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[PMID]:29326040
[Au] Autor:Noh MR; Jang HS; Song DK; Lee SR; Lipschutz JH; Park KM; Kim JI
[Ad] Endereço:Department of Anatomy and BK21 Plus, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
[Ti] Título:Downregulation of exocyst Sec10 accelerates kidney tubule cell recovery through enhanced cell migration.
[So] Source:Biochem Biophys Res Commun;496(2):309-315, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Migration of surviving kidney tubule cells after sub-lethal injury, for example ischemia/reperfusion (I/R), plays a critical role in recovery. Exocytosis is known to be involved in cell migration, and a key component in exocytosis is the highly-conserved eight-protein exocyst complex. We investigated the expression of a central exocyst complex member, Sec10, in kidneys following I/R injury, as well as the role of Sec10 in wound healing following scratch injury of cultured Madin-Darby canine kidney (MDCK) cells. Sec10 overexpression and knockdown (KD) in MDCK cells were used to investigate the speed of wound healing and the mechanisms underlying recovery. In mice, Sec10 decreased after I/R injury, and increased during the recovery period. In cell culture, Sec10 OE inhibited ruffle formation and wound healing, while Sec10 KD accelerated it. Sec10 OE cells had higher amounts of diacylglycerol kinase (DGK) gamma at the leading edge than did control cells. A DGK inhibitor reversed the inhibition of wound healing and ruffle formation in Sec10 OE cells. Conclusively, downregulation of Sec10 following I/R injury appears to accelerate recovery of kidney tubule cells through activated ruffle formation and enhanced cell migration.
[Mh] Termos MeSH primário: Diacilglicerol Quinase/antagonistas & inibidores
Túbulos Renais/metabolismo
Traumatismo por Reperfusão/prevenção & controle
Proteínas de Transporte Vesicular/genética
[Mh] Termos MeSH secundário: Animais
Bioensaio
Linhagem Celular
Movimento Celular/efeitos dos fármacos
Diacilglicerol Quinase/genética
Diacilglicerol Quinase/metabolismo
Cães
Inibidores Enzimáticos/farmacologia
Exocitose
Regulação da Expressão Gênica
Túbulos Renais/patologia
Células Madin Darby de Rim Canino
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Piperidinas/farmacologia
Quinazolinonas/farmacologia
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Traumatismo por Reperfusão/genética
Traumatismo por Reperfusão/metabolismo
Traumatismo por Reperfusão/patologia
Proteínas de Transporte Vesicular/agonistas
Proteínas de Transporte Vesicular/antagonistas & inibidores
Proteínas de Transporte Vesicular/metabolismo
Cicatrização/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (EXOC5 protein, mouse); 0 (Enzyme Inhibitors); 0 (Piperidines); 0 (Quinazolinones); 0 (RNA, Small Interfering); 0 (Vesicular Transport Proteins); 120166-69-0 (R 59949); EC 2.7.1.107 (Diacylglycerol Kinase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180113
[St] Status:MEDLINE


  2 / 1083 MEDLINE  
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[PMID]:28980804
[Au] Autor:Hutchison JM; Lu Z; Li GC; Travis B; Mittal R; Deatherage CL; Sanders CR
[Ad] Endereço:Department of Biochemistry, Vanderbilt University School of Medicine , Nashville, Tennessee 37240, United States.
[Ti] Título:Dodecyl-ß-melibioside Detergent Micelles as a Medium for Membrane Proteins.
[So] Source:Biochemistry;56(41):5481-5484, 2017 Oct 17.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:There remains a need for new non-ionic detergents that are suitable for use in biochemical and biophysical studies of membrane proteins. Here we explore the properties of n-dodecyl-ß-melibioside (ß-DDMB) micelles as a medium for membrane proteins. Melibiose is d-galactose-α(1→6)-d-glucose. Light scattering showed the ß-DDMB micelle to be roughly 30 kDa smaller than micelles formed by the commonly used n-dodecyl-ß-maltoside (ß-DDM). ß-DDMB stabilized diacylglycerol kinase (DAGK) against thermal inactivation. Moreover, activity assays conducted using aliquots of DAGK purified into ß-DDMB yielded activities that were 40% higher than those of DAGK purified into ß-DDM. ß-DDMB yielded similar or better TROSY-HSQC NMR spectra for two single-pass membrane proteins and the tetraspan membrane protein peripheral myelin protein 22. ß-DDMB appears be a useful addition to the toolbox of non-ionic detergents available for membrane protein research.
