Base de dados : MEDLINE
Pesquisa : G04.144.220.625 [Categoria DeCS]
Referências encontradas : 968 [refinar]
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[PMID]:28282748
[Au] Autor:Loprinzi PD; Loenneke JP
[Ad] Endereço:a Physical Activity Epidemiology Laboratory, Exercise Psychology Laboratory, Department of Health, Exercise Science and Recreation Management , The University of Mississippi , University , MS , USA.
[Ti] Título:Leukocyte telomere length and mortality among U.S. adults: Effect modification by physical activity behaviour.
[So] Source:J Sports Sci;36(2):213-219, 2018 Jan.
[Is] ISSN:1466-447X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The purpose of this study was to examine the association between leukocyte telomere length (LTL) and mortality (outcome variable), with consideration by physical activity behaviour. Data from the 1999-2002 National Health and Nutrition Examination Survey were employed (N = 6,611; 20-85 yrs), with follow-up mortality assessment through 31 December 2006. DNA was extracted from whole blood to assess LTL via quantitative polymerase chain reaction. Compared to those in the first LTL tertile, the adjusted hazard ratio for all-cause mortality for those in the 2 and 3 LTL tertiles, respectively, was 0.82 (95% CI: 0.60-1.12; P = .22) and 0.76 (95% CI: 0.50-1.14; P = .18). However, after adjustments, LTL tertile 3 (vs. 1) was associated with all-cause mortality (HR = 0.37; 95% CI: 0.14-0.93; P = .03) for those who engaged in moderate-intensity exercise. Similarly, LTL was associated with CVD-specific mortality for those who engaged in moderate-intensity exercise (HR = 0.17; 95% CI: 0.04-0.73; P = .02). Longer telomeres are associated with increased survival, particularly among men and those who are active, underscoring the importance of promotion of physical activity behaviour.
[Mh] Termos MeSH primário: Exercício/fisiologia
Leucócitos/fisiologia
Mortalidade
Homeostase do Telômero
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Envelhecimento/fisiologia
Doenças Cardiovasculares/mortalidade
Feminino
Seres Humanos
Masculino
Meia-Idade
Inquéritos Nutricionais
Estados Unidos/epidemiologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170312
[St] Status:MEDLINE
[do] DOI:10.1080/02640414.2017.1293280


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[PMID]:29321523
[Au] Autor:Chudasama P; Mughal SS; Sanders MA; Hübschmann D; Chung I; Deeg KI; Wong SH; Rabe S; Hlevnjak M; Zapatka M; Ernst A; Kleinheinz K; Schlesner M; Sieverling L; Klink B; Schröck E; Hoogenboezem RM; Kasper B; Heilig CE; Egerer G; Wolf S; von Kalle C; Eils R; Stenzinger A; Weichert W; Glimm H; Gröschel S; Kopp HG; Omlor G; Lehner B; Bauer S; Schimmack S; Ulrich A; Mechtersheimer G; Rippe K; Brors B; Hutter B; Renner M; Hohenberger P; Scholl C; Fröhling S
[Ad] Endereço:Division of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
[Ti] Título:Integrative genomic and transcriptomic analysis of leiomyosarcoma.
[So] Source:Nat Commun;9(1):144, 2018 01 10.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Leiomyosarcoma (LMS) is an aggressive mesenchymal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. Here we show, using whole-exome and transcriptome sequencing, that LMS tumors are characterized by substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations including chromothripsis, and frequent whole-genome duplication. Furthermore, we detect alternative telomere lengthening in 78% of cases and identify recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and SP100, providing insight into the genetic basis of this mechanism. Finally, most tumors display hallmarks of "BRCAness", including alterations in homologous recombination DNA repair genes, multiple structural rearrangements, and enrichment of specific mutational signatures, and cultured LMS cells are sensitive towards olaparib and cisplatin. This comprehensive study of LMS genomics has uncovered key biological features that may inform future experimental research and enable the design of novel therapies.
