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[PMID]:27771433
[Au] Autor:Wilson A; Yakovlev VA
[Ad] Endereço:Department of Radiation Oncology, Massey Cancer Center, Virginia Commonwealth University, 401 College Street, Richmond, VA 23298, United States.
[Ti] Título:Cells redox environment modulates BRCA1 expression and DNA homologous recombination repair.
[So] Source:Free Radic Biol Med;101:190-201, 2016 12.
[Is] ISSN:1873-4596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cancer development and progression have been linked to oxidative stress, a condition characterized by unbalanced increase in ROS and RNS production. The main endogenous initiators of the redox imbalance in cancer cells are defective mitochondria, elevated NOX activity, and uncoupled NOS3. Traditionally, most attention has been paid to direct oxidative damage to DNA by certain ROS. However, increase in oxidative DNA lesions does not always lead to malignancy. Hence, additional ROS-dependent, pro-carcinogenic mechanisms must be important. Our recent study demonstrated that Tyr nitration of PP2A stimulates its activity and leads to downregulation of BRCA1 expression. This provides a mechanism for chromosomal instability essential for tumor progression. In the present work, we demonstrated that inhibition of ROS production by generating mitochondrial-electron-transport-deficient cell lines (ρ cells) or by inhibition of NOX activity with a selective peptide inhibitor significantly reduced PP2A Tyr nitration and its activity in different cancer cell lines. As a result of the decreased PP2A activity, BRCA1 expression was restored along with a significantly enhanced level of DNA HRR. We used TCGA database to analyze the correlation between expressions of the NOX regulatory subunits, NOS isoforms, and BRCA1 in the 3 cancer research studies: breast invasive carcinoma, ovarian cystadenocarcinoma, and lung adenocarcinoma. TCGA database analysis demonstrated that the high expression levels of most of the NOX regulatory subunits responsible for stimulation of NOX1-NOX4 were associated with significant downregulation of BRCA1 expression.
[Mh] Termos MeSH primário: Regulação Neoplásica da Expressão Gênica
NADPH Oxidase 1/genética
Óxido Nítrico Sintase Tipo III/genética
Fosfoproteínas Fosfatases/genética
Reparo de DNA por Recombinação
Ubiquitina-Proteína Ligases/genética
[Mh] Termos MeSH secundário: Células A549
Adenocarcinoma/genética
Adenocarcinoma/metabolismo
Adenocarcinoma/patologia
Neoplasias da Mama/genética
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Carcinoma Ductal de Mama/genética
Carcinoma Ductal de Mama/metabolismo
Carcinoma Ductal de Mama/patologia
Instabilidade Cromossômica
Cistadenocarcinoma Seroso/genética
Cistadenocarcinoma Seroso/metabolismo
Cistadenocarcinoma Seroso/patologia
Bases de Dados Genéticas
Transporte de Elétrons
Feminino
Seres Humanos
Isoenzimas/genética
Isoenzimas/metabolismo
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/metabolismo
Neoplasias Pulmonares/patologia
Células MCF-7
Mitocôndrias/metabolismo
Mitocôndrias/patologia
NADPH Oxidase 1/metabolismo
Óxido Nítrico Sintase Tipo III/metabolismo
Neoplasias Ovarianas/genética
Neoplasias Ovarianas/metabolismo
Neoplasias Ovarianas/patologia
Oxirredução
Estresse Oxidativo
Fosfoproteínas Fosfatases/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais
Ubiquitina-Proteína Ligases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Isoenzymes); 0 (Reactive Oxygen Species); EC 1.14.13.39 (NOS3 protein, human); EC 1.14.13.39 (Nitric Oxide Synthase Type III); EC 1.6.3.- (NADPH Oxidase 1); EC 1.6.3.- (NOX1 protein, human); EC 2.3.2.27 (BRAP protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 3.1.3.16 (Phosphoprotein Phosphatases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180131
[Lr] Data última revisão:
180131
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE


  2 / 2323 MEDLINE  
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[PMID]:28741487
[Au] Autor:van Jaarsveld RH; Kops GJPL
[Ad] Endereço:Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Uppsalalaan 8, 3584 CT Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
[Ti] Título:Difference Makers: Chromosomal Instability versus Aneuploidy in Cancer.
