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Pesquisa : G03.143.310.100 [Categoria DeCS]
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[PMID]:29378242
[Au] Autor:Wang X; Xue M; Zhao M; He F; Li C; Li X
[Ad] Endereço:Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
[Ti] Título:Identification of a novel mutation (Ala66Thr) of SRY gene causes XY pure gonadal dysgenesis by affecting DNA binding activity and nuclear import.
[So] Source:Gene;651:143-151, 2018 Apr 20.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Sex-determining region of the Y chromosome (SRY) gene plays a crucial role in male sexual differentiation and development. Several mutations in the SRY gene have been reported in the high mobility group (HMG) box domain and can cause gonadal dysgenesis symptoms. In this study, we report that a novel missense mutation in the SRY gene, a G to A transition within the HMG box, causes the Ala66Thr amino acid substitution in a female patient presenting 46,XY karyotype with pure gonadal dysgenesis. The G to A base transition was not found in the SRY sequence after the screening of 100 normal males. Furthermore, Ala66Thr mutation drastically reduced the binding capacity of SRY to DNA sequences, whereas wild-type SRY protein showed the normal binding capacity to DNA sequences in vitro. We also found that the mutant SRY protein was partly localized in cytoplasm, whereas wild-type SRY protein was strictly localized in cell nucleus. In addition, we analyzed the three-dimensional structure of SRY protein by homology modeling methods. In conclusion, we identified a novel SRY mutation in a 46,XY female patient with pure gonadal dysgenesis, demonstrating the importance of the Ala66Thr mutation in DNA binding activity and nuclear transport.
[Mh] Termos MeSH primário: Disgenesia Gonadal 46 XY/genética
Mutação de Sentido Incorreto
Proteína da Região Y Determinante do Sexo/genética
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular
Adolescente
Adulto
Alanina
DNA/metabolismo
Feminino
Células HEK293
Seres Humanos
Cariotipagem
Masculino
Ligação Proteica
Conformação Proteica
Análise de Sequência de DNA
Proteína da Região Y Determinante do Sexo/química
Proteína da Região Y Determinante do Sexo/metabolismo
Treonina
Adulto Jovem
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Sex-Determining Region Y Protein); 2ZD004190S (Threonine); 9007-49-2 (DNA); OF5P57N2ZX (Alanine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180130
[St] Status:MEDLINE


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[PMID]:29031765
[Au] Autor:Boakye YD; Groyer L; Heiss EH
[Ad] Endereço:Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
[Ti] Título:An increased autophagic flux contributes to the anti-inflammatory potential of urolithin A in macrophages.
[So] Source:Biochim Biophys Acta;1862(1):61-70, 2018 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: An extract of Phyllanthus muellerianus and its constituent geraniin have been reported to exert anti-inflammatory activity in vivo. However, orally consumed geraniin, an ellagitannin, shows low bioavailability and undergoes metabolization to urolithins by gut microbiota. This study aimed at comparing geraniin and urolithin A with respect to inhibition of M1 (LPS) polarization of murine J774.1 macrophages and shedding more light on possible underlying mechanisms. METHODS: Photometric, fluorimetric as well as luminescence-based assays monitored production of reactive oxygen species (ROS) and nitric oxide (NO), cell viability or reporter gene expression. Western blot analyses and confocal microscopy showed abundance and localization of target proteins, respectively. RESULTS: Urolithin A is a stronger inhibitor of M1 (LPS) macrophage polarization (production of NO, ROS and pro-inflammatory proteins) than geraniin. Urolithin A leads to an elevated autophagic flux in macrophages. Inhibition of autophagy in M1 (LPS) macrophages overcomes the suppressed nuclear translocation of p65 (NF-kB; nuclear factor kB), the reduced expression of pro-inflammatory genes as well as the diminished NO production brought about by urolithin A. The increased autophagic flux is furthermore associated with impaired Akt/mTOR (mammalian target of rapamycin) signaling in urolithin A-treated macrophages. CONCLUSIONS AND GENERAL SIGNIFICANCE: Intestinal metabolization may boost the potential health benefit of widely consumed dietary ellagitannins, as suggested by side by side comparison of geraniin and urolithin A in M1(LPS) macrophages. Increased activity of the autophagic cellular recycling machinery aids the anti-inflammatory bioactivity of urolithin A.