[Mh] Termos MeSH primário: Precursor de Proteína beta-Amiloide/metabolismo
Detergentes/química
Diacilglicerol Quinase/metabolismo
Dissacarídeos/química
Proteínas de Escherichia coli/metabolismo
Glicolipídeos/química
Proteínas da Mielina/metabolismo
Receptor Notch1/metabolismo
[Mh] Termos MeSH secundário: Precursor de Proteína beta-Amiloide/química
Detergentes/síntese química
Diacilglicerol Quinase/química
Dissacarídeos/síntese química
Difusão Dinâmica da Luz
Estabilidade Enzimática
Proteínas de Escherichia coli/química
Glucosídeos/química
Glicolipídeos/síntese química
Temperatura Alta/efeitos adversos
Seres Humanos
Micelas
Proteínas da Mielina/química
Ressonância Magnética Nuclear Biomolecular
Tamanho da Partícula
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/metabolismo
Domínios e Motivos de Interação entre Proteínas
Estabilidade Proteica
Receptor Notch1/química
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (APP protein, human); 0 (Amyloid beta-Protein Precursor); 0 (Detergents); 0 (Disaccharides); 0 (Escherichia coli Proteins); 0 (Glucosides); 0 (Glycolipids); 0 (Micelles); 0 (Myelin Proteins); 0 (NOTCH1 protein, human); 0 (PMP22 protein, human); 0 (Peptide Fragments); 0 (Receptor, Notch1); 0 (dodecyl-beta-melibioside); 69227-93-6 (dodecyl maltoside); EC 2.7.1.107 (Diacylglycerol Kinase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171006
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00810


  3 / 1083 MEDLINE  
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[PMID]:28916658
[Au] Autor:Jing W; Gershan JA; Holzhauer S; Weber J; Palen K; McOlash L; Pulakanti K; Wesley E; Rao S; Johnson BD; Riese MJ
[Ad] Endereço:Division of Hematology/Oncology/Transplant, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.
[Ti] Título:T Cells Deficient in Diacylglycerol Kinase ζ Are Resistant to PD-1 Inhibition and Help Create Persistent Host Immunity to Leukemia.
[So] Source:Cancer Res;77(20):5676-5686, 2017 Oct 15.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Efforts to improve the efficacy of adoptive T-cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the antileukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ ) mice than wild-type mice. T cells transferred from DGKζ-deficient mice to wild-type tumor-bearing recipients conferred this benefit. Leukemia clearance was similar to mice treated with anti-PD-L1. Strikingly, we found that the activity of adoptively transferred DGKζ T cells relied partly on induction of sustainable host T-cell immunity. Transferring DGKζ-deficient T cells increased the levels of IFNγ and other cytokines in recipient mice, especially with coadministration of anti-PD-L1. Overall, our results offered evidence that targeting DGKζ may leverage the efficacy of adoptive T-cell and immune checkpoint therapies in leukemia treatment. Furthermore, they suggest that DGKζ targeting might decrease risks of antigen escape or resistance to immune checkpoint blockade. .
