Base de dados : MEDLINE
Pesquisa : D13.695.827 [Categoria DeCS]
Referências encontradas : 4683 [refinar]
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[PMID]:28977480
[Au] Autor:Peralta-Castro A; Baruch-Torres N; Brieba LG
[Ad] Endereço:Laboratorio Nacional de Genómica para la Biodiversidad, Centro de Investigación y de Estudios Avanzados del IPN, Apartado Postal 629, Irapuato, Guanajuato, CP 36821, México.
[Ti] Título:Plant organellar DNA primase-helicase synthesizes RNA primers for organellar DNA polymerases using a unique recognition sequence.
[So] Source:Nucleic Acids Res;45(18):10764-10774, 2017 Oct 13.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:DNA primases recognize single-stranded DNA (ssDNA) sequences to synthesize RNA primers during lagging-strand replication. Arabidopsis thaliana encodes an ortholog of the DNA primase-helicase from bacteriophage T7, dubbed AtTwinkle, that localizes in chloroplasts and mitochondria. Herein, we report that AtTwinkle synthesizes RNA primers from a 5'-(G/C)GGA-3' template sequence. Within this sequence, the underlined nucleotides are cryptic, meaning that they are essential for template recognition but are not instructional during RNA synthesis. Thus, in contrast to all primases characterized to date, the sequence recognized by AtTwinkle requires two nucleotides (5'-GA-3') as a cryptic element. The divergent zinc finger binding domain (ZBD) of the primase module of AtTwinkle may be responsible for template sequence recognition. During oligoribonucleotide synthesis, AtTwinkle shows a strong preference for rCTP as its initial ribonucleotide and a moderate preference for rGMP or rCMP incorporation during elongation. RNA products synthetized by AtTwinkle are efficiently used as primers for plant organellar DNA polymerases. In sum, our data strongly suggest that AtTwinkle primes organellar DNA polymerases during lagging strand synthesis in plant mitochondria and chloroplast following a primase-mediated mechanism. This mechanism contrasts to lagging-strand DNA replication in metazoan mitochondria, in which transcripts synthesized by mitochondrial RNA polymerase prime mitochondrial DNA polymerase γ.
[Mh] Termos MeSH primário: Proteínas de Arabidopsis/metabolismo
DNA Helicases/metabolismo
DNA Primase/metabolismo
DNA Polimerase Dirigida por DNA/metabolismo
Enzimas Multifuncionais/metabolismo
RNA/biossíntese
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Proteínas de Arabidopsis/química
Proteínas de Arabidopsis/genética
Sequência de Bases
Proteínas de Cloroplastos/química
Proteínas de Cloroplastos/genética
Proteínas de Cloroplastos/metabolismo
Sequência Conservada
DNA Helicases/química
DNA Helicases/genética
DNA Primase/química
DNA Primase/genética
DNA de Cadeia Simples/química
Proteínas Mitocondriais/química
Proteínas Mitocondriais/genética
Proteínas Mitocondriais/metabolismo
Enzimas Multifuncionais/química
Enzimas Multifuncionais/genética
Ligação Proteica
Ribonucleotídeos/biossíntese
Moldes Genéticos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arabidopsis Proteins); 0 (Chloroplast Proteins); 0 (DNA, Single-Stranded); 0 (Mitochondrial Proteins); 0 (Multifunctional Enzymes); 0 (RNA primers); 0 (Ribonucleotides); 0 (Twinkle protein, Arabidopsis); 63231-63-0 (RNA); EC 2.7.7.- (DNA Primase); EC 2.7.7.7 (DNA-Directed DNA Polymerase); EC 3.6.4.- (DNA Helicases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx745


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[PMID]:28911097
[Au] Autor:Moon AF; Pryor JM; Ramsden DA; Kunkel TA; Bebenek K; Pedersen LC
[Ad] Endereço:Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
[Ti] Título:Structural accommodation of ribonucleotide incorporation by the DNA repair enzyme polymerase Mu.