[Mh] Termos MeSH primário: Anti-Inflamatórios/farmacologia
Autofagia/efeitos dos fármacos
Cumarínicos/farmacologia
Macrófagos/metabolismo
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/efeitos dos fármacos
Animais
Células CHO
Núcleo Celular/metabolismo
Cricetinae
Cricetulus
Células HEK293
Seres Humanos
Lipopolissacarídeos/toxicidade
Camundongos
Óxido Nítrico/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Fator de Transcrição RelA/metabolismo
Proteínas ral de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Coumarins); 0 (Lipopolysaccharides); 0 (RELA protein, human); 0 (Reactive Oxygen Species); 0 (Transcription Factor RelA); 1143-70-0 (3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one); 31C4KY9ESH (Nitric Oxide); EC 3.6.1.- (Rala protein, mouse); EC 3.6.5.2 (ral GTP-Binding Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE


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[PMID]:29362359
[Au] Autor:Naumann M; Pal A; Goswami A; Lojewski X; Japtok J; Vehlow A; Naujock M; Günther R; Jin M; Stanslowsky N; Reinhardt P; Sterneckert J; Frickenhaus M; Pan-Montojo F; Storkebaum E; Poser I; Freischmidt A; Weishaupt JH; Holzmann K; Troost D; Ludolph AC; Boeckers TM; Liebau S; Petri S; Cordes N; Hyman AA; Wegner F; Grill SW; Weis J; Storch A; Hermann A
[Ad] Endereço:Department of Neurology, Technische Universität Dresden, 01307, Dresden, Germany.
[Ti] Título:Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation.
[So] Source:Nat Commun;9(1):335, 2018 01 23.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Cytoplasmic fused in sarcoma (FUS) aggregates are pathological hallmarks of FUS-ALS. Proper shuttling between the nucleus and cytoplasm is essential for physiological cell function. However, the initial event in the pathophysiology of FUS-ALS remains enigmatic. Using human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs), we show that impairment of poly(ADP-ribose) polymerase (PARP)-dependent DNA damage response (DDR) signaling due to mutations in the FUS nuclear localization sequence (NLS) induces additional cytoplasmic FUS mislocalization which in turn results in neurodegeneration and FUS aggregate formation. Our work suggests that a key pathophysiologic event in ALS is upstream of aggregate formation. Targeting DDR signaling could lead to novel therapeutic routes for ameliorating ALS.
[Mh] Termos MeSH primário: Esclerose Amiotrófica Lateral/metabolismo
Dano ao DNA
Neurônios Motores/metabolismo
Mutação
Agregação Patológica de Proteínas/metabolismo
Proteína FUS de Ligação a RNA/metabolismo
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/genética
Idoso
Idoso de 80 Anos ou mais
Esclerose Amiotrófica Lateral/genética
Esclerose Amiotrófica Lateral/patologia
Diferenciação Celular
Núcleo Celular/metabolismo
Citoplasma/metabolismo
Feminino
Expressão Gênica
Seres Humanos
Células-Tronco Pluripotentes Induzidas/metabolismo
Células-Tronco Pluripotentes Induzidas/patologia
Masculino
Meia-Idade
Neurônios Motores/patologia
Sinais de Localização Nuclear/genética
Sinais de Localização Nuclear/metabolismo
Poli(ADP-Ribose) Polimerase-1/genética
Poli(ADP-Ribose) Polimerase-1/metabolismo
Agregação Patológica de Proteínas/genética
Agregação Patológica de Proteínas/patologia
Proteína FUS de Ligação a RNA/genética
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Nuclear Localization Signals); 0 (RNA-Binding Protein FUS); EC 2.4.2.30 (PARP1 protein, human); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180125
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02299-1


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[PMID]:28453191
[Au] Autor:Wang K; Chen Z; Huang J; Huang L; Luo N; Liang X; Liang M; Xie W
[Ad] Endereço:Southern Medical University, Guangzhou, China.
[Ti] Título:Naringenin prevents ischaemic stroke damage via anti-apoptotic and anti-oxidant effects.
[So] Source:Clin Exp Pharmacol Physiol;44(8):862-871, 2017 Aug.