[So] Source:Trends Cancer;2(10):561-571, 2016 Oct.
[Is] ISSN:2405-8025
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human cancers harbor great numbers of genomic alterations. One of the most common alterations is aneuploidy, an imbalance at the chromosome level. Some aneuploid cancer cell populations show varying chromosome copy number alterations over time, a phenotype known as 'chromosomal instability' (CIN). Chromosome segregation errors in mitosis are the most common cause for CIN in vitro, and these are also thought to underlie the aneuploidies seen in clinical cancer samples. However, CIN and aneuploidy are different traits and they are likely to have distinct impacts on tumor evolution and clinical tumor behavior. In this opinion article, we discuss these differences and describe scenarios in which distinguishing them can be clinically relevant.
[Mh] Termos MeSH primário: Aneuploidia
Instabilidade Cromossômica
Neoplasias/genética
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Neoplasias/patologia
Neoplasias/terapia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[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


  3 / 2323 MEDLINE  
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[PMID]:28740117
[Au] Autor:Glover TW; Wilson TE; Arlt MF
[Ad] Endereço:Department of Human Genetics; the Department of Pathology; and the Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
[Ti] Título:Fragile sites in cancer: more than meets the eye.
[So] Source:Nat Rev Cancer;17(8):489-501, 2017 07 25.
[Is] ISSN:1474-1768
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Ever since initial suggestions that instability at common fragile sites (CFSs) could be responsible for chromosome rearrangements in cancers, CFSs and associated genes have been the subject of numerous studies, leading to questions and controversies about their role and importance in cancer. It is now clear that CFSs are not frequently involved in translocations or other cancer-associated recurrent gross chromosome rearrangements. However, recent studies have provided new insights into the mechanisms of CFS instability, their effect on genome instability, and their role in generating focal copy number alterations that affect the genomic landscape of many cancers.
[Mh] Termos MeSH primário: Instabilidade Cromossômica
Sítios Frágeis do Cromossomo
Variações do Número de Cópias de DNA
Neoplasias/genética
Oncogenes/genética
[Mh] Termos MeSH secundário: Anáfase
Animais
Quebra Cromossômica
Quebras de DNA de Cadeia Dupla
Replicação do DNA
Rearranjo Gênico
Seres Humanos
Metáfase
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, N.I.H., INTRAMURAL
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1038/nrc.2017.52


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[PMID]:28746311
[Au] Autor:Choi J; Huebner AJ; Clement K; Walsh RM; Savol A; Lin K; Gu H; Di Stefano B; Brumbaugh J; Kim SY; Sharif J; Rose CM; Mohammad A; Odajima J; Charron J; Shioda T; Gnirke A; Gygi S; Koseki H; Sadreyev RI; Xiao A; Meissner A; Hochedlinger K
[Ad] Endereço:Massachusetts General Hospital Department of Molecular Biology, Boston, Massachusetts 02114, USA.
[Ti] Título:Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells.
[So] Source:Nature;548(7666):219-223, 2017 08 10.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Concomitant activation of the Wnt pathway and suppression of Mapk signalling by two small molecule inhibitors (2i) in the presence of leukaemia inhibitory factor (LIF) (hereafter termed 2i/L) induces a naive state in mouse embryonic stem (ES) cells that resembles the inner cell mass (ICM) of the pre-implantation embryo. Since the ICM exists only transiently in vivo, it remains unclear how sustained propagation of naive ES cells in vitro affects their stability and functionality. Here we show that prolonged culture of male mouse ES cells in 2i/L results in irreversible epigenetic and genomic changes that impair their developmental potential. Furthermore, we find that female ES cells cultured in conventional serum plus LIF medium phenocopy male ES cells cultured in 2i/L. Mechanistically, we demonstrate that the inhibition of Mek1/2 is predominantly responsible for these effects, in part through the downregulation of DNA methyltransferases and their cofactors. Finally, we show that replacement of the Mek1/2 inhibitor with a Src inhibitor preserves the epigenetic and genomic integrity as well as the developmental potential of ES cells. Taken together, our data suggest that, although short-term suppression of Mek1/2 in ES cells helps to maintain an ICM-like epigenetic state, prolonged suppression results in irreversible changes that compromise their developmental potential.
