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[PMID]:28754315
[Au] Autor:Pulido SA; Nguyen VH; Alzate JF; Cedeño DL; Makurath MA; Ríos-Vásquez A; Duque-Benítez SM; Jones MA; Robledo SM; Friesen JA
[Ad] Endereço:Program for Study and Control of Tropical Diseases-PECET, School of Medicine, University of Antioquia, Medellin, Colombia.
[Ti] Título:Insights into the phosphatidylcholine and phosphatidylethanolamine biosynthetic pathways in Leishmania parasites and characterization of a choline kinase from Leishmania infantum.
[So] Source:Comp Biochem Physiol B Biochem Mol Biol;213:45-54, 2017 Nov.
[Is] ISSN:1879-1107
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The protozoan parasite Leishmania infantum is a causative agent of the disease visceral leishmaniasis, which can be fatal if not properly treated. Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) biosynthesis pathways are attractive targets for new antileishmanial compounds since these Leishmania cell membrane phospholipids are important for parasite morphology and physiology. In this work we observed Leishmania synthesize PC and PE from extracellular choline and ethanolamine, respectively, suggesting the presence of CDP-choline and CDP-ethanolamine pathways. In addition, Leishmania converted PE to PC, indicating the parasite possesses phosphatidylethanolamine N-methyltransferase (PEMT) activity. The first step in the biosynthesis of PC or PE requires the phosphorylation of choline or ethanolamine by a kinase. We cloned the gene encoding a putative choline/ethanolamine kinase from Leishmania infantum and expressed and purified the encoded recombinant protein. The enzyme possesses choline kinase activity with a V of 3.52µmol/min/mg and an apparent K value of 0.089mM with respect to choline. The enzyme can also phosphorylate ethanolamine in vitro, but the apparent K for ethanolamine is 850-fold greater than for choline. In an effort to probe requirements for small molecule inhibition of Leishmania choline kinase, the recombinant enzyme was evaluated for the ability to be inhibited by novel quaternary ammonium salts. The most effective inhibitor was N-iodomethyl-N,N,-dimethyl-N-(6,6-diphenyl hex-5-en-1-yle) ammonium iodide, denoted compound C6. In the presence of 4mM compound C6, the V /K decreased to approximately 1% of the wild-type catalytic efficiency. In addition, in Leishmania cells treated with compound C6 choline transport was inhibited.
[Mh] Termos MeSH primário: Colina Quinase/metabolismo
Leishmania infantum/metabolismo
Fosfatidilcolinas/biossíntese
Fosfatidiletanolaminas/biossíntese
Proteínas de Protozoários/metabolismo
[Mh] Termos MeSH secundário: Colina Quinase/antagonistas & inibidores
Colina Quinase/genética
Inibidores Enzimáticos/química
Leishmania infantum/genética
Fosfatidilcolinas/genética
Fosfatidiletanolaminas/genética
Proteínas de Protozoários/genética
Especificidade por Substrato/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Phosphatidylcholines); 0 (Phosphatidylethanolamines); 0 (Protozoan Proteins); 39382-08-6 (phosphatidylethanolamine); EC 2.7.1.32 (Choline Kinase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170730
[St] Status:MEDLINE


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[PMID]:28652252
[Au] Autor:Marchan R; Büttner B; Lambert J; Edlund K; Glaeser I; Blaszkewicz M; Leonhardt G; Marienhoff L; Kaszta D; Anft M; Watzl C; Madjar K; Grinberg M; Rempel E; Hergenröder R; Selinski S; Rahnenführer J; Lesjak MS; Stewart JD; Cadenas C; Hengstler JG
[Ad] Endereço:Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund (IfADo), Dortmund, Germany. marchan@ifado.de.
[Ti] Título:Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma.
[So] Source:Cancer Res;77(17):4589-4601, 2017 Sep 01.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glycerophosphodiesterase EDI3 (GPCPD1; GDE5; GDPD6) has been suggested to promote cell migration, adhesion, and spreading, but its mechanisms of action remain uncertain. In this study, we targeted the glycerol-3-phosphate acyltransferase GPAM along with choline kinase-α (CHKA), the enzymes that catabolize the products of EDI3 to determine which downstream pathway is relevant for migration. Our results clearly showed that GPAM influenced cell migration via the signaling lipid lysophosphatidic acid (LPA), linking it with GPAM to cell migration. Analysis of GPAM expression in different cancer types revealed a significant association between high GPAM expression and reduced overall survival in ovarian cancer. Silencing GPAM in ovarian cancer cells decreased cell migration and reduced the growth of tumor xenografts. In contrast to these observations, manipulating CHKA did not influence cell migration in the same set of cell lines. Overall, our findings show how GPAM influences intracellular LPA levels to promote cell migration and tumor growth. .