[Mh] Termos MeSH primário: Diacilglicerol Quinase/imunologia
Imunoterapia Adotiva/métodos
Leucemia/imunologia
Leucemia/terapia
Receptor de Morte Celular Programada 1/antagonistas & inibidores
Linfócitos T/enzimologia
[Mh] Termos MeSH secundário: Animais
Antígeno B7-H1/antagonistas & inibidores
Antígeno B7-H1/imunologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Receptor de Morte Celular Programada 1/imunologia
Transdução de Sinais
Linfócitos T/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (B7-H1 Antigen); 0 (Cd274 protein, mouse); 0 (Pdcd1 protein, mouse); 0 (Programmed Cell Death 1 Receptor); EC 2.7.1.107 (Diacylglycerol Kinase); EC 2.7.1.107 (diacylglycerol kinase zeta, mouse)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170917
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-17-1309


  4 / 1083 MEDLINE  
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[PMID]:28829789
[Au] Autor:Gupta RS; Epand RM
[Ad] Endereço:Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
[Ti] Título:Phylogenetic analysis of the diacylglycerol kinase family of proteins and identification of multiple highly-specific conserved inserts and deletions within the catalytic domain that are distinctive characteristics of different classes of DGK homologs.
[So] Source:PLoS One;12(8):e0182758, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Diacylglycerol kinase (DGK) family of proteins, which phosphorylates diacylglycerol into phosphatidic acid, play important role in controlling diverse cellular processes in eukaryotic organisms. Most vertebrate species contain 10 different DGK isozymes, which are grouped into 5 different classes based on the presence or absence of specific functional domains. However, the relationships among different DGK isozymes or how they have evolved from a common ancestor is unclear. The catalytic domain constitutes the single largest sequence element within the DGK proteins that is commonly and uniquely shared by all family members, but there is limited understanding of the overall function of this domain. In this work, we have used the catalytic domain sequences to construct a phylogenetic tree for the DGK family members from representatives of the main vertebrate classes and have also examined the distributions of various DGK isozymes in eukaryotic phyla. In a tree based on catalytic domain sequences, the DGK homologs belonging to different classes formed strongly supported clusters which were separated by long branches, and the different isozymes within each class also generally formed monophyletic groupings. Further, our analysis of the sequence alignments of catalytic domains has identified >10 novel sequence signatures consisting of conserved signature indels (inserts or deletions, CSIs) that are distinctive characteristics of either particular classes of DGK isozymes, or are commonly shared by members of two or more classes of DGK isozymes. The conserved indels in protein sequences are known to play important functional roles in the proteins/organisms where they are found. Thus, our identification of multiple highly specific CSIs that are distinguishing characteristics of different classes of DGK homologs points to the existence of important differences in the catalytic domain function among the DGK isozymes. The identified CSIs in conjunction with the results of blast searches on species distribution of DGK isozymes also provide useful insights into the evolutionary relationships among the DGK family of proteins.
[Mh] Termos MeSH primário: Diacilglicerol Quinase/genética
Filogenia
[Mh] Termos MeSH secundário: Animais
Domínio Catalítico
Cercopithecus aethiops
Diacilglicerol Quinase/classificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.1.107 (Diacylglycerol Kinase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170823
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182758


  5 / 1083 MEDLINE  
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[PMID]:28712745
[Au] Autor:Franks CE; Campbell ST; Purow BW; Harris TE; Hsu KL
[Ad] Endereço:Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
[Ti] Título:The Ligand Binding Landscape of Diacylglycerol Kinases.
[So] Source:Cell Chem Biol;24(7):870-880.e5, 2017 Jul 20.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Diacylglycerol kinases (DGKs) are integral components of signal transduction cascades that regulate cell biology through ATP-dependent phosphorylation of the lipid messenger diacylglycerol. Methods for direct evaluation of DGK activity in native biological systems are lacking and needed to study isoform-specific functions of these multidomain lipid kinases. Here, we utilize ATP acyl phosphate activity-based probes and quantitative mass spectrometry to define, for the first time, ATP and small-molecule binding motifs of representative members from all five DGK subtypes. We use chemical proteomics to discover an unusual binding mode for the DGKα inhibitor, ritanserin, including interactions at the atypical C1 domain distinct from the ATP binding region. Unexpectedly, deconstruction of ritanserin yielded a fragment compound that blocks DGKα activity through a conserved binding mode and enhanced selectivity against the kinome. Collectively, our studies illustrate the power of chemical proteomics to profile protein-small molecule interactions of lipid kinases for fragment-based lead discovery.