[Mh] Termos MeSH primário: Leiomiossarcoma/genética
Leiomiossarcoma/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Cromotripsia
Variações do Número de Cópias de DNA
Feminino
Duplicação Gênica
Perfilação da Expressão Gênica
Genes do Retinoblastoma
Genes p53
Genômica
Seres Humanos
Masculino
Meia-Idade
Mutação
Análise de Sequência de RNA
Homeostase do Telômero
Sequenciamento Completo do Exoma
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02602-0


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[PMID]:28462821
[Au] Autor:de Witte SFH; Lambert EE; Merino A; Strini T; Douben HJCW; O'Flynn L; Elliman SJ; de Klein AJEMM; Newsome PN; Baan CC; Hoogduijn MJ
[Ad] Endereço:Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. Electronic address: s.dewitte@erasmusmc.nl.
[Ti] Título:Aging of bone marrow- and umbilical cord-derived mesenchymal stromal cells during expansion.
[So] Source:Cytotherapy;19(7):798-807, 2017 07.
[Is] ISSN:1477-2566
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) are used as experimental immunotherapy. Extensive culture expansion is necessary to obtain clinically relevant cell numbers, although the impact on MSCs stability and function is unclear. This study investigated the effects of long-term in vitro expansion on the stability and function of MSCs. METHODS: Human bone marrow-derived (bmMSCs) and umbilical cord-derived (ucMSCs) MSCs were in vitro expanded. During expansion, their proliferative capacity was examined. At passages 4, 8 and 12, analyses were performed to investigate the ploidy, metabolic stability, telomere length and immunophenotype. In addition, their potential to suppress lymphocyte proliferation and susceptibility to natural killer cell lysis was examined. RESULTS: BmMSCs and ucMSCs showed decreasing proliferative capacity over time, while their telomere lengths and mitochondrial activity remained stable. Percentage of aneuploidy in cultures was unchanged after expansion. Furthermore, expression of MSC markers and markers associated with stress or aging remained unchanged. Reduced capacity to suppress CD4 and CD8 T-cell proliferation was observed for passage 8 and 12 bmMSCs and ucMSCs. Finally, susceptibility of bmMSCs and ucMSCs to NK-cell lysis remained stable. CONCLUSIONS: We showed that after long-term expansion, phenotype of bmMSCs and ucMSCs remains stable and cells exhibit similar immunogenic properties compared with lower passage cells. However, immunosuppressive properties of MSCs are reduced. These findings reveal the consequences of application of higher passage MSCs in the clinic, which will help increase the yield of therapeutic MSCs but may interfere with their efficacy.
[Mh] Termos MeSH primário: Células da Medula Óssea/citologia
Células Mesenquimais Estromais/fisiologia
Cordão Umbilical/citologia
[Mh] Termos MeSH secundário: Linfócitos T CD4-Positivos/citologia
Linfócitos T CD4-Positivos/fisiologia
Linfócitos T CD8-Positivos/citologia
Linfócitos T CD8-Positivos/fisiologia
Diferenciação Celular/efeitos dos fármacos
Proliferação Celular
Células Cultivadas
Feminino
Seres Humanos
Imunofenotipagem
Células Matadoras Naturais/imunologia
Células Matadoras Naturais/fisiologia
Células Mesenquimais Estromais/citologia
Ploidias
Gravidez
Homeostase do Telômero
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


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[PMID]:28454681
[Au] Autor:Trachana V; Petrakis S; Fotiadis Z; Siska EK; Balis V; Gonos ES; Kaloyianni M; Koliakos G
[Ad] Endereço:Laboratory of Biology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41500 Larisa, Greece. Electronic address: vtrachana@med.uth.gr.
[Ti] Título:Human mesenchymal stem cells with enhanced telomerase activity acquire resistance against oxidative stress-induced genomic damage.
