Is] ISSN:1432-2013
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Inward rectifier K channels are important for maintaining normal electrical function in many cell types. The proper function of these channels requires the presence of membrane phosphoinositide 4,5-bisphosphate (PIP ). Stimulation of the Ca -sensing receptor CaR, a pleiotropic G protein-coupled receptor, activates both G , which decreases PIP , and phosphatidylinositol 4-kinase (PI-4-K), which, conversely, increases PIP . How membrane PIP levels are regulated by CaR activation and whether these changes modulate inward rectifier K are unknown. In this study, we found that activation of CaR by the allosteric agonist, NPSR568, increased inward rectifier K current (I ) in guinea pig ventricular myocytes and currents mediated by Kir2.1 channels exogenously expressed in HEK293T cells with a similar sensitivity. Moreover, using the fluorescent PIP reporter tubby-R332H-cYFP to monitor PIP levels, we found that CaR activation in HEK293T cells increased membrane PIP concentrations. Pharmacological studies showed that both phospholipase C (PLC) and PI-4-K are activated by CaR stimulation with the latter played a dominant role in regulating membrane PIP and, thus, Kir currents. These results provide the first direct evidence that CaR activation upregulates currents through inward rectifier K channels by accelerating PIP synthesis. The regulation of I plays a critical role in the stability of the electrical properties of many excitable cells, including cardiac myocytes and neurons. Further, synthetic allosteric modulators that increase CaR activity have been used to treat hyperparathyroidism, and negative CaR modulators are of potential importance in the treatment of osteoporosis. Thus, our results provide further insight into the roles played by CaR in the cardiovascular system and are potentially valuable for heart disease treatment and drug safety.
[Mh] Termos MeSH primário: 1-Fosfatidilinositol 4-Quinase/metabolismo
Potenciais de Ação
Fosfatidilinositol 4,5-Difosfato/metabolismo
Canais de Potássio Corretores do Fluxo de Internalização/metabolismo
Receptores de Detecção de Cálcio/metabolismo
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Cobaias
Células HEK293
Seres Humanos
Miócitos Cardíacos/metabolismo
Miócitos Cardíacos/fisiologia
Fosfolipases Tipo C/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Kir2.1 channel); 0 (Phosphatidylinositol 4,5-Diphosphate); 0 (Potassium Channels, Inwardly Rectifying); 0 (Receptors, Calcium-Sensing); EC 2.7.1.67 (1-Phosphatidylinositol 4-Kinase); EC 3.1.4.- (Type C Phospholipases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170629
[Lr] Data última revisão:
170629
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161114
[St] Status:MEDLINE


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[PMID]:27788957
[Au] Autor:Kwon J; Kim DH; Park JM; Park YH; Hwang YH; Wu HG; Shin KH; Kim IA
[Ad] Endereço:Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.
[Ti] Título:Targeting Phosphatidylinositol 4-Kinase IIIα for Radiosensitization: A Potential Model of Drug Repositioning Using an Anti-Hepatitis C Viral Agent.
[So] Source:Int J Radiat Oncol Biol Phys;96(4):867-876, 2016 Nov 15.
[Is] ISSN:1879-355X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: To investigate which isotype of phosphatidylinositol 4-kinase (PI4K) may affect radiosensitivity and examine whether anti-hepatitis C viral (HCV) agents, some of which have been shown to inhibit PI4K IIIα activity, could be repositioned as a radiosensitizer in human cancer cells. METHODS AND MATERIALS: U251, BT474, and HepG2 cell lines and normal human astrocyte were used. Ribonucleic acid interference, clonogenic assays, Western blotting, immunofluorescence, annexin V assay, lysotracker staining, and ß-galactosidase assay were performed. RESULTS: Of the 4 PI4K isotypes, specific inhibition of IIIα increased radiosensitivity. For pharmacologic inhibition of PI4K IIIα, we screened 9 anti-HCV agents by half-maximal inhibitory concentration assay. Simeprevir was selected, and its inhibition of PI4K IIIα activity was confirmed. Combination of simeprevir treatment and radiation significantly attenuated expression of phospho-phospho-PKC and phospho-Akt and increased radiation-induced cell death in tested cell lines. Pretreatment with simeprevir prolonged γH2AX foci formation and down-regulation of phospho-DNA-PKcs, indicating impairment of nonhomologous end-joining repair. Cells pretreated with simeprevir exhibited mixed modes of cell death, including apoptosis and autophagy. CONCLUSION: These data demonstrate that targeting PI4K IIIα using an anti-HCV agent is a viable approach to enhance the therapeutic efficacy of radiation therapy in various human cancers, such as glioma, breast, and hepatocellular carcinoma.