[Mh] Termos MeSH primário: Células-Tronco Embrionárias/citologia
Células-Tronco Embrionárias/enzimologia
MAP Quinase Quinase 1/antagonistas & inibidores
MAP Quinase Quinase 2/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Blastocisto
Instabilidade Cromossômica
Metilação de DNA
Feminino
Impressão Genômica
Cariotipagem
Masculino
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 2.7.12.2 (MAP Kinase Kinase 1); EC 2.7.12.2 (MAP Kinase Kinase 2)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180110
[Lr] Data última revisão:
180110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1038/nature23274


  5 / 2323 MEDLINE  
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[PMID]:28981863
[Au] Autor:Tashiro S; Nishihara Y; Kugou K; Ohta K; Kanoh J
[Ad] Endereço:Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
[Ti] Título:Subtelomeres constitute a safeguard for gene expression and chromosome homeostasis.
[So] Source:Nucleic Acids Res;45(18):10333-10349, 2017 Oct 13.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The subtelomere, a telomere-adjacent chromosomal domain, contains species-specific homologous DNA sequences, in addition to various genes. However, the functions of subtelomeres, particularly subtelomeric homologous (SH) sequences, remain elusive. Here, we report the first comprehensive analyses of the cellular functions of SH sequences in the fission yeast, Schizosaccharomyces pombe. Complete removal of SH sequences from the genome revealed that they are dispensable for mitosis, meiosis and telomere length control. However, when telomeres are lost, SH sequences prevent deleterious inter-chromosomal end fusion by facilitating intra-chromosomal circularization. Surprisingly, SH-deleted cells sometimes survive telomere loss through inter-chromosomal end fusions via homologous loci such as LTRs, accompanied by centromere inactivation of either chromosome. Moreover, SH sequences function as a buffer region against the spreading of subtelomeric heterochromatin into the neighboring gene-rich regions. Furthermore, we found a nucleosome-free region at the subtelomeric border, which may be a second barrier that blocks heterochromatin spreading into the subtelomere-adjacent euchromatin. Thus, our results demonstrate multiple defense functions of subtelomeres in chromosome homeostasis and gene expression.
[Mh] Termos MeSH primário: Cromossomos Fúngicos/fisiologia
Expressão Gênica
Homeostase/genética
Proteínas de Schizosaccharomyces pombe/genética
Schizosaccharomyces/genética
Telômero/fisiologia
[Mh] Termos MeSH secundário: Centrômero/metabolismo
Instabilidade Cromossômica/genética
Regulação Fúngica da Expressão Gênica
Heterocromatina/metabolismo
Organismos Geneticamente Modificados
Deleção de Sequência
Proteínas de Ligação a Telômeros/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heterochromatin); 0 (Schizosaccharomyces pombe Proteins); 0 (Telomere-Binding Proteins)
[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:171006
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx780


  6 / 2323 MEDLINE  
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[PMID]:28927539
[Au] Autor:Stepanenko AA; Heng HH
[Ad] Endereço:Laboratory of Biosynthesis of Nucleic Acids, Department of Functional Genomics, Institute of Molecular Biology and Genetics, Zabolotnogo Str. 150, Kyiv 03680, Ukraine. Electronic address: a.a.stepanenko@gmail.com.
[Ti] Título:Transient and stable vector transfection: Pitfalls, off-target effects, artifacts.
[So] Source:Mutat Res;773:91-103, 2017 Jul.
[Is] ISSN:1873-135X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Transient and stable vector transfections have played important roles in illustrating the function of specific genes/proteins. The general assumption is that such a platform could effectively link a given gene/protein to gained phenotypes, revealing the mechanism of how a gene works. However, in reality, increased studies have surprisingly noticed some unexpected results. In this review, we demonstrate that an assumption that empty vector-transfected cells preserve the cytogenetic and phenotypic characteristics, and represent the adequate control in transfection experiments is not universally valid. A DNA vector, a transfection reagent, expression of an antibiotic resistance (trans)gene, expression of a reporter (trans)gene, and selection by acute/chronic antibiotic treatment may evoke cellular responses that affect the biochemical processes under investigation. We exemplify a number of studies, which reported obvious genomic, transcriptomic and phenotypic changes of tumor cells after transient/stable transfection of an empty vector. To further address the common mechanisms of these unexpected findings, we will apply the genome theory of somatic evolution to explain stress-mediated system dynamics and the limitations of predicting the system behavior solely based on targeted genes. We conceptualize that the diverse experimental manipulations (e.g., transgene overexpression, gene knock out/down, chemical treatments, acute changes in culture conditions, etc.) may act as a system stress, promoting intensive genome-level alterations (chromosomal instability, CIN), epigenetic and phenotypic alterations, which are beyond the function of manipulated genes. Such analysis calls for more attention on the reduced specificities of gene-focused methodologies.