[Is] ISSN:1440-1681
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:Apoptosis and oxidative stress are considered to be the major factors associated with the development and progression of many ischaemic cerebrovascular diseases. Naringenin (NAR) is an abundant flavanone in citrus plants and has been found to exhibit anti-oxidant, anti-carcinogenic and anti-apoptotic effects. This study aimed to investigate the anti-apoptotic and anti-oxidant effects of naringenin on ischaemic stroke. In vitro, cortical neuron cells isolated from the brains of neonatal Sprague-Dawley rats were randomly divided into control, oxygen and glucose deprivation/reperfusion (OGD/Rep), NAR-L, NAR-M and NAR-H groups. MTT and RT-PCR were used for cell proliferation and apoptosis-related proteins analyses. The effects of NAR on the Nrf2 signalling pathway were investigated using transfection approaches. Differences in mitochondrial dysfunction were analyzed by flow cytometry. In vivo, middle cerebral artery occlusion (MCAO) model was prepared and neurological defects and the brain wet/dry (W/D) ratio were assessed and recorded; apoptosis was measured based on the TUNEL assay. Additionally, biochemical indices were detected both in vitro and in vivo. NAR promoted cortical neuron cell proliferation, inhibited apoptosis and oxidative stress, and regulated the localization of Nrf2 protein (P<.05). Furthermore, silencing and overexpression of Nrf2 affected cortical neuron cell proliferation and apoptosis (P<.05). In vivo, NAR could alleviate cerebral oedema, improve neurological defects, and reduce apoptosis and oxidative stress (P<.05). These findings demonstrated that NAR could reduce apoptosis and oxidative stress and that Nrf2 signalling pathway is involved in this regulatory process. NAR has health-promoting properties because of its anti-apoptotic and anti-oxidant effects in cases of ischaemic stroke.
[Mh] Termos MeSH primário: Antioxidantes/farmacologia
Apoptose/efeitos dos fármacos
Flavanonas/farmacologia
Infarto da Artéria Cerebral Média/complicações
Acidente Vascular Cerebral/complicações
Acidente Vascular Cerebral/patologia
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/efeitos dos fármacos
Animais
Núcleo Celular/efeitos dos fármacos
Núcleo Celular/metabolismo
Proliferação Celular/efeitos dos fármacos
Citoproteção/efeitos dos fármacos
Regulação da Expressão Gênica/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Fator 2 Relacionado a NF-E2/metabolismo
Neurônios/efeitos dos fármacos
Neurônios/patologia
Estresse Oxidativo/efeitos dos fármacos
Ratos
Ratos Sprague-Dawley
Acidente Vascular Cerebral/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Flavanones); 0 (NF-E2-Related Factor 2); 0 (Nfe2l2 protein, rat); HN5425SBF2 (naringenin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1111/1440-1681.12775


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[PMID]:28463106
[Au] Autor:Zhong Y; Wang J; Henderson MJ; Yang P; Hagen BM; Siddique T; Vogel BE; Deng HX; Fang S
[Ad] Endereço:Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States.
[Ti] Título:Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus.
[So] Source:Elife;6, 2017 05 02.
[Is] ISSN:2050-084X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Over 170 different mutations in the gene encoding SOD1 all cause amyotrophic lateral sclerosis (ALS). Available studies have been primarily focused on the mechanisms underlying mutant SOD1 cytotoxicity. How cells defend against the cytotoxicity remains largely unknown. Here, we show that misfolding of ALS-linked SOD1 mutants and wild-type (wt) SOD1 exposes a normally buried nuclear export signal (NES)-like sequence. The nuclear export carrier protein CRM1 recognizes this NES-like sequence and exports misfolded SOD1 to the cytoplasm. Antibodies against the NES-like sequence recognize misfolded SOD1, but not native wt SOD1 both in vitro and in vivo. Disruption of the NES consensus sequence relocalizes mutant SOD1 to the nucleus, resulting in higher toxicity in cells, and severer impairments in locomotion, egg-laying, and survival in . Our data suggest that SOD1 mutants are removed from the nucleus by CRM1 as a defense mechanism against proteotoxicity of misfolded SOD1 in the nucleus.