[Mh] Termos MeSH primário: Diacilglicerol Quinase/metabolismo
Ligantes
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/química
Trifosfato de Adenosina/metabolismo
Sítios de Ligação
Cromatografia Líquida de Alta Pressão
Diacilglicerol Quinase/química
Diacilglicerol Quinase/genética
Células HEK293
Seres Humanos
Marcação por Isótopo
Ketanserina/química
Ketanserina/metabolismo
Peptídeos/análise
Ligação Proteica
Isoformas de Proteínas/química
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Proteoma/análise
Proteínas Recombinantes/biossíntese
Proteínas Recombinantes/química
Proteínas Recombinantes/isolamento & purificação
Ritanserina/química
Ritanserina/metabolismo
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Peptides); 0 (Protein Isoforms); 0 (Proteome); 0 (Recombinant Proteins); 145TFV465S (Ritanserin); 8L70Q75FXE (Adenosine Triphosphate); 97F9DE4CT4 (Ketanserin); EC 2.7.1.107 (Diacylglycerol Kinase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE


  6 / 1083 MEDLINE  
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[PMID]:28526779
[Au] Autor:Azukaitis K; Simkova E; Majid MA; Galiano M; Benz K; Amann K; Bockmeyer C; Gajjar R; Meyers KE; Cheong HI; Lange-Sperandio B; Jungraithmayr T; Frémeaux-Bacchi V; Bergmann C; Bereczki C; Miklaszewska M; Csuka D; Prohászka Z; Gipson P; Sampson MG; Lemaire M; Schaefer F
[Ad] Endereço:Clinic of Pediatrics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania; k.azukaitis@gmail.com.
[Ti] Título:The Phenotypic Spectrum of Nephropathies Associated with Mutations in Diacylglycerol Kinase .
[So] Source:J Am Soc Nephrol;28(10):3066-3075, 2017 Oct.
[Is] ISSN:1533-3450
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The recent discovery of mutations in the gene encoding diacylglycerol kinase (DGKE) identified a novel pathophysiologic mechanism leading to HUS and/or MPGN. We report ten new patients from eight unrelated kindreds with DGKE nephropathy. We combined these cases with all previously published cases to characterize the phenotypic spectrum and outcomes of this new disease entity. Most patients presented with HUS accompanied by proteinuria, whereas a subset of patients exhibited clinical and histologic patterns of MPGN without TMA. We also report the first two patients with clinical and histologic HUS/MPGN overlap. DGKE-HUS typically manifested in the first year of life but was not exclusively limited to infancy, and viral triggers frequently preceded HUS episodes. We observed signs of complement activation in some patients with DGKE-HUS, but the role of complement activation remains unclear. Most patients developed a slowly progressive proteinuric nephropathy: 80% of patients did not have ESRD within 10 years of diagnosis. Many patients experienced HUS remission without specific treatment, and a few patients experienced HUS recurrence despite complete suppression of the complement pathway. Five patients received renal allografts, with no post-transplant recurrence reported. In conclusion, we did not observe a clear genotype-phenotype correlation in patients with DGKE nephropathy, suggesting additional factors mediating phenotypic heterogeneity. Furthermore, the benefits of anti-complement therapy are questionable but renal transplant may be a feasible option in the treatment of patients with this condition.
[Mh] Termos MeSH primário: Síndrome Hemolítico-Urêmica Atípica/genética
Diacilglicerol Quinase/genética
Glomerulonefrite Membranoproliferativa/genética
[Mh] Termos MeSH secundário: Síndrome Hemolítico-Urêmica Atípica/epidemiologia
Síndrome Hemolítico-Urêmica Atípica/terapia
Pré-Escolar
Análise Mutacional de DNA
Feminino
Glomerulonefrite Membranoproliferativa/epidemiologia
Glomerulonefrite Membranoproliferativa/terapia
Seres Humanos
Incidência
Lactente
Lituânia/epidemiologia
Masculino
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.1.107 (Diacylglycerol Kinase); EC 2.7.1.107 (diacylglycerol kinase epsilon, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170521
[St] Status:MEDLINE
[do] DOI:10.1681/ASN.2017010031


  7 / 1083 MEDLINE  
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[PMID]:28521876
[Au] Autor:Maki T; Maeda Y; Sonoda N; Makimura H; Kimura S; Maeno S; Takayanagi R; Inoguchi T
[Ad] Endereço:Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
[Ti] Título:Renoprotective effect of a novel selective PPARα modulator K-877 in db/db mice: A role of diacylglycerol-protein kinase C-NAD(P)H oxidase pathway.