[So] Source:Nucleic Acids Res;45(15):9138-9148, 2017 Sep 06.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:While most DNA polymerases discriminate against ribonucleotide triphosphate (rNTP) incorporation very effectively, the Family X member DNA polymerase µ (Pol µ) incorporates rNTPs almost as efficiently as deoxyribonucleotides. To gain insight into how this occurs, here we have used X-ray crystallography to describe the structures of pre- and post-catalytic complexes of Pol µ with a ribonucleotide bound at the active site. These structures reveal that Pol µ binds and incorporates a rNTP with normal active site geometry and no distortion of the DNA substrate or nucleotide. Moreover, a comparison of rNTP incorporation kinetics by wildtype and mutant Pol µ indicates that rNTP accommodation involves synergistic interactions with multiple active site residues not found in polymerases with greater discrimination. Together, the results are consistent with the hypothesis that rNTP incorporation by Pol µ is advantageous in gap-filling synthesis during DNA double strand break repair by nonhomologous end joining, particularly in nonreplicating cells containing very low deoxyribonucleotide concentrations.
[Mh] Termos MeSH primário: Reparo do DNA por Junção de Extremidades
DNA Polimerase Dirigida por DNA/química
DNA/química
Desoxirribonucleotídeos/química
Ribonucleotídeos/química
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Sequência de Bases
Domínio Catalítico
Clonagem Molecular
Cristalografia por Raios X
DNA/metabolismo
DNA Polimerase Dirigida por DNA/genética
DNA Polimerase Dirigida por DNA/metabolismo
Desoxirribonucleotídeos/metabolismo
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Seres Humanos
Cinética
Modelos Moleculares
Conformação de Ácido Nucleico
Ligação Proteica
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Domínios e Motivos de Interação entre Proteínas
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Ribonucleotídeos/metabolismo
Especificidade por Substrato
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Deoxyribonucleotides); 0 (Recombinant Proteins); 0 (Ribonucleotides); 9007-49-2 (DNA); EC 2.7.7.- (DNA polymerase mu); EC 2.7.7.7 (DNA-Directed DNA Polymerase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170916
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx527


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[PMID]:28719670
[Au] Autor:Matoba R; Morizane Y; Shiode Y; Hirano M; Doi S; Toshima S; Araki R; Hosogi M; Yonezawa T; Shiraga F
[Ad] Endereço:Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
[Ti] Título:Suppressive effect of AMP-activated protein kinase on the epithelial-mesenchymal transition in retinal pigment epithelial cells.
[So] Source:PLoS One;12(7):e0181481, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The epithelial-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells plays a central role in the development of proliferative vitreoretinopathy (PVR). The purpose of this study was to investigate the effect of AMP-activated protein kinase (AMPK), a key regulator of energy homeostasis, on the EMT in RPE cells. In this study, EMT-associated formation of cellular aggregates was induced by co-stimulation of cultured ARPE-19 cells with tumor necrosis factor (TNF)-α (10 ng/ml) and transforming growth factor (TGF)-ß2 (5 ng/ml). 5-Aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR), a potent activator of AMPK, significantly suppressed TNF-α and TGF-ß2-induced cellular aggregate formation (p < 0.01). Dipyridamole almost completely reversed the suppressive effect of AICAR, whereas 5'-amino-5'-deoxyadenosine restored aggregate formation by approximately 50%. AICAR suppressed the downregulation of E-cadherin and the upregulation of fibronectin and α-smooth muscle actin by TNF-α and TGF-ß2. The levels of matrix metalloproteinase (MMP)-2, MMP-9, interleukin-6, and vascular endothelial growth factor were significantly decreased by AICAR. Activation of the mitogen-activated protein kinase and mammalian target of rapamycin pathways, but not the Smad pathway, was inhibited by AICAR. These findings indicate that AICAR suppresses the EMT in RPE cells at least partially via activation of AMPK. AMPK is a potential target molecule for the prevention and treatment of PVR, so AICAR may be a promising candidate for PVR therapy.
[Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/metabolismo
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Epitélio Pigmentado da Retina/citologia
[Mh] Termos MeSH secundário: Aminoimidazol Carboxamida/análogos & derivados
Aminoimidazol Carboxamida/farmacologia
Agregação Celular/efeitos dos fármacos
Linhagem Celular
Sinergismo Farmacológico
Ativação Enzimática/efeitos dos fármacos
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Interleucina-6/metabolismo
Metaloproteinase 2 da Matriz/metabolismo
Metaloproteinase 9 da Matriz/metabolismo
Ribonucleotídeos/farmacologia
Fator de Crescimento Transformador beta2/farmacologia
Fator de Necrose Tumoral alfa/farmacologia
Fator A de Crescimento do Endotélio Vascular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interleukin-6); 0 (Ribonucleotides); 0 (Transforming Growth Factor beta2); 0 (Tumor Necrosis Factor-alpha); 0 (Vascular Endothelial Growth Factor A); 360-97-4 (Aminoimidazole Carboxamide); EC 2.7.11.31 (AMP-Activated Protein Kinases); EC 3.4.24.24 (Matrix Metalloproteinase 2); EC 3.4.24.35 (Matrix Metalloproteinase 9); F0X88YW0YK (AICA ribonucleotide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181481


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[PMID]:28669113
[Au] Autor:Yarus M
[Ad] Endereço:Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, 80309-0347, USA. yarus@stripe.colorado.edu.
[Ti] Título:Efficient Heritable Gene Expression Readily Evolves in RNA Pools.
[So] Source:J Mol Evol;84(5-6):236-252, 2017 Jun.
[Is] ISSN:1432-1432
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Heritable gene expression arises readily in a simple non-genetic system employing known small-RNA biochemistry. Pooled cross-templating ribonucleotides show varied chemical competence on which selection acts, even calculating only minimal effects. Evolution can be quick-computed progress toward encoded gene expression can require only days or weeks for two millimolar, partly activated complementary 5' ribonucleotides. After only one product selection cycle, early templating can become prevailing pool behavior. Subsequently, a selected templated product is efficiently amplified as a pool ages, frequently accumulated in the same order of concentration as incoming nucleotides. Pools spontaneously favor templating because sporadic nucleotide accumulations increase it-and selection increases templating in pools of all ages. Nonetheless, templated chemical competence appears most easily in young pools. Pool history is critical-pools can perish from periodic hazards (like tides), or alternatively, from hazards roughly constant in time (like rainfall). Selection is greatly enhanced in constant hazard pools-more effective if pools have varied ages. Stronger selection is disproportionately more effective. Selected evolutionary change has an uncomplicated molecular basis-progress from chemical product synthesis to templated, proto-genetic inheritance exploits identity between templating and entropic catalysis. Though discovered by computation, selection of an elevated product of template catalysis is plausible, independent of any chemical or mathematical assumption. Selected chemical variation before genetics (chance utility) therefore inaugurates inheritance, even when hindered by unstable, dilute nucleotides, erratically supplied in undependable quantities. Remarkably, such uncontrolled conditions are not necessarily hostile, but can instead accelerate appearance of primordial gene-like behavior.
[Mh] Termos MeSH primário: RNA/química
RNA/genética
[Mh] Termos MeSH secundário: Expressão Gênica/genética
Nucleotídeos/genética
Origem da Vida
Ribonucleotídeos/genética
Seleção Genética/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nucleotides); 0 (Ribonucleotides); 63231-63-0 (RNA)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170703
[St] Status:MEDLINE
[do] DOI:10.1007/s00239-017-9800-1


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[PMID]:28627020
[Au] Autor:Biswas A; Shukla A; Chaudhary SK; Santhosh R; Jeyakanthan J; Sekar K
[Ad] Endereço:Department of Physics, Indian Institute of Science, Bangalore, India.
[Ti] Título:Structural studies of a hyperthermophilic thymidylate kinase enzyme reveal conformational substates along the reaction coordinate.