[Mh] Termos MeSH primário: Transporte Ativo do Núcleo Celular
Carioferinas/metabolismo
Dobramento de Proteína
Receptores Citoplasmáticos e Nucleares/metabolismo
Superóxido Dismutase-1/metabolismo
Superóxido Dismutase-1/toxicidade
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Animais
Caenorhabditis elegans
Proteínas Mutantes/genética
Proteínas Mutantes/metabolismo
Proteínas Mutantes/toxicidade
Ligação Proteica
Sinais Direcionadores de Proteínas
Superóxido Dismutase-1/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Karyopherins); 0 (Mutant Proteins); 0 (Protein Sorting Signals); 0 (Receptors, Cytoplasmic and Nuclear); 0 (exportin 1 protein); EC 1.15.1.1 (Superoxide Dismutase-1)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


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[PMID]:28460446
[Au] Autor:Kapil S; Sharma BK; Patil M; Elattar S; Yuan J; Hou SX; Kolhe R; Satyanarayana A
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Molecular Oncology & Biomarkers Program, Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
[Ti] Título:The cell polarity protein Scrib functions as a tumor suppressor in liver cancer.
[So] Source:Oncotarget;8(16):26515-26531, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Scrib is a membrane protein that is involved in the maintenance of apical-basal cell polarity of the epithelial tissues. However, Scrib has also been shown to be mislocalized to the cytoplasm in breast and prostate cancer. Here, for the first time, we report that Scrib not only translocates to the cytoplasm but also to the nucleus in hepatocellular carcinoma (HCC) cells, and in mouse and human liver tumor samples. We demonstrate that Scrib overexpression suppresses the growth of HCC cells in vitro, and Scrib deficiency enhances liver tumor growth in vivo. At the molecular level, we have identified the existence of a positive feed-back loop between Yap1 and c-Myc in HCC cells, which Scrib disrupts by simultaneously regulating the MAPK/ERK and Hippo signaling pathways. Overall, Scrib inhibits liver cancer cell proliferation by suppressing the expression of three oncogenes, Yap1, c-Myc and cyclin D1, thereby functioning as a tumor suppressor in liver cancer.
[Mh] Termos MeSH primário: Neoplasias Hepáticas/metabolismo
Proteínas de Membrana/metabolismo
Proteínas Supressoras de Tumor/metabolismo
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular
Proteínas Adaptadoras de Transdução de Sinal/genética
Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Animais
Ciclo Celular/genética
Linhagem Celular Tumoral
Proliferação Celular
Transformação Celular Neoplásica/induzido quimicamente
Transformação Celular Neoplásica/genética
Transformação Celular Neoplásica/metabolismo
Ciclina D1/genética
Ciclina D1/metabolismo
Modelos Animais de Doenças
Expressão Gênica
Xenoenxertos
Seres Humanos
Neoplasias Hepáticas/genética
Sistema de Sinalização das MAP Quinases
Proteínas de Membrana/genética
Camundongos
Fosfoproteínas/genética
Fosfoproteínas/metabolismo
Ligação Proteica
Transporte Proteico
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Proto-Oncogênicas c-myc/genética
Proteínas Proto-Oncogênicas c-myc/metabolismo
Transdução de Sinais
Proteínas Supressoras de Tumor/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Membrane Proteins); 0 (Phosphoproteins); 0 (Proto-Oncogene Proteins c-myc); 0 (SCRIB protein, human); 0 (Tumor Suppressor Proteins); 0 (YAP1 (Yes-associated) protein, human); 136601-57-5 (Cyclin D1); EC 2.7.11.1 (Hippo protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15713


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[PMID]:28460443
[Au] Autor:Fan Q; Cheng Y; Chang HM; Deguchi M; Hsueh AJ; Leung PCK
[Ad] Endereço:Department of Obstetrics and Gynaecology, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada.
[Ti] Título:Sphingosine-1-phosphate promotes ovarian cancer cell proliferation by disrupting Hippo signaling.
[So] Source:Oncotarget;8(16):27166-27176, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Epithelial ovarian carcinomas account for more than 90% of human ovarian cancers and have become the primary cause of death for gynecological malignancies. Unlimited cell proliferation and resistance to cell apoptosis contribute to the development of ovarian cancers. However, the underlying mechanisms involved in these processes in epithelial ovarian carcinomas are yet poorly understood. In the present study, we examined the Hippo signaling gene expression and investigated the effects of Sphingosine 1-phosphate (S1P) on cell proliferation and the underlying mechanisms in human ovarian cancer cell lines, OVCAR3 and SKOV3. Our results demonstrate that S1P disrupts Hippo signaling by reducing YAP phosphorylation and increasing the expression of CCN1 and CCN2 in both ovarian cancer cells. Furthermore, the increase in CCN1/CCN2 expression contributes to the S1P-induced increase in cancer cell proliferation.