[Mh] Termos MeSH primário: Artefatos
Vetores Genéticos
Transfecção
[Mh] Termos MeSH secundário: Animais
Antibacterianos/farmacologia
Instabilidade Cromossômica/genética
Clonagem Molecular
Resistência Microbiana a Medicamentos/genética
Epigenômica
Dosagem de Genes
Regulação da Expressão Gênica
Genes Reporter
Seres Humanos
Plasmídeos/genética
Plasmídeos/metabolismo
Transgenes
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-Bacterial Agents)
[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:170921
[St] Status:MEDLINE


  7 / 2323 MEDLINE  
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[PMID]:28863940
[Au] Autor:Bouali N; Francou B; Bouligand J; Imanci D; Dimassi S; Tosca L; Zaouali M; Mougou S; Young J; Saad A; Guiochon-Mantel A
[Ad] Endereço:Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Sousse, Tunisia. Electronic address: nouha_bmail@yahoo.fr.
[Ti] Título:New MCM8 mutation associated with premature ovarian insufficiency and chromosomal instability in a highly consanguineous Tunisian family.
[So] Source:Fertil Steril;108(4):694-702, 2017 Oct.
[Is] ISSN:1556-5653
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To identify the gene(s) involved in the etiology of premature ovarian insufficiency in a highly consanguineous Tunisian family. DESIGN: Genetic analysis of a large consanguineous family with several affected siblings. SETTING: University hospital-based cytogenetics and molecular genetics laboratories. PATIENT(S): A highly consanguineous Tunisian family with several affected siblings born to healthy second-degree cousins. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Targeted exome sequencing was performed by next-generation sequencing for affected family members. Mutations were validated by Sanger sequencing. Functional experiments were performed to explore the deleterious effects of the identified mutation. DNA damage was induced by increasing mitomycin C (MMC) concentrations on cultured peripheral lymphocytes. RESULT(S): Analysis of the next-generation sequencing data revealed a new homozygous missense mutation in the minichromosome maintenance 8 gene (MCM8).This homozygous mutation (c. 482A>C; p.His161Pro) was predicted to be deleterious and segregated with the disease in the family. MCM8 participates in homologous recombination during meiosis and DNA double-stranded break repair by dimerizing with MCM9. Mcm8 knock out results in an early block in follicle development and small gonads. Given this, we tested the chromosomal breakage repair capacity of homozygous and heterozygous MCM8 p.His161Pro mutation on cultured peripheral lymphocytes exposed to increasing MMC concentrations. We found that chromosomal breakage after MMC exposure was significantly higher in cells from homozygously affected individuals than in those from a healthy control. CONCLUSION(S): Our findings provide additional support to the view that MCM8 mutations are involved in the primary ovarian insufficiency phenotype.
[Mh] Termos MeSH primário: Instabilidade Cromossômica/genética
Consanguinidade
Menopausa Precoce/genética
Proteínas de Manutenção de Minicromossomo/genética
Insuficiência Ovariana Primária/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Família
Feminino
Seres Humanos
Masculino
Meia-Idade
Mutação de Sentido Incorreto
Linhagem
Insuficiência Ovariana Primária/complicações
Tunísia
Adulto Jovem
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.6.4.12 (MCM8 protein, human); EC 3.6.4.12 (Minichromosome Maintenance Proteins)
[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:170903
[St] Status:MEDLINE


  8 / 2323 MEDLINE  
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[PMID]:28829762
[Au] Autor:Gayarre J; Martín-Gimeno P; Osorio A; Paumard B; Barroso A; Fernández V; de la Hoya M; Rojo A; Caldés T; Palacios J; Urioste M; Benítez J; García MJ
[Ad] Endereço:Human Genetics Group, Spanish National Cancer Research Center, C/Melchor Fernández Almagro 3, Madrid 28029, Spain.