[So] Source:FEBS J;284(15):2527-2544, 2017 Aug.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Thymidylate kinase (TMK) is a key enzyme which plays an important role in DNA synthesis. It belongs to the family of nucleoside monophosphate kinases, several of which undergo structure-encoded conformational changes to perform their function. However, the absence of three-dimensional structures for all the different reaction intermediates of a single TMK homolog hinders a clear understanding of its functional mechanism. We herein report the different conformational states along the reaction coordinate of a hyperthermophilic TMK from Aquifex aeolicus, determined via X-ray diffraction and further validated through normal-mode studies. The analyses implicate an arginine residue in the Lid region in catalysis, which was confirmed through site-directed mutagenesis and subsequent enzyme assays on the wild-type protein and mutants. Furthermore, the enzyme was found to exhibit broad specificity toward phosphate group acceptor nucleotides. Our comprehensive analyses of the conformational landscape of TMK, together with associated biochemical experiments, provide insights into the mechanistic details of TMK-driven catalysis, for example, the order of substrate binding and the reaction mechanism for phosphate transfer. Such a study has utility in the design of potent inhibitors for these enzymes. DATABASE: Structural data are available in the PDB under the accession numbers 2PBR, 4S2E, 5H5B, 5XAI, 4S35, 5XB2, 5H56, 5XB3, 5H5K, 5XB5, and 5XBH.
[Mh] Termos MeSH primário: Bactérias Termodúricas/enzimologia
Proteínas de Bactérias/metabolismo
Modelos Moleculares
Núcleosídeo-Fosfato Quinase/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Substituição de Aminoácidos
Apoenzimas/química
Apoenzimas/genética
Apoenzimas/metabolismo
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Biocatálise
Domínio Catalítico
Cristalografia por Raios X
Estabilidade Enzimática
Holoenzimas/química
Holoenzimas/genética
Holoenzimas/metabolismo
Ligantes
Mutagênese Sítio-Dirigida
Mutação
Núcleosídeo-Fosfato Quinase/química
Núcleosídeo-Fosfato Quinase/genética
Conformação Proteica
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Ribonucleotídeos/química
Ribonucleotídeos/metabolismo
Alinhamento de Sequência
Especificidade por Substrato
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apoenzymes); 0 (Bacterial Proteins); 0 (Holoenzymes); 0 (Ligands); 0 (Recombinant Proteins); 0 (Ribonucleotides); EC 2.7.4.4 (Nucleoside-Phosphate Kinase); EC 2.7.4.9 (dTMP kinase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170620
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14140


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[PMID]:28595015
[Au] Autor:Zhou S; Mahmoud S; Liu P; Zhou L; Ehteshami M; Bassit L; Tao S; Domaoal RA; Sari O; Schutter C; Amiralaei S; Khalil A; Ollinger Russell O; McBrayer T; Whitaker T; Abou-Taleb N; Amblard F; Coats SJ; Schinazi RF
[Ad] Endereço:Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine , Atlanta, Georgia 30307, United States.
[Ti] Título:2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
[So] Source:J Med Chem;60(13):5424-5437, 2017 Jul 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a ß-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
[Mh] Termos MeSH primário: Antivirais/farmacologia
Hepacivirus/efeitos dos fármacos
Pró-Fármacos/farmacologia
Ribonucleotídeos/farmacologia
[Mh] Termos MeSH secundário: Antivirais/síntese química
Antivirais/química
Células Cultivadas
Relação Dose-Resposta a Droga
Genótipo
Células Hep G2
Hepacivirus/genética
Seres Humanos
Testes de Sensibilidade Microbiana
Estrutura Molecular
Pró-Fármacos/síntese química
Pró-Fármacos/química
Ribonucleotídeos/síntese química
Ribonucleotídeos/química
Relação Estrutura-Atividade
Proteínas não Estruturais Virais/antagonistas & inibidores
Proteínas não Estruturais Virais/metabolismo
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (NS-5 protein, hepatitis C virus); 0 (Prodrugs); 0 (Ribonucleotides); 0 (Viral Nonstructural Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170609
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00067


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[PMID]:28494020
[Au] Autor:Iwamoto T; Nakamura T; Ishikawa M; Yoshizaki K; Sugimoto A; Ida-Yonemochi H; Ohshima H; Saito M; Yamada Y; Fukumoto S
[Ad] Endereço:Department of Pediatric Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, Kuramoto-cho, Tokushima, Japan.