[Mh] Termos MeSH primário: Movimento Celular
Colina Quinase/metabolismo
Glicerol-3-Fosfato O-Aciltransferase/metabolismo
Neoplasias Ovarianas/mortalidade
Neoplasias Ovarianas/patologia
[Mh] Termos MeSH secundário: Animais
Feminino
Seres Humanos
Camundongos
Camundongos Nus
Neoplasias Ovarianas/enzimologia
Prognóstico
Transdução de Sinais
Taxa de Sobrevida
Células Tumorais Cultivadas
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.3.1.15 (Glycerol-3-Phosphate O-Acyltransferase); EC 2.7.1.32 (CHKA protein, human); EC 2.7.1.32 (Choline Kinase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-16-2065


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[PMID]:28644842
[Au] Autor:Kim HS; Tian L; Kim H; Moon WK
[Ad] Endereço:Department of Radiology, Seoul National University Hospital, Jongno-gu, Seoul, Korea.
[Ti] Título:Investigation of discriminant metabolites in tamoxifen-resistant and choline kinase-alpha-downregulated breast cancer cells using 1H-nuclear magnetic resonance spectroscopy.
[So] Source:PLoS One;12(6):e0179773, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metabolites linked to changes in choline kinase-α (CK-α) expression and drug resistance, which contribute to survival and autophagy mechanisms, are attractive targets for breast cancer therapies. We previously reported that autophagy played a causative role in driving tamoxifen (TAM) resistance of breast cancer cells (BCCs) and was also promoted by CK-α knockdown, resulting in the survival of TAM-resistant BCCs. There is no comparative study yet about the metabolites resulting from BCCs with TAM-resistance and CK-α knockdown. Therefore, the aim of this study was to explore the discriminant metabolic biomarkers responsible for TAM resistance as well as CK-α expression, which might be linked with autophagy through a protective role. A total of 33 intracellular metabolites, including a range of amino acids, energy metabolism-related molecules and others from cell extracts of the parental cells (MCF-7), TAM-resistant cells (MCF-7/TAM) and CK-α knockdown cells (MCF-7/shCK-α, MCF-7/TAM/shCK-α) were analyzed by proton nuclear magnetic resonance spectroscopy (1H-NMRS). Principal component analysis (PCA) and partial least square discriminant analysis (PLS-DA) revealed the existence of differences in the intracellular metabolites to separate the 4 groups: MCF-7 cells, MCF-7/TAM cells, MCF-7-shCK-α cells, and MCF-7/TAM/shCK-α cells. The metabolites with VIP>1 contributed most to the differentiation of the cell groups, and they included fumarate, UA (unknown A), lactate, myo-inositol, glycine, phosphocholine, UE (unknown E), glutamine, formate, and AXP (AMP/ADP/ATP). Our results suggest that these altered metabolites would be promising metabolic biomarkers for a targeted therapeutic strategy in BCCs that exhibit TAM-resistance and aberrant CK-α expression, which triggers a survival and drug resistance mechanism.
[Mh] Termos MeSH primário: Neoplasias da Mama/metabolismo
Colina Quinase/deficiência
Resistência a Medicamentos Antineoplásicos/fisiologia
[Mh] Termos MeSH secundário: Antineoplásicos Hormonais/uso terapêutico
Western Blotting
Neoplasias da Mama/patologia
Linhagem Celular Tumoral
Colina Quinase/genética
Regulação para Baixo
Técnicas de Silenciamento de Genes
Vetores Genéticos
Seres Humanos
Análise dos Mínimos Quadrados
Lentivirus/genética
Mitocôndrias/metabolismo
Mitocôndrias/patologia
Ressonância Magnética Nuclear Biomolecular
Análise de Componente Principal
Espectroscopia de Prótons por Ressonância Magnética
Tamoxifeno/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Hormonal); 094ZI81Y45 (Tamoxifen); EC 2.7.1.32 (CHKA protein, human); EC 2.7.1.32 (Choline Kinase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170624
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179773


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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]:28157707
[Au] Autor:Arlauckas SP; Kumar M; Popov AV; Poptani H; Delikatny EJ
[Ad] Endereço:Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
[Ti] Título:Near infrared fluorescent imaging of choline kinase alpha expression and inhibition in breast tumors.