[Mh] Termos MeSH primário: 1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores
Antivirais/uso terapêutico
Reparo do DNA/efeitos dos fármacos
Reposicionamento de Medicamentos
Inibidores de Proteases/uso terapêutico
Radiossensibilizantes/uso terapêutico
Simeprevir/uso terapêutico
[Mh] Termos MeSH secundário: Apoptose
Astrócitos/efeitos dos fármacos
Astrócitos/efeitos da radiação
Autofagia
Neoplasias Encefálicas/tratamento farmacológico
Neoplasias Encefálicas/radioterapia
Neoplasias da Mama/tratamento farmacológico
Neoplasias da Mama/radioterapia
Linhagem Celular Tumoral
Regulação para Baixo
Ativação Enzimática
Feminino
Glioma/tratamento farmacológico
Glioma/radioterapia
Histonas/efeitos dos fármacos
Seres Humanos
Proteína Quinase C/antagonistas & inibidores
Proteína Quinase C/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
RNA Interferente Pequeno
Ensaio Tumoral de Célula-Tronco
beta-Galactosidase/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (H2AFX protein, human); 0 (Histones); 0 (Protease Inhibitors); 0 (RNA, Small Interfering); 0 (Radiation-Sensitizing Agents); 9WS5RD66HZ (Simeprevir); EC 2.7.1.67 (1-Phosphatidylinositol 4-Kinase); EC 2.7.1.67 (PI4KIIIalpha protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.13 (Protein Kinase C); EC 3.2.1.23 (beta-Galactosidase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161030
[St] Status:MEDLINE


  9 / 826 MEDLINE  
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[PMID]:27529511
[Au] Autor:Tang Y; Zhao CY; Tan ST; Xue HW
[Ad] Endereço:National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
[Ti] Título:Arabidopsis Type II Phosphatidylinositol 4-Kinase PI4Kγ5 Regulates Auxin Biosynthesis and Leaf Margin Development through Interacting with Membrane-Bound Transcription Factor ANAC078.
[So] Source:PLoS Genet;12(8):e1006252, 2016 Aug.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Normal leaf margin development is important for leaf morphogenesis and contributes to diverse leaf shapes in higher plants. We here show the crucial roles of an atypical type II phosphatidylinositol 4-kinase, PI4Kγ5, in Arabidopsis leaf margin development. PI4Kγ5 presents a dynamics expression pattern along with leaf development and a T-DNA mutant lacking PI4Kγ5, pi4kγ5-1, presents serrated leaves, which is resulted from the accelerated cell division and increased auxin concentration at serration tips. Studies revealed that PI4Kγ5 interacts with and phosphorylates a membrane-bound NAC transcription factor, ANAC078. Previous studies demonstrated that membrane-bound transcription factors regulate gene transcription by undergoing proteolytic process to translocate into nucleus, and ANAC078 undergoes proteolysis by cleaving off the transmembrane region and carboxyl terminal. Western blot analysis indeed showed that ANAC078 deleting of carboxyl terminal is significantly reduced in pi4kγ5-1, indicating that PI4Kγ5 is important for the cleavage of ANAC078. This is consistent with the subcellular localization observation showing that fluorescence by GFP-ANAC078 is detected at plasma membrane but not nucleus in pi4kγ5-1 mutant and that expression of ANAC078 deleting of carboxyl terminal, driven by PI4Kγ5 promoter, could rescue the leaf serration defects of pi4kγ5-1. Further analysis showed that ANAC078 suppresses the auxin synthesis by directly binding and regulating the expression of auxin synthesis-related genes. These results indicate that PI4Kγ5 interacts with ANAC078 to negatively regulate auxin synthesis and hence influences cell proliferation and leaf development, providing informative clues for the regulation of in situ auxin synthesis and cell division, as well as the cleavage and functional mechanism of membrane-bound transcription factors.