[Ti] Título:Pannexin 3 regulates proliferation and differentiation of odontoblasts via its hemichannel activities.
[So] Source:PLoS One;12(5):e0177557, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Highly coordinated regulation of cell proliferation and differentiation contributes to the formation of functionally shaped and sized teeth; however, the mechanism underlying the switch from cell cycle exit to cell differentiation during odontogenesis is poorly understood. Recently, we identified pannexin 3 (Panx3) as a member of the pannexin gap junction protein family from tooth germs. The expression of Panx3 was predominately localized in preodontoblasts that arise from dental papilla cells and can differentiate into dentin-secreting odontoblasts. Panx3 also co-localized with p21, a cyclin-dependent kinase inhibitor protein, in preodontoblasts. Panx3 was expressed in primary dental mesenchymal cells and in the mDP dental mesenchymal cell line. Both Panx3 and p21 were induced during the differentiation of mDP cells. Overexpression of Panx3 in mDP cells reduced cell proliferation via up-regulation of p21, but not of p27, and promoted the Bone morphogenetic protein 2 (BMP2)-induced phosphorylation of Smad1/5/8 and the expression of dentin sialophosphoprotein (Dspp), a marker of differentiated odontoblasts. Furthermore, Panx3 released intracellular ATP into the extracellular space through its hemichannel and induced the phosphorylation of AMP-activated protein kinase (AMPK). 5-Aminoimidazole-4-carboxamide-ribonucleoside (AICAR), an activator of AMPK, reduced mDP cell proliferation and induced p21 expression. Conversely, knockdown of endogenous Panx3 by siRNA inhibited AMPK phosphorylation, p21 expression, and the phosphorylation of Smad1/5/8 even in the presence of BMP2. Taken together, our results suggest that Panx3 modulates intracellular ATP levels, resulting in the inhibition of odontoblast proliferation through the AMPK/p21 signaling pathway and promotion of cell differentiation by the BMP/Smad signaling pathway.
[Mh] Termos MeSH primário: Diferenciação Celular
Conexinas/metabolismo
Odontoblastos/citologia
Odontoblastos/metabolismo
[Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/metabolismo
Trifosfato de Adenosina/metabolismo
Aminoimidazol Carboxamida/análogos & derivados
Aminoimidazol Carboxamida/farmacologia
Animais
Proteínas Morfogenéticas Ósseas/metabolismo
Diferenciação Celular/efeitos dos fármacos
Diferenciação Celular/genética
Proliferação Celular/efeitos dos fármacos
Conexinas/genética
Inibidor de Quinase Dependente de Ciclina p21/metabolismo
Papila Dentária/citologia
Ativação Enzimática/efeitos dos fármacos
Proteínas da Matriz Extracelular/metabolismo
Regulação da Expressão Gênica/efeitos dos fármacos
Espaço Intracelular/metabolismo
Camundongos Endogâmicos ICR
Modelos Biológicos
Odontoblastos/efeitos dos fármacos
Fosfoproteínas/metabolismo
Fosforilação/efeitos dos fármacos
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
RNA Interferente Pequeno/metabolismo
Ribonucleotídeos/farmacologia
Sialoglicoproteínas/metabolismo
Transdução de Sinais/efeitos dos fármacos
Proteínas Smad/metabolismo
Germe de Dente/metabolismo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bone Morphogenetic Proteins); 0 (Connexins); 0 (Cyclin-Dependent Kinase Inhibitor p21); 0 (Extracellular Matrix Proteins); 0 (Phosphoproteins); 0 (RNA, Messenger); 0 (RNA, Small Interfering); 0 (Ribonucleotides); 0 (Sialoglycoproteins); 0 (Smad Proteins); 0 (dentin sialophosphoprotein); 0 (pannexin 3 protein, mouse); 360-97-4 (Aminoimidazole Carboxamide); 8L70Q75FXE (Adenosine Triphosphate); EC 2.7.11.31 (AMP-Activated Protein Kinases); F0X88YW0YK (AICA ribonucleotide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170512
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0177557


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[PMID]:28408437
[Au] Autor:Dejure FR; Royla N; Herold S; Kalb J; Walz S; Ade CP; Mastrobuoni G; Vanselow JT; Schlosser A; Wolf E; Kempa S; Eilers M
[Ad] Endereço:Theodor Boveri Institute and Comprehensive Cancer Center Mainfranken, Biocenter, University of Würzburg, Würzburg, Germany.