[So] Source:Metabolism;71:33-45, 2017 Jun.
[Is] ISSN:1532-8600
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Several clinical studies have shown the beneficial effects of peroxisome proliferator-activated receptor α (PPARα) agonists on diabetic nephropathy. However, the molecular mechanism is not fully understood. Here we show that K-877, a novel selective PPARα modulator, ameliorates nephropathy in db/db mice via inhibition of renal lipid content and oxidative stress. METHODS AND RESULTS: K-877 (0.5mg/kg/day) was administered to db/db mice for 2 or 12weeks. Short-term treatment did not affect body weight or plasma glucose levels in db/db mice, but attenuated albuminuria, along with improvement of plasma lipid profiles, lipid content including total diacylglycerol (DAG) levels, protein kinase C (PKC) activity, NAD(P)H oxidase-4 expression, and oxidative stress markers, all of which were significantly increased in diabetic kidneys. It increased phosphorylation of 5'-AMP activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), and expression of several genes mediating fatty acid ß-oxidation. In addition, long-term treatment ameliorated renal mesangial expansion in db/db mice and improved glycemic control. CONCLUSIONS: K-877 administration ameliorates diabetic nephropathy, at least in part, via inhibition of renal lipid content and oxidative stress. The underlying mechanism may be mediated by modulating the renal AMPK-ACC pathway, subsequent acceleration of fatty acid ß-oxidation and inhibition of fatty acid synthesis, and thus inhibition of the DAG-PKC-NAD(P)H oxidase pathway, in addition to its systemic effect including improvement of the plasma lipid profile and glycemic control.
[Mh] Termos MeSH primário: Benzoxazóis/farmacologia
Butiratos/farmacologia
Nefropatias Diabéticas/prevenção & controle
Diacilglicerol Quinase/metabolismo
NADPH Oxidases/metabolismo
PPAR alfa/agonistas
Proteína Quinase C/metabolismo
[Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/metabolismo
Acetil-CoA Carboxilase/metabolismo
Animais
Diabetes Mellitus Experimental/metabolismo
Nefropatias Diabéticas/metabolismo
Rim/efeitos dos fármacos
Rim/metabolismo
Lipídeos/sangue
Masculino
Redes e Vias Metabólicas/efeitos dos fármacos
Camundongos
Camundongos Endogâmicos C57BL
Estresse Oxidativo/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoxazoles); 0 (Butyrates); 0 (K-877 compound); 0 (Lipids); 0 (PPAR alpha); EC 1.6.3.- (NADPH Oxidases); EC 2.7.1.107 (Diacylglycerol Kinase); EC 2.7.11.13 (Protein Kinase C); EC 2.7.11.31 (AMP-Activated Protein Kinases); EC 6.4.1.2 (Acetyl-CoA Carboxylase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE


  8 / 1083 MEDLINE  
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[PMID]:28416508
[Au] Autor:Jokiranta TS
[Ad] Endereço:Research Programs Unit, Immunobiology, University of Helsinki, Helsinki University Central Hospital, and United Medix Laboratories, Helsinki, Finland sakari.jokiranta@helsinki.fi.
[Ti] Título:HUS and atypical HUS.