[Mh] Termos MeSH primário: 1-Fosfatidilinositol 4-Quinase/genética
Proteínas de Arabidopsis/genética
Ácidos Indolacéticos/metabolismo
Desenvolvimento Vegetal/genética
Fatores de Transcrição/genética
[Mh] Termos MeSH secundário: 1-Fosfatidilinositol 4-Quinase/biossíntese
Arabidopsis/genética
Arabidopsis/crescimento & desenvolvimento
Proteínas de Arabidopsis/biossíntese
Divisão Celular/genética
Proliferação Celular/genética
DNA Bacteriano/genética
Regulação da Expressão Gênica de Plantas
Mutação
Folhas de Planta/genética
Folhas de Planta/crescimento & desenvolvimento
Plantas Geneticamente Modificadas
Fatores de Transcrição/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ANAC078 protein, Arabidopsis); 0 (Arabidopsis Proteins); 0 (DNA, Bacterial); 0 (Indoleacetic Acids); 0 (T-DNA); 0 (Transcription Factors); EC 2.7.1.67 (1-Phosphatidylinositol 4-Kinase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170523
[Lr] Data última revisão:
170523
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160817
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006252


  10 / 826 MEDLINE  
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Fotocópia
Texto completo
[PMID]:27480860
[Au] Autor:Dorobantu CM; Harak C; Klein R; van der Linden L; Strating JR; van der Schaar HM; Lohmann V; van Kuppeveld FJ
[Ad] Endereço:Department of Infectious Diseases & Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
[Ti] Título:Tyrphostin AG1478 Inhibits Encephalomyocarditis Virus and Hepatitis C Virus by Targeting Phosphatidylinositol 4-Kinase IIIα.
[So] Source:Antimicrob Agents Chemother;60(10):6402-6, 2016 Oct.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Encephalomyocarditis virus (EMCV), like hepatitis C virus (HCV), requires phosphatidylinositol 4-kinase IIIα (PI4KA) for genome replication. Here, we demonstrate that tyrphostin AG1478, a known epidermal growth factor receptor (EGFR) inhibitor, also inhibits PI4KA activity, both in vitro and in cells. AG1478 impaired replication of EMCV and HCV but not that of an EMCV mutant previously shown to escape PI4KA inhibition. This work uncovers novel cellular and antiviral properties of AG1478, a compound previously regarded only as a cancer chemotherapy agent.
[Mh] Termos MeSH primário: 1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores
Antivirais/farmacologia
Vírus da Encefalomiocardite/efeitos dos fármacos
Inibidores Enzimáticos/farmacologia
Hepacivirus/efeitos dos fármacos
Quinazolinas/farmacologia
Tirfostinas/farmacologia
[Mh] Termos MeSH secundário: 1-Fosfatidilinositol 4-Quinase/metabolismo
Relação Dose-Resposta a Droga
Vírus da Encefalomiocardite/genética
Vírus da Encefalomiocardite/fisiologia
Células HeLa/efeitos dos fármacos
Células HeLa/virologia
Hepacivirus/fisiologia
Seres Humanos
Terapia de Alvo Molecular/métodos
Mutação
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Enzyme Inhibitors); 0 (Quinazolines); 0 (Tyrphostins); 170449-18-0 (tyrphostin AG 1478); EC 2.7.1.67 (1-Phosphatidylinositol 4-Kinase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160803
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.01331-16



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