[Ti] Título:The mRNA 3'-UTR couples RNA polymerase II function to glutamine and ribonucleotide levels.
[So] Source:EMBO J;36(13):1854-1868, 2017 Jul 03.
[Is] ISSN:1460-2075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Deregulated expression of enhances glutamine utilization and renders cell survival dependent on glutamine, inducing "glutamine addiction". Surprisingly, colon cancer cells that express high levels of due to WNT pathway mutations are not glutamine-addicted but undergo a reversible cell cycle arrest upon glutamine deprivation. We show here that glutamine deprivation suppresses translation of endogenous via the 3'-UTR of the mRNA, enabling escape from apoptosis. This regulation is mediated by glutamine-dependent changes in adenosine-nucleotide levels. Glutamine deprivation causes a global reduction in promoter association of RNA polymerase II (RNAPII) and slows transcriptional elongation. While activation of MYC restores binding of MYC and RNAPII function on most promoters, restoration of elongation is imperfect and activation of MYC in the absence of glutamine causes stalling of RNAPII on multiple genes, correlating with R-loop formation. Stalling of RNAPII and R-loop formation can cause DNA damage, arguing that the 3'-UTR is critical for maintaining genome stability when ribonucleotide levels are low.
[Mh] Termos MeSH primário: Regiões 3´ não Traduzidas
Regulação Enzimológica da Expressão Gênica
Glutamina/metabolismo
Proteínas Proto-Oncogênicas c-myc/biossíntese
RNA Polimerase II/metabolismo
RNA Mensageiro/metabolismo
Ribonucleotídeos/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular
Seres Humanos
Proteínas Proto-Oncogênicas c-myc/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (MYC protein, human); 0 (Proto-Oncogene Proteins c-myc); 0 (RNA, Messenger); 0 (Ribonucleotides); 0RH81L854J (Glutamine); EC 2.7.7.- (RNA Polymerase II)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170415
[St] Status:MEDLINE
[do] DOI:10.15252/embj.201796662


  9 / 4683 MEDLINE  
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[PMID]:28335578
[Au] Autor:Li Z; Guo JR; Chen QQ; Wang CY; Zhang WJ; Yao MC; Zhang W
[Ad] Endereço:State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China. lizhengcpu@163.com.
[Ti] Título:Exploring the Antitumor Mechanism of High-Dose Cytarabine through the Metabolic Perturbations of Ribonucleotide and Deoxyribonucleotide in Human Promyelocytic Leukemia HL-60 Cells.
[So] Source:Molecules;22(3), 2017 Mar 21.
[Is] ISSN:1420-3049
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Despite the apparent clinical benefits of high-dose cytarabine (Ara-C) over lower dose Ara-C in acute myeloid leukemia (AML) therapy, the mechanism behind high-dose Ara-C therapy remains uncertain. In this study, a LC-MS-based method was carried out to investigate the metabolic alteration of ribonucleotide and deoxyribonucleotide in human promyelocytic leukemia cells (HL-60) after treatment with Ara-C to reveal its antitumor mechanism. The metabolic results revealed that four nucleotides (ATP, ADP, CDP, and dCTP) could be used as potential biomarkers indicating the benefit of high-dose Ara-C over lower dose Ara-C treatment. Combining metabolic perturbation and cell cycle analysis, we conjectured that, apart from the acknowledged mechanism of Ara-C on tumor inhibition, high-dose Ara-C could present a specific action pathway. It was suggested that the pronounced rise in AMP/ATP ratio induced by high-dose Ara-C can trigger AMP-activated protein kinase (AMPK) and subsequently Forkhead Box, class O (FoxO), to promote cell cycle arrest. Moreover, the significant decrease in CDP pool induced by high-dose Ara-C might further accelerate the reduction of dCTP, which then aggravates DNA synthesis disturbance. As a result, all of these alterations led to heightened tumor inhibition. This study provides new insight in the investigation of potential mechanisms in the clinical benefits of high-dose Ara-C in therapy for AML.