[Ti] Título:Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes.
[So] Source:Br J Cancer;117(7):1048-1062, 2017 Sep 26.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Despite a high prevalence of deleterious missense variants, most studies of RAD51C ovarian cancer susceptibility gene only provide in silico pathogenicity predictions of missense changes. We identified a novel deleterious RAD51C missense variant (p.Arg312Trp) in a high-risk family, and propose a criteria to prioritise RAD51C missense changes qualifying for functional analysis. METHODS: To evaluate pathogenicity of p.Arg312Trp variant we used sequence homology, loss of heterozygosity (LOH) and segregation analysis, and a comprehensive functional characterisation. To define a functional-analysis prioritisation criteria, we used outputs for the known functionally confirmed deleterious and benign RAD51C missense changes from nine pathogenicity prediction algorithms. RESULTS: The p.Arg312Trp variant failed to correct mitomycin and olaparib hypersensitivity and to complement abnormal RAD51C foci formation according to functional assays, which altogether with LOH and segregation data demonstrated deleteriousness. Prioritisation criteria were based on the number of predictors providing a deleterious output, with a minimum of 5 to qualify for testing and a PredictProtein score greater than 33 to assign high-priority indication. CONCLUSIONS: Our study points to a non-negligible number of RAD51C missense variants likely to impair protein function, provides a guideline to prioritise and encourage their selection for functional analysis and anticipates that reference laboratories should have available resources to conduct such assays.
[Mh] Termos MeSH primário: Neoplasias da Mama/genética
Carcinoma/genética
Neoplasias Colorretais/genética
Proteínas de Ligação a DNA/genética
Neoplasias Ovarianas/genética
Neoplasias Gástricas/diagnóstico por imagem
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Algoritmos
Estudos de Casos e Controles
Ciclo Celular/efeitos dos fármacos
Ciclo Celular/genética
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/genética
Células Cultivadas
Instabilidade Cromossômica
Análise Mutacional de DNA
Exoma
Feminino
Predisposição Genética para Doença
Genótipo
Histonas/metabolismo
Seres Humanos
Perda de Heterozigosidade
Masculino
Meia-Idade
Mitomicina/farmacologia
Mutação de Sentido Incorreto
Linhagem
Medição de Risco/métodos
Homologia de Sequência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (H2AFX protein, human); 0 (Histones); 0 (RAD51C protein, human); 50SG953SK6 (Mitomycin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170823
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.286


  9 / 2323 MEDLINE  
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[PMID]:28807937
[Au] Autor:Sun M; Tong P; Kong W; Dong B; Huang Y; Park IY; Zhou L; Liu XD; Ding Z; Zhang X; Bai S; German P; Powell R; Wang Q; Tong X; Tannir NM; Matin SF; Rathmell WK; Fuller GN; McCutcheon IE; Walker CL; Wang J; Jonasch E
[Ad] Endereço:Department of Genitourinary Medical Oncology, University of Texas at MD Anderson Cancer Center, Houston, Texas.
[Ti] Título:HNF1B Loss Exacerbates the Development of Chromophobe Renal Cell Carcinomas.
[So] Source:Cancer Res;77(19):5313-5326, 2017 Oct 01.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here, we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of loss is unique to ChRCC. We also observed a strong correlation between reduced expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell-cycle checkpoint proteins RB1 and p27. Furthermore, it altered the chromatin accessibility of , , and genes and triggered aneuploidy development. Analysis of The Cancer Genome Atlas database revealed mutations in 33% of ChRCC where expression was repressed. In clinical specimens, combining loss with mutation produced an association with poor patient prognosis. In cells, combining loss and mutation increased cell proliferation and aneuploidy. Our results show how loss leads to abnormal mitotic protein regulation and induction of aneuploidy. We propose that coordinate loss of and may enhance cellular survival and confer an aggressive phenotype in ChRCC. .