[So] Source:Cytotherapy;19(7):808-820, 2017 07.
[Is] ISSN:1477-2566
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Human mesenchymal stem cells (MSC) are important tools for several cell-based therapies. However, their use in such therapies requires in vitro expansion during which MSCs quickly reach replicative senescence. Replicative senescence has been linked to macromolecular damage, and especially oxidative stress-induced DNA damage. Recent studies on the other hand, have implicated telomerase in the cellular response to oxidative damage, suggesting that telomerase has a telomere-length independent function that promotes survival. METHODS: Here, we studied the DNA damage accumulation and repair during in vitro expansion as well as after acute external oxidative exposure of control MSCs and MSCs that overexpress the catalytic subunit of telomerase (hTERT MSCs). RESULTS: We showed that hTERT MSCs at high passages have a significant lower percentage of DNA lesions as compared to control cells of the same passages. Additionally, less damage was accumulated due to external oxidative insult in the nuclei of hTERT overexpressing cells as compared to the control cells. Moreover, we demonstrated that oxidative stress leads to diverse nucleus malformations, such as multillobular nuclei or donut-shaped nuclei, in the control cells whereas hTERT MSCs showed significant resistance to the formation of such defects. Finally, hTERT MSCs were found to possess higher activities of the basic antioxidant enzymes, superoxide dismutase and catalase, than control MSCs. DISCUSSION: On the basis of these results, we propose that hTERT enhancement confers resistance to genomic damage due to the amelioration of the cell's basic antioxidant machinery.
[Mh] Termos MeSH primário: Antioxidantes/metabolismo
Dano ao DNA
Células Mesenquimais Estromais/fisiologia
Estresse Oxidativo
Telomerase/metabolismo
[Mh] Termos MeSH secundário: Catalase/metabolismo
Células Cultivadas
Senescência Celular/fisiologia
Seres Humanos
Peróxido de Hidrogênio/farmacologia
Células Mesenquimais Estromais/efeitos dos fármacos
Estresse Oxidativo/efeitos dos fármacos
Subunidades Proteicas
Superóxido Dismutase/metabolismo
Telomerase/genética
Telômero
Homeostase do Telômero
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Protein Subunits); BBX060AN9V (Hydrogen Peroxide); EC 1.11.1.6 (Catalase); EC 1.15.1.1 (Superoxide Dismutase); EC 2.7.7.49 (Telomerase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


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[PMID]:28741530
[Au] Autor:Voon HPJ; Collas P; Wong LH
[Ad] Endereço:Department of Biochemistry and Molecular Biology, The Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
[Ti] Título:Compromised Telomeric Heterochromatin Promotes ALTernative Lengthening of Telomeres.
[So] Source:Trends Cancer;2(3):114-116, 2016 Mar.
[Is] ISSN:2405-8025
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Alternative lengthening of telomeres (ALT) is an enigmatic process that allows certain cancers to maintain telomeres in the absence of telomerase. ALT cancers are frequently defective for ATRX/DAXX, a chaperone complex that deposits histone variant H3.3 at telomeres. We propose that mutations in alpha thalassemia-mental retardation syndrome X-linked (ATRX)/death-domain associated protein (DAXX) prime ALT activation by disrupting telomeric heterochromatin.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/genética
Heterocromatina/metabolismo
Neoplasias/genética
Proteínas Nucleares/genética
Homeostase do Telômero
Proteína Nuclear Ligada ao X/genética
[Mh] Termos MeSH secundário: Seres Humanos
Mutação
Telômero
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (DAXX protein, human); 0 (Heterochromatin); 0 (Nuclear Proteins); EC 3.6.4.12 (ATRX protein, human); EC 3.6.4.12 (X-linked Nuclear Protein)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE


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[PMID]:29069086
[Au] Autor:Maicher A; Gazy I; Sharma S; Marjavaara L; Grinberg G; Shemesh K; Chabes A; Kupiec M
[Ad] Endereço:Dept. of Molecular Microbiology & Biotechnology, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel.