[So] Source:Oncotarget;8(10):16518-16530, 2017 Mar 07.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Choline kinase alpha (ChoKα) overexpression is associated with an aggressive tumor phenotype. ChoKα inhibitors induce apoptosis in tumors, however validation of their specificity is difficult in vivo. We report the use of optical imaging to assess ChoKα status in cells and in vivo using JAS239, a carbocyanine-based ChoKα inhibitor with inherent near infrared fluorescence. JAS239 attenuated choline phosphorylation and viability in a panel of human breast cancer cell lines. Antibody blockade prevented cellular retention of JAS239 indicating direct interaction with ChoKα independent of the choline transporters and catabolic choline pathways. In mice bearing orthotopic MCF7 breast xenografts, optical imaging with JAS239 distinguished tumors overexpressing ChoKα from their empty vector counterparts and delineated tumor margins. Pharmacological inhibition of ChoK by the established inhibitor MN58b led to a growth inhibition in 4175-Luc+ tumors that was accompanied by concomitant reduction in JAS239 uptake and decreased total choline metabolite levels as measured using magnetic resonance spectroscopy. At higher therapeutic doses, JAS239 was as effective as MN58b at arresting tumor growth and inducing apoptosis in MDA-MB-231 tumors, significantly reducing tumor choline below baseline levels without observable systemic toxicity. These data introduce a new method to monitor therapeutically effective inhibitors of choline metabolism in breast cancer using a small molecule companion diagnostic.
[Mh] Termos MeSH primário: Neoplasias da Mama/enzimologia
Colina Quinase/biossíntese
[Mh] Termos MeSH secundário: Animais
Neoplasias da Mama/patologia
Linhagem Celular Tumoral
Colina Quinase/antagonistas & inibidores
Estudos de Coortes
Feminino
Seres Humanos
Células MCF-7
Camundongos
Camundongos Nus
Espectroscopia de Luz Próxima ao Infravermelho
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.1.32 (CHKA protein, human); EC 2.7.1.32 (Choline Kinase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170204
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.14965


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[PMID]:28065789
[Au] Autor:Lin XM; Hu L; Gu J; Wang RY; Li L; Tang J; Zhang BH; Yan XZ; Zhu YJ; Hu CL; Zhou WP; Li S; Liu JF; Gonzalez FJ; Wu MC; Wang HY; Chen L
[Ad] Endereço:International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China; Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
[Ti] Título:Choline Kinase α Mediates Interactions Between the Epidermal Growth Factor Receptor and Mechanistic Target of Rapamycin Complex 2 in Hepatocellular Carcinoma Cells to Promote Drug Resistance and Xenograft Tumor Progression.
[So] Source:Gastroenterology;152(5):1187-1202, 2017 Apr.
[Is] ISSN:1528-0012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: Choline kinase α (CHKA) catalyzes conversion of choline to phosphocholine and can contribute to carcinogenesis. Little is known about the role of CHKA in the pathogenesis of hepatocellular carcinoma (HCC). METHODS: We performed whole-exome and transcriptome sequence analyses of 9 paired HCC and non-tumor-adjacent tissues. We performed tissue chip analyses of 120 primary HCC and non-tumor-adjacent tissues from patients who received surgery in Shanghai, China from January 2006 through December 2009; 48 sets of specimens (HCC and non-tumor-adjacent tissues) were also analyzed. CHKA gene copy number was quantified and findings were validated by quantitative reverse transcription polymerase chain reaction analysis. CHKA messenger RNA and protein levels were determined by polymerase chain reaction, immunohistochemical, and immunoblot analyses. CHKA was examined in 2 hepatocyte cell lines and 7 HCC-derived cell lines, and knocked down with small interfering RNAs in 3 HCC cell lines. Cells were analyzed in proliferation, wound healing, migration, and invasion assays. Cells were injected into tail veins of mice and tumor growth and metastasis were quantified. Immunoprecipitation and immunofluorescence assays were conducted to determine interactions between CHKA and the epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin complex 2. RESULTS: Levels of CHKA messenger RNA were frequently increased in HCC tissues compared with nontumor tissues; increased expression was associated with amplification at the CHKA loci. Tumors that expressed high levels of CHKA had more aggressive phenotypes, and patients with these tumors had shorter survival times after surgery compared to patients whose tumors expressed low levels of CHKA. HCC cell lines that stably overexpressed CHKA had higher levels of migration and invasion than control HCC cells, and formed larger xenograft tumors with more metastases in mice compared to HCC cells that did not overexpress CHKA. CHKA was required for physical interaction between EGFR and mechanistic target of rapamycin complex 2. This complex was required for HCC cells to form metastatic xenograft tumors in mice and to become resistant to EGFR inhibitors. CONCLUSIONS: We found levels of CHKA to be increased in human HCCs compared to nontumor tissues, and increased expression to be associated with tumor aggressiveness and reduced survival times of patients. Overexpression of CHKA in HCC cell lines increased their invasiveness, resistance to EGFR inhibitors, and ability to form metastatic tumors in mice by promoting interaction of EGFR with mechanistic target of rapamycin complex 2.