[Mh] Termos MeSH primário: Carcinoma de Células Renais/patologia
Proteínas de Ciclo Celular/metabolismo
Fator 1-beta Nuclear de Hepatócito/metabolismo
Neoplasias Renais/patologia
Proteínas Mad2/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
[Mh] Termos MeSH secundário: Aneuploidia
Animais
Apoptose
Carcinoma de Células Renais/genética
Carcinoma de Células Renais/metabolismo
Ciclo Celular
Proteínas de Ciclo Celular/genética
Proliferação Celular
Células Cultivadas
Instabilidade Cromossômica
Embrião de Mamíferos/citologia
Embrião de Mamíferos/metabolismo
Fibroblastos/citologia
Fibroblastos/metabolismo
Fator 1-beta Nuclear de Hepatócito/genética
Seres Humanos
Neoplasias Renais/genética
Neoplasias Renais/metabolismo
Proteínas Mad2/genética
Camundongos
Proteínas Serina-Treonina Quinases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BUB1B protein, human); 0 (Cell Cycle Proteins); 0 (HNF1B protein, human); 0 (MAD2L1 protein, human); 0 (Mad2 Proteins); 138674-15-4 (Hepatocyte Nuclear Factor 1-beta); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170816
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-17-0986


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[PMID]:28760857
[Au] Autor:Takada M; Zhang W; Suzuki A; Kuroda TS; Yu Z; Inuzuka H; Gao D; Wan L; Zhuang M; Hu L; Zhai B; Fry CJ; Bloom K; Li G; Karpen GH; Wei W; Zhang Q
[Ad] Endereço:Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
[Ti] Título:FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2-Mediated Phosphorylation of CENP-A.
[So] Source:Cancer Res;77(18):4881-4893, 2017 Sep 15.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The centromere regulates proper chromosome segregation, and its dysfunction is implicated in chromosomal instability (CIN). However, relatively little is known about how centromere dysfunction occurs in cancer. Here, we define the consequences of phosphorylation by cyclin E1/CDK2 on a conserved Ser18 residue of centromere-associated protein CENP-A, an essential histone H3 variant that specifies centromere identity. Ser18 hyperphosphorylation in cells occurred upon loss of FBW7, a tumor suppressor whose inactivation leads to CIN. This event on CENP-A reduced its centromeric localization, increased CIN, and promoted anchorage-independent growth and xenograft tumor formation. Overall, our results revealed a pathway that cyclin E1/CDK2 activation coupled with FBW7 loss promotes CIN and tumor progression via CENP-A-mediated centromere dysfunction. .
[Mh] Termos MeSH primário: Autoantígenos/metabolismo
Neoplasias da Mama/patologia
Proteínas de Ciclo Celular/metabolismo
Transformação Celular Neoplásica/patologia
Instabilidade Cromossômica
Proteínas Cromossômicas não Histona/metabolismo
Neoplasias do Colo/patologia
Ciclina E/metabolismo
Quinase 2 Dependente de Ciclina/metabolismo
Proteínas F-Box/metabolismo
Proteínas Oncogênicas/metabolismo
Ubiquitina-Proteína Ligases/metabolismo
[Mh] Termos MeSH secundário: Apoptose
Biomarcadores Tumorais/metabolismo
Neoplasias da Mama/genética
Neoplasias da Mama/metabolismo
Ciclo Celular
Proliferação Celular
Transformação Celular Neoplásica/genética
Transformação Celular Neoplásica/metabolismo
Centrômero
Proteína Centromérica A
Neoplasias do Colo/genética
Neoplasias do Colo/metabolismo
Proteína 7 com Repetições F-Box-WD
Feminino
Histonas/metabolismo
Seres Humanos
Fosforilação
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantigens); 0 (Biomarkers, Tumor); 0 (CCNE1 protein, human); 0 (CENPA protein, human); 0 (Cell Cycle Proteins); 0 (Centromere Protein A); 0 (Chromosomal Proteins, Non-Histone); 0 (Cyclin E); 0 (F-Box Proteins); 0 (F-Box-WD Repeat-Containing Protein 7); 0 (FBXW7 protein, human); 0 (Histones); 0 (Oncogene Proteins); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 2.7.11.22 (CDK2 protein, human); EC 2.7.11.22 (Cyclin-Dependent Kinase 2)
[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:170802
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-17-1240



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