[Ti] Título:Rnr1, but not Rnr3, facilitates the sustained telomerase-dependent elongation of telomeres.
[So] Source:PLoS Genet;13(10):e1007082, 2017 Oct.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ribonucleotide reductase (RNR) provides the precursors for the generation of dNTPs, which are required for DNA synthesis and repair. Here, we investigated the function of the major RNR subunits Rnr1 and Rnr3 in telomere elongation in budding yeast. We show that Rnr1 is essential for the sustained elongation of short telomeres by telomerase. In the absence of Rnr1, cells harbor very short, but functional, telomeres, which cannot become elongated by increased telomerase activity or by tethering of telomerase to telomeres. Furthermore, we demonstrate that Rnr1 function is critical to prevent an early onset of replicative senescence and premature survivor formation in telomerase-negative cells but dispensable for telomere elongation by Homology-Directed-Repair. Our results suggest that telomerase has a "basal activity" mode that is sufficient to compensate for the "end-replication-problem" and does not require the presence of Rnr1 and a different "sustained activity" mode necessary for the elongation of short telomeres, which requires an upregulation of dNTP levels and dGTP ratios specifically through Rnr1 function. By analyzing telomere length and dNTP levels in different mutants showing changes in RNR complex composition and activity we provide evidence that the Mec1ATR checkpoint protein promotes telomere elongation by increasing both dNTP levels and dGTP ratios through Rnr1 upregulation in a mechanism that cannot be replaced by its homolog Rnr3.
[Mh] Termos MeSH primário: Ribonucleotídeo Redutases/genética
Saccharomycetales/genética
Telomerase/metabolismo
Homeostase do Telômero
Telômero
[Mh] Termos MeSH secundário: Senescência Celular
Replicação do DNA
Saccharomycetales/citologia
Saccharomycetales/crescimento & desenvolvimento
Saccharomycetales/metabolismo
Telomerase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 1.17.4.- (Ribonucleotide Reductases); EC 2.7.7.49 (Telomerase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171026
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1007082


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[PMID]:29017469
[Au] Autor:Suzuki A; Matsumoto Y; Enokido M; Shirata T; Goto K; Otani K
[Ad] Endereço:Department of Psychiatry, Yamagata University School of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan. suzukiakihito@hotmail.com.
[Ti] Título:Relationship between interpersonal sensitivity and leukocyte telomere length.
[So] Source:BMC Med Genet;18(1):112, 2017 Oct 10.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Telomeres are repetitive DNA sequences located at the ends of chromosomes, and telomere length represents a biological marker for cellular aging. Interpersonal sensitivity, excessive sensitivity to the behavior and feelings of others, is one of the vulnerable factors to depression. In the present study, we examined the effect of interpersonal sensitivity on telomere length in healthy subjects. METHODS: The subjects were 159 unrelated healthy Japanese volunteers. Mean age ± SD (range) of the subjects was 42.3 ± 7.8 (30-61) years. Interpersonal sensitivity was assessed by the Japanese version of the Interpersonal Sensitivity Measure (IPSM). Leukocyte telomere length was determined by a quantitative real-time PCR method. RESULTS: Higher scores of the total IPSM were significantly (ß = -0.163, p = 0.038) related to shorter telomere length. In the sub-scale analysis, higher scores of timidity were significantly (ß = -0.220, p = 0.044) associated with shorter telomere length. CONCLUSIONS: The present study suggests that subjects with higher interpersonal sensitivity have shorter leukocyte telomere length, implying that interpersonal sensitivity has an impact on cellular aging.