[So] Source:Blood;129(21):2847-2856, 2017 May 25.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis, thrombocytopenia, and acute kidney failure. HUS is usually categorized as typical, caused by Shiga toxin-producing (STEC) infection, as atypical HUS (aHUS), usually caused by uncontrolled complement activation, or as secondary HUS with a coexisting disease. In recent years, a general understanding of the pathogenetic mechanisms driving HUS has increased. Typical HUS (ie, STEC-HUS) follows a gastrointestinal infection with STEC, whereas aHUS is associated primarily with mutations or autoantibodies leading to dysregulated complement activation. Among the 30% to 50% of patients with HUS who have no detectable complement defect, some have either impaired diacylglycerol kinase ε (DGKε) activity, cobalamin C deficiency, or plasminogen deficiency. Some have secondary HUS with a coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs, or pregnancy. The common pathogenetic features in STEC-HUS, aHUS, and secondary HUS are simultaneous damage to endothelial cells, intravascular hemolysis, and activation of platelets leading to a procoagulative state, formation of microthrombi, and tissue damage. In this review, the differences and similarities in the pathogenesis of STEC-HUS, aHUS, and secondary HUS are discussed. Common for the pathogenesis seems to be the vicious cycle of complement activation, endothelial cell damage, platelet activation, and thrombosis. This process can be stopped by therapeutic complement inhibition in most patients with aHUS, but usually not those with a DGKε mutation, and some patients with STEC-HUS or secondary HUS. Therefore, understanding the pathogenesis of the different forms of HUS may prove helpful in clinical practice.
[Mh] Termos MeSH primário: Síndrome Hemolítico-Urêmica Atípica
Hemólise
Ativação Plaquetária
Trombose
[Mh] Termos MeSH secundário: Síndrome Hemolítico-Urêmica Atípica/sangue
Síndrome Hemolítico-Urêmica Atípica/genética
Síndrome Hemolítico-Urêmica Atípica/patologia
Síndrome Hemolítico-Urêmica Atípica/terapia
Ativação do Complemento/genética
Diacilglicerol Quinase/sangue
Diacilglicerol Quinase/genética
Células Endoteliais/metabolismo
Células Endoteliais/patologia
Seres Humanos
Trombose/sangue
Trombose/genética
Trombose/patologia
Trombose/terapia
Vitamina B 12/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
EC 2.7.1.107 (Diacylglycerol Kinase); EC 2.7.1.107 (diacylglycerol kinase epsilon, human); P6YC3EG204 (Vitamin B 12)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-11-709865


  9 / 1083 MEDLINE  
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[PMID]:28276191
[Au] Autor:Miner GE; Starr ML; Hurst LR; Fratti RA
[Ad] Endereço:Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois.
[Ti] Título:Deleting the DAG kinase Dgk1 augments yeast vacuole fusion through increased Ypt7 activity and altered membrane fluidity.
[So] Source:Traffic;18(5):315-329, 2017 May.
[Is] ISSN:1600-0854
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Diacylglycerol (DAG) is a fusogenic lipid that can be produced through phospholipase C activity on phosphatidylinositol 4,5-bisphosphate [PI(4,5)P ], or through phosphatidic acid (PA) phosphatase activity. The fusion of Saccharomyces cerevisiae vacuoles requires DAG, PA and PI(4,5)P , and the production of these lipids is thought to provide temporally specific stoichiometries that are critical for each stage of fusion. Furthermore, DAG and PA can be interconverted by the DAG kinase Dgk1 and the PA phosphatase Pah1. Previously we found that pah1 Δ vacuoles were fragmented, blocked in SNARE priming and showed arrested endosomal maturation. In other pathways the effects of deleting PAH1 can be compensated for by additionally deleting DGK1 ; however, deleting both genes did not rescue the pah1 Δ vacuolar defects. Deleting DGK1 alone caused a marked increase in vacuole fusion that was attributed to elevated DAG levels. This was accompanied by a gain in resistance to the inhibitory effects of PA as well as inhibitors of Ypt7 activity. Together these data show that Dgk1 function can act as a negative regulator of vacuole fusion through the production of PA at the cost of depleting DAG and reducing Ypt7 activity.