[Mh] Termos MeSH primário: Antimetabólitos Antineoplásicos/farmacologia
Citarabina/farmacologia
Desoxirribonucleotídeos/análise
Ribonucleotídeos/análise
[Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/metabolismo
Ciclo Celular/efeitos dos fármacos
Cromatografia Gasosa-Espectrometria de Massas
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Células HL-60
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimetabolites, Antineoplastic); 0 (Deoxyribonucleotides); 0 (Ribonucleotides); 04079A1RDZ (Cytarabine); EC 2.7.11.31 (AMP-Activated Protein Kinases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170325
[St] Status:MEDLINE


  10 / 4683 MEDLINE  
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[PMID]:28325600
[Au] Autor:Alaoui S; Dufies M; Driowya M; Demange L; Bougrin K; Robert G; Auberger P; Pagès G; Benhida R
[Ad] Endereço:Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272, 06108 Nice, France; Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, URAC23, Faculté des Sciences, Université Mohammed V, B.P. 1014 Rabat, Morocco.
[Ti] Título:Synthesis and anti-cancer activities of new sulfonamides 4-substituted-triazolyl nucleosides.
[So] Source:Bioorg Med Chem Lett;27(9):1989-1992, 2017 05 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nucleoside analogues are among the most known drugs commonly used in antiviral and anticancer chemotherapies. Among them, those featuring a five-membered ring nucleobase are of utmost interest such as the anti-cancer agent AICAR or the anti-viral drug ribavirin. Despite its low activity in vitro in different cell lines, AICAR is under clinical development for several pathologies, thanks to its original mode of action. Indeed, AICAR induced autophagy cell death and is able, following this mechanism, to circumvent resistance to apoptotic drugs including kinase inhibitors currently on the market. To improve the activity of AICAR, we report herein an efficient synthesis of new series of sulfonamide-4-substituted-1,2,3-triazolyl nucleosides using a Cu-catalyzed 1,3-dipolar cycloaddition. All these molecules have been fully characterized and evaluated against two aggressive tumor cell lines, RCC4 and MDA-MB-231. Among them, nucleoside analogue 5i belonging to the ribose series was found to be 19 to 66-fold more active than AICAR. Western blot analyses on RCC4 cells showed that 5i displayed an interesting mode of action by inducing both apoptosis and autophagy cell death, making therefore this class of molecules highly promising for further hit-to-lead optimization.
[Mh] Termos MeSH primário: Antineoplásicos/química
Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Nucleosídeos/química
Nucleosídeos/farmacologia
Sulfonamidas/química
Sulfonamidas/farmacologia
[Mh] Termos MeSH secundário: Aminoimidazol Carboxamida/análogos & derivados
Aminoimidazol Carboxamida/síntese química
Aminoimidazol Carboxamida/química
Aminoimidazol Carboxamida/farmacologia
Antineoplásicos/síntese química
Linhagem Celular Tumoral
Reação de Cicloadição
Seres Humanos
Neoplasias/tratamento farmacológico
Nucleosídeos/síntese química
Ribonucleotídeos/síntese química
Ribonucleotídeos/química
Ribonucleotídeos/farmacologia
Sulfonamidas/síntese química
Triazóis/síntese química
Triazóis/química
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Nucleosides); 0 (Ribonucleotides); 0 (Sulfonamides); 0 (Triazoles); 360-97-4 (Aminoimidazole Carboxamide); F0X88YW0YK (AICA ribonucleotide)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170323
[St] Status:MEDLINE



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