[Mh] Termos MeSH primário: Leucócitos/citologia
Personalidade/genética
Telômero/ultraestrutura
[Mh] Termos MeSH secundário: Adulto
Grupo com Ancestrais do Continente Asiático/genética
Senescência Celular/genética
Estudos Transversais
Depressão/genética
Feminino
Marcadores Genéticos
Seres Humanos
Masculino
Meia-Idade
Reação em Cadeia da Polimerase em Tempo Real
Fatores de Risco
Análise de Sequência de DNA
Homeostase do Telômero
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Genetic Markers)
[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:171012
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0473-9


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[PMID]:28886139
[Au] Autor:Dagnall CL; Hicks B; Teshome K; Hutchinson AA; Gadalla SM; Khincha PP; Yeager M; Savage SA
[Ad] Endereço:Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), Bethesda, Maryland, United States of America.
[Ti] Título:Effect of pre-analytic variables on the reproducibility of qPCR relative telomere length measurement.
[So] Source:PLoS One;12(9):e0184098, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Telomeres, long nucleotide repeats and a protein complex at chromosome ends, shorten with each cell division and are susceptible to oxidative damage. Quantitative PCR (qPCR) is a widely-used technique to measure relative telomere length (RTL) in DNA samples but is challenging to optimize and significant lab-to-lab variability has been reported. In this study, we evaluated factors that may contribute to qPCR RTL measurement variability including DNA extraction methods, methods used for removing potential residual PCR inhibitors, sample storage conditions, and sample location in the PCR plate. Our results show that the DNA extraction and purification techniques, as well as sample storage conditions introduce significant variability in qPCR RTL results. We did not find significant differences in results based on sample location in the PCR plate or qPCR instrument used. These data suggest that lack of reproducibility in published association studies of RTL could be, in part, due to methodological inconsistencies. This study illustrates the importance of uniform sample handling, from DNA extraction through data generation and analysis, in using qPCR to determine RTL.
[Mh] Termos MeSH primário: Reação em Cadeia da Polimerase em Tempo Real
Homeostase do Telômero/genética
Telômero/genética
[Mh] Termos MeSH secundário: DNA/genética
DNA/isolamento & purificação
Seres Humanos
Reação em Cadeia da Polimerase em Tempo Real/métodos
Reação em Cadeia da Polimerase em Tempo Real/normas
Reprodutibilidade dos Testes
Manejo de Espécimes/métodos
Manejo de Espécimes/normas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9007-49-2 (DNA)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170909
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184098


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[PMID]:28877996
[Au] Autor:Sobinoff AP; Allen JA; Neumann AA; Yang SF; Walsh ME; Henson JD; Reddel RR; Pickett HA
[Ad] Endereço:Telomere Length Regulation Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW, Australia.
[Ti] Título:BLM and SLX4 play opposing roles in recombination-dependent replication at human telomeres.
[So] Source:EMBO J;36(19):2907-2919, 2017 Oct 02.
[Is] ISSN:1460-2075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Alternative lengthening of telomeres (ALT) is a telomere lengthening pathway that predominates in aggressive tumors of mesenchymal origin; however, the underlying mechanism of telomere synthesis is not fully understood. Here, we show that the BLM-TOP3A-RMI (BTR) dissolvase complex is required for ALT-mediated telomere synthesis. We propose that recombination intermediates formed during strand invasion are processed by the BTR complex, initiating rapid and extensive POLD3-dependent telomere synthesis followed by dissolution, with no overall exchange of telomeric DNA. This process is counteracted by the SLX4-SLX1-ERCC4 complex, which promotes resolution of the recombination intermediate, resulting in telomere exchange in the absence of telomere extension. Our data are consistent with ALT being a conservative DNA replication process, analogous to break-induced replication, which is dependent on BTR and counteracted by SLX4 complex-mediated resolution events.