[Mh] Termos MeSH primário: Diacilglicerol Quinase/metabolismo
Fluidez de Membrana/fisiologia
Proteínas Repressoras/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/metabolismo
Proteínas de Transporte Vesicular/metabolismo
Proteínas rab de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Endossomos/metabolismo
Fusão de Membrana/fisiologia
Fosfatidato Fosfatase/metabolismo
Fosfatos de Fosfatidilinositol/metabolismo
Ligação Proteica/fisiologia
Proteínas SNARE/metabolismo
Vacúolos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DGK1 protein, S cerevisiae); 0 (Phosphatidylinositol Phosphates); 0 (Repressor Proteins); 0 (SNARE Proteins); 0 (Saccharomyces cerevisiae Proteins); 0 (Vesicular Transport Proteins); EC 2.7.1.107 (Diacylglycerol Kinase); EC 3.1.3.4 (Phosphatidate Phosphatase); EC 3.6.1.- (YPT7 protein, S cerevisiae); EC 3.6.5.2 (rab GTP-Binding Proteins)
[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:170310
[St] Status:MEDLINE
[do] DOI:10.1111/tra.12479


  10 / 1083 MEDLINE  
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[PMID]:28218473
[Au] Autor:Kai M; Yamamoto E; Sato A; Yamano HO; Niinuma T; Kitajima H; Harada T; Aoki H; Maruyama R; Toyota M; Hatahira T; Nakase H; Sugai T; Yamashita T; Toyota M; Suzuki H
[Ad] Endereço:Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
[Ti] Título:Epigenetic silencing of diacylglycerol kinase gamma in colorectal cancer.
[So] Source:Mol Carcinog;56(7):1743-1752, 2017 Jul.
[Is] ISSN:1098-2744
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Diacylglycerol kinases (DGKs) are important regulators of cell signaling and have been implicated in human malignancies. Whether epigenetic alterations are involved in the dysregulation of DGKs in cancer is unknown, however. We therefore analyzed methylation of the promoter CpG islands of DGK genes in colorectal cancer (CRC) cell lines. We found that DGKG, which encodes DGKγ, was hypermethylated in all CRC cell lines tested (n = 9), but was not methylated in normal colonic tissue. Correspondingly, DGKG expression was suppressed in CRC cell lines but not in normal colonic tissue, and was restored in CRC cells by treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC). DGKG methylation was frequently observed in primary CRCs (73/141, 51.8%) and was positively associated with KRAS and BRAF mutations and with the CpG island methylator phenotype (CIMP). DGKG methylation was also frequently detected in colorectal adenomas (89 of 177, 50.3%), which suggests it is an early event during colorectal tumorigenesis. Ectopic expression of wild-type DGKγ did not suppress CRC cell proliferation, but did suppress cell migration and invasion. Notably, both constitutively active and kinase-dead DGKγ mutants exerted inhibitory effects on CRC cell proliferation, migration and invasion, and the wild-type and mutant forms of DGKγ all suppressed Rac1 activity in CRC cells. These data suggest DGKG may play a tumor suppressor role in CRC.
[Mh] Termos MeSH primário: Adenoma/genética
Neoplasias Colorretais/genética
Metilação de DNA
Diacilglicerol Quinase/genética
Epigênese Genética
Regulação Neoplásica da Expressão Gênica
[Mh] Termos MeSH secundário: Adenoma/patologia
Apoptose
Biomarcadores Tumorais/genética
Biomarcadores Tumorais/metabolismo
Movimento Celular
Proliferação Celular
Neoplasias Colorretais/patologia
Diacilglicerol Quinase/metabolismo
Feminino
Seres Humanos
Masculino
Meia-Idade
Invasividade Neoplásica
Estadiamento de Neoplasias
Prognóstico
Regiões Promotoras Genéticas
Taxa de Sobrevida
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); EC 2.7.1.107 (Diacylglycerol Kinase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171011
[Lr] Data última revisão:
171011
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170221
[St] Status:MEDLINE
[do] DOI:10.1002/mc.22631



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