[Mh] Termos MeSH primário: Carcinoma Hepatocelular/metabolismo
Colina Quinase/genética
Resistência a Medicamentos Antineoplásicos/genética
Neoplasias Hepáticas/metabolismo
Complexos Multiproteicos/metabolismo
RNA Mensageiro/metabolismo
Receptor do Fator de Crescimento Epidérmico/metabolismo
Serina-Treonina Quinases TOR/metabolismo
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacologia
Carcinoma Hepatocelular/tratamento farmacológico
Carcinoma Hepatocelular/patologia
Linhagem Celular
Linhagem Celular Tumoral
Movimento Celular/genética
Colina Quinase/metabolismo
Cloridrato de Erlotinib/farmacologia
Células Hep G2
Seres Humanos
Immunoblotting
Imuno-Histoquímica
Neoplasias Hepáticas/tratamento farmacológico
Neoplasias Hepáticas/patologia
Alvo Mecanístico do Complexo 2 de Rapamicina
Camundongos
Invasividade Neoplásica/genética
Transplante de Neoplasias
Quinazolinas/farmacologia
Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores
Cicatrização/genética
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Multiprotein Complexes); 0 (Quinazolines); 0 (RNA, Messenger); DA87705X9K (Erlotinib Hydrochloride); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.32 (CHKA protein, human); EC 2.7.1.32 (Choline Kinase); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2); S65743JHBS (gefitinib)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170110
[St] Status:MEDLINE


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[PMID]:27489281
[Au] Autor:Wong MT; Chen SS
[Ad] Endereço:Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China.
[Ti] Título:Human Choline Kinase-α Promotes Hepatitis C Virus RNA Replication through Modulation of Membranous Viral Replication Complex Formation.
[So] Source:J Virol;90(20):9075-95, 2016 Oct 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: Hepatitis C virus (HCV) infection reorganizes cellular membranes to create an active viral replication site named the membranous web (MW). The role that human choline kinase-α (hCKα) plays in HCV replication remains elusive. Here, we first showed that hCKα activity, not the CDP-choline pathway, promoted viral RNA replication. Confocal microscopy and subcellular fractionation of HCV-infected cells revealed that a small fraction of hCKα colocalized with the viral replication complex (RC) on the endoplasmic reticulum (ER) and that HCV infection increased hCKα localization to the ER. In the pTM-NS3-NS5B model, NS3-NS5B expression increased the localization of the wild-type, not the inactive D288A mutant, hCKα on the ER, and hCKα activity was required for effective trafficking of hCKα and NS5A to the ER. Coimmunoprecipitation showed that hCKα was recruited onto the viral RC presumably through its binding to NS5A domain 1 (D1). hCKα silencing or treatment with CK37, an hCKα activity inhibitor, abolished HCV-induced MW formation. In addition, hCKα depletion hindered NS5A localization on the ER, interfered with NS5A and NS5B colocalization, and mitigated NS5A-NS5B interactions but had no apparent effect on NS5A-NS4B and NS4B-NS5B interactions. Nevertheless, hCKα activity was not essential for the binding of NS5A to hCKα or NS5B. These findings demonstrate that hCKα forms a complex with NS5A and that hCKα activity enhances the targeting of the complex to the ER, where hCKα protein, not activity, mediates NS5A binding to NS5B, thereby promoting functional membranous viral RC assembly and viral RNA replication. IMPORTANCE: HCV infection reorganizes the cellular membrane to create an active viral replication site named the membranous web (MW). Here, we report that human choline kinase-α (hCKα) acts as an essential host factor for HCV RNA replication. A fraction of hCKα colocalizes with the viral replication complex (RC) on the endoplasmic reticulum (ER) in HCV-infected cells. NS3-NS5B expression increases ER localization of wild-type, but not D288A mutant, hCKα, and hCKα activity facilitates the transport of itself and NS5A to the ER. Silencing or inactivation of hCKα abrogates MW formation. Moreover, hCKα is recruited by NS5A independent of hCKα activity, presumably through binding to NS5A D1. hCKα activity then mediates the ER targeting of the hCKα-NS5A complex. On the ER membrane, hCKα protein, per se, induces NS5A binding to NS5B, thereby promoting membranous RC formation and viral RNA replication. Our study may benefit the development of hCKα-targeted anti-HCV therapeutics.