[Mh] Termos MeSH primário: Replicação do DNA/genética
RecQ Helicases/fisiologia
Recombinases/fisiologia
Recombinação Genética/genética
Homeostase do Telômero/genética
[Mh] Termos MeSH secundário: Células Cultivadas
DNA Topoisomerases Tipo I/metabolismo
DNA Topoisomerases Tipo I/fisiologia
DNA Polimerase Dirigida por DNA/metabolismo
DNA Polimerase Dirigida por DNA/fisiologia
Seres Humanos
Complexos Multienzimáticos/metabolismo
Complexos Multienzimáticos/fisiologia
RecQ Helicases/metabolismo
Recombinases/metabolismo
Telômero/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Multienzyme Complexes); 0 (Recombinases); EC 2.7.7.- (DNA synthesome); EC 2.7.7.7 (DNA-Directed DNA Polymerase); EC 3.1.- (SLX4 protein, human); EC 3.6.1.- (Bloom syndrome protein); EC 3.6.4.12 (RecQ Helicases); EC 5.99.1.2 (DNA Topoisomerases, Type I); EC 5.99.1.2 (DNA topoisomerase III)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.15252/embj.201796889


  10 / 968 MEDLINE  
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[PMID]:28854735
[Au] Autor:Wang S; Pike AM; Lee SS; Strong MA; Connelly CJ; Greider CW
[Ad] Endereço:Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
[Ti] Título:BRD4 inhibitors block telomere elongation.
[So] Source:Nucleic Acids Res;45(14):8403-8410, 2017 Aug 21.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cancer cells maintain telomere length equilibrium to avoid senescence and apoptosis induced by short telomeres, which trigger the DNA damage response. Limiting the potential for telomere maintenance in cancer cells has been long been proposed as a therapeutic target. Using an unbiased shRNA screen targeting known kinases, we identified bromodomain-containing protein 4 (BRD4) as a telomere length regulator. Four independent BRD4 inhibitors blocked telomere elongation, in a dose-dependent manner, in mouse cells overexpressing telomerase. Long-term treatment with BRD4 inhibitors caused telomere shortening in both mouse and human cells, suggesting BRD4 plays a role in telomere maintenance in vivo. Telomerase enzymatic activity was not directly affected by BRD4 inhibition. BRD4 is in clinical trials for a number of cancers, but its effects on telomere maintenance have not been previously investigated.
[Mh] Termos MeSH primário: Proteínas Nucleares/genética
Homeostase do Telômero/genética
Encurtamento do Telômero/genética
Fatores de Transcrição/genética
[Mh] Termos MeSH secundário: Acetanilidas/farmacologia
Animais
Azepinas/farmacologia
Southern Blotting
Linhagem Celular
Relação Dose-Resposta a Droga
Fibroblastos/citologia
Fibroblastos/efeitos dos fármacos
Fibroblastos/metabolismo
Expressão Gênica/efeitos dos fármacos
Células HeLa
Compostos Heterocíclicos com 3 Anéis/farmacologia
Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia
Seres Humanos
Hibridização in Situ Fluorescente
Camundongos
Morfolinas/farmacologia
Proteínas Nucleares/antagonistas & inibidores
Proteínas Nucleares/metabolismo
Pironas/farmacologia
Interferência de RNA
Telomerase/genética
Telomerase/metabolismo
Telômero/efeitos dos fármacos
Telômero/enzimologia
Telômero/genética
Homeostase do Telômero/efeitos dos fármacos
Encurtamento do Telômero/efeitos dos fármacos
Fatores de Transcrição/antagonistas & inibidores
Fatores de Transcrição/metabolismo
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 ((+)-JQ1 compound); 0 (2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one); 0 (Acetanilides); 0 (Azepines); 0 (BRD4 protein, human); 0 (Brd4 protein, mouse); 0 (GSK1210151A); 0 (Heterocyclic Compounds, 3-Ring); 0 (Heterocyclic Compounds, 4 or More Rings); 0 (Morpholines); 0 (Nuclear Proteins); 0 (OTX015); 0 (Pyrones); 0 (Transcription Factors); 0 (Triazoles); EC 2.7.7.49 (Telomerase)
[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:170901
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx561



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