[Mh] Termos MeSH primário: Hepacivirus/fisiologia
Interações Hospedeiro-Patógeno
Proteínas não Estruturais Virais/metabolismo
Replicação Viral
[Mh] Termos MeSH secundário: Linhagem Celular
Colina Quinase
Retículo Endoplasmático/virologia
Hepatócitos/virologia
Seres Humanos
Ligação Proteica
RNA Viral/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NS-5 protein, hepatitis C virus); 0 (RNA, Viral); 0 (Viral Nonstructural Proteins); EC 2.7.1.32 (CHKA protein, human); EC 2.7.1.32 (Choline Kinase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170510
[Lr] Data última revisão:
170510
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160805
[St] Status:MEDLINE
[do] DOI:10.1128/JVI.00960-16


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[PMID]:27149373
[Au] Autor:Chang CC; Few LL; Konrad M; See Too WC
[Ad] Endereço:School of Health Sciences, Health Campus, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.
[Ti] Título:Phosphorylation of Human Choline Kinase Beta by Protein Kinase A: Its Impact on Activity and Inhibition.
[So] Source:PLoS One;11(5):e0154702, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Choline kinase beta (CKß) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. CKß is important for normal mitochondrial function and muscle development as the lack of the ckß gene in human and mice results in the development of muscular dystrophy. In contrast, CKα is implicated in tumorigenesis and has been extensively studied as an anticancer target. Phosphorylation of human CKα was found to regulate the enzyme's activity and its subcellular location. This study provides evidence for CKß phosphorylation by protein kinase A (PKA). In vitro phosphorylation of CKß by PKA was first detected by phosphoprotein staining, as well as by in-gel kinase assays. The phosphorylating kinase was identified as PKA by Western blotting. CKß phosphorylation by MCF-7 cell lysate was inhibited by a PKA-specific inhibitor peptide, and the intracellular phosphorylation of CKß was shown to be regulated by the level of cyclic adenosine monophosphate (cAMP), a PKA activator. Phosphorylation sites were located on CKß residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKß phosphorylation mimic behaved kinetically very similar. Remarkably, phosphorylation drastically increased the sensitivity of CKß to hemicholinium-3 (HC-3) inhibition by about 30-fold. These findings suggest that CKß, in concert with CKα, and depending on its phosphorylation status, might play a critical role as a druggable target in carcinogenesis.
[Mh] Termos MeSH primário: Colina Quinase/metabolismo
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Colina Quinase/antagonistas & inibidores
Seres Humanos
Fosforilação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.1.32 (Choline Kinase); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
[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:160506
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0154702


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[PMID]:27123443
[Au] Autor:Yis U; Baydan F; Karakaya M; Hiz Kurul S; Cirak S
[Ad] Endereço:Division of Child Neurology, Department of Pediatrics, School of Medicine, Dokuz Eylül University, 35340 Izmir, Turkey.
[Ti] Título:Importance of Skin Changes in the Differential Diagnosis of Congenital Muscular Dystrophies.
[So] Source:Biomed Res Int;2016:3128735, 2016.
[Is] ISSN:2314-6141
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Megaconial congenital muscular dystrophy (OMIM 602541) is characterized with early-onset hypotonia, muscle wasting, proximal weakness, cardiomyopathy, mildly elevated serum creatine kinase (CK) levels, and mild-to-moderate intellectual disability. We report two siblings in a consanguineous family admitted for psychomotor delay. Physical examination revealed proximal muscle weakness, contractures in the knee of elder sibling, diffuse mild generalized muscle atrophy, and dry skin with ichthyosis together with multiple nummular eczema in both siblings. Serum CK values were elevated up to 500 U/L. For genetic work-up, we performed whole exome sequencing (WES) after Nimblegen enrichment on the Illumina platform. The WES revealed a novel homozygous missense mutation in the Choline Kinase-Beta (CHKB) gene c.1031G>A (p.R344Q) in exon 9. Ichthyosis-like skin changes with intense pruritus and nummular eczema may lead to clinical diagnosis in cases with megaconial congenital muscular dystrophy.
[Mh] Termos MeSH primário: Colina Quinase/genética
Deficiência Intelectual/genética
Miopatias Mitocondriais/genética
Distrofias Musculares/genética
[Mh] Termos MeSH secundário: Criança
Pré-Escolar
Diagnóstico Diferencial
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Ictiose/diagnóstico
Ictiose/genética
Ictiose/fisiopatologia
Deficiência Intelectual/diagnóstico
Deficiência Intelectual/fisiopatologia
Miopatias Mitocondriais/diagnóstico
Miopatias Mitocondriais/fisiopatologia
Distrofias Musculares/diagnóstico
Distrofias Musculares/fisiopatologia
Mutação
Prurido/diagnóstico
Prurido/genética
Prurido/fisiopatologia
Transtornos Psicomotores/diagnóstico
Transtornos Psicomotores/genética
Transtornos Psicomotores/fisiopatologia
Irmãos
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.1.32 (CHKB protein, human); EC 2.7.1.32 (Choline Kinase)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170131
[Lr] Data última revisão:
170131
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160429
[St] Status:MEDLINE
[do] DOI:10.1155/2016/3128735


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[PMID]:27073147
[Au] Autor:Arlauckas SP; Popov AV; Delikatny EJ
[Ad] Endereço:Department of Radiology, 317 Anatomy-Chemistry Building, 3620 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104, USA.
[Ti] Título:Choline kinase alpha-Putting the ChoK-hold on tumor metabolism.
[So] Source:Prog Lipid Res;63:28-40, 2016 07.
[Is] ISSN:1873-2194
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:It is well established that lipid metabolism is drastically altered during tumor development and response to therapy. Choline kinase alpha (ChoKα) is a key mediator of these changes, as it represents the first committed step in the Kennedy pathway of phosphatidylcholine biosynthesis and ChoKα expression is upregulated in many human cancers. ChoKα activity is associated with drug resistant, metastatic, and malignant phenotypes, and represents a robust biomarker and therapeutic target in cancer. Effective ChoKα inhibitors have been developed and have recently entered clinical trials. ChoKα's clinical relevance was, until recently, attributed solely to its production of second messenger intermediates of phospholipid synthesis. The recent discovery of a non-catalytic scaffolding function of ChoKα may link growth receptor signaling to lipid biogenesis and requires a reinterpretation of the design and validation of ChoKα inhibitors. Advances in positron emission tomography, magnetic resonance spectroscopy, and optical imaging methods now allow for a comprehensive understanding of ChoKα expression and activity in vivo. We will review the current understanding of ChoKα metabolism, its role in tumor biology and the development and validation of targeted therapies and companion diagnostics for this important regulatory enzyme. This comes at a critical time as ChoKα-targeting programs receive more clinical interest.
[Mh] Termos MeSH primário: Neoplasias Encefálicas/metabolismo
Colina Quinase/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Neoplasias Encefálicas/diagnóstico por imagem
Neoplasias Encefálicas/tratamento farmacológico
Neoplasias Encefálicas/patologia
Colina Quinase/antagonistas & inibidores
Colina Quinase/genética
Diacilglicerol Colinofosfotransferase/metabolismo
Inibidores Enzimáticos/metabolismo
Inibidores Enzimáticos/uso terapêutico
Inibidores Enzimáticos/toxicidade
Hemicolínio 3/metabolismo
Hemicolínio 3/uso terapêutico
Hemicolínio 3/toxicidade
Seres Humanos
Espectroscopia de Ressonância Magnética
Tomografia por Emissão de Pósitrons
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; REVIEW
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 312-45-8 (Hemicholinium 3); EC 2.7.1.32 (Choline Kinase); EC 2.7.8.2 (Diacylglycerol Cholinephosphotransferase)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170701
[Lr] Data última revisão:
170701
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160414
[St] Status:MEDLINE



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