[Mh] Termos MeSH primário: Lisofosfolipídeos/farmacologia
Neoplasias Ovarianas/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
Transdução de Sinais/efeitos dos fármacos
Esfingosina/análogos & derivados
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Fator de Crescimento do Tecido Conjuntivo/genética
Fator de Crescimento do Tecido Conjuntivo/metabolismo
Proteína Rica em Cisteína 61/genética
Proteína Rica em Cisteína 61/metabolismo
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Proteínas Nucleares/metabolismo
Neoplasias Ovarianas/genética
Neoplasias Ovarianas/mortalidade
Neoplasias Ovarianas/patologia
Fosforilação
Fosfotransferases (Aceptor do Grupo Álcool)/genética
Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
Prognóstico
Esfingosina/farmacologia
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cysteine-Rich Protein 61); 0 (Lysophospholipids); 0 (Nuclear Proteins); 0 (Transcription Factors); 0 (YY1AP1 protein, human); 139568-91-5 (Connective Tissue Growth Factor); 26993-30-6 (sphingosine 1-phosphate); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 2.7.1.- (sphingosine kinase); EC 2.7.1.91 (sphingosine kinase 2, human); EC 2.7.11.1 (Hippo protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); NGZ37HRE42 (Sphingosine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15677


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[PMID]:29212662
[Au] Autor:Chatterjee K; Majumder S; Wan Y; Shah V; Wu J; Huang HY; Hopper AK
[Ad] Endereço:The Ohio State University Comprehensive Cancer Research Center, The Ohio State University, Columbus, Ohio 43210, USA.
[Ti] Título:Sharing the load: Mex67-Mtr2 cofunctions with Los1 in primary tRNA nuclear export.
[So] Source:Genes Dev;31(21):2186-2198, 2017 11 01.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Eukaryotic transfer RNAs (tRNAs) are exported from the nucleus, their site of synthesis, to the cytoplasm, their site of function for protein synthesis. The evolutionarily conserved ß-importin family member Los1 (Exportin-t) has been the only exporter known to execute nuclear export of newly transcribed intron-containing pre-tRNAs. Interestingly, is unessential in all tested organisms. As tRNA nuclear export is essential, we previously interrogated the budding yeast proteome to identify candidates that function in tRNA nuclear export. Here, we provide molecular, genetic, cytological, and biochemical evidence that the Mex67-Mtr2 (TAP-p15) heterodimer, best characterized for its essential role in mRNA nuclear export, cofunctions with Los1 in tRNA nuclear export. Inactivation of Mex67 or Mtr2 leads to rapid accumulation of end-matured unspliced tRNAs in the nucleus. Remarkably, merely fivefold overexpression of Mex67-Mtr2 can substitute for Los1 in Δ cells. Moreover, in vivo coimmunoprecipitation assays with tagged Mex67 document that the Mex67 binds tRNAs. Our data also show that tRNA exporters surprisingly exhibit differential tRNA substrate preferences. The existence of multiple tRNA exporters, each with different tRNA preferences, may indicate that the proteome can be regulated by tRNA nuclear export. Thus, our data show that Mex67-Mtr2 functions in primary nuclear export for a subset of yeast tRNAs.
[Mh] Termos MeSH primário: Transporte Ativo do Núcleo Celular/genética
Proteoma/genética
RNA de Transferência/metabolismo
Proteínas de Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/genética
Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: Inativação Gênica
Proteínas de Membrana Transportadoras/genética
Proteínas de Membrana Transportadoras/metabolismo
Complexo de Proteínas Formadoras de Poros Nucleares/genética
Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo
Proteínas Nucleares/genética
Proteínas Nucleares/metabolismo
Proteínas de Transporte Nucleocitoplasmático/genética
Proteínas de Transporte Nucleocitoplasmático/metabolismo
Ligação Proteica
Proteínas de Ligação a RNA/genética
Proteínas de Ligação a RNA/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Los1 protein, S cerevisiae); 0 (MEX67 protein, S cerevisiae); 0 (Membrane Transport Proteins); 0 (Mtr2 protein, S cerevisiae); 0 (Nuclear Pore Complex Proteins); 0 (Nuclear Proteins); 0 (Nucleocytoplasmic Transport Proteins); 0 (Proteome); 0 (RNA-Binding Proteins); 0 (Saccharomyces cerevisiae Proteins); 9014-25-9 (RNA, Transfer)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE
[do] DOI:10.1101/gad.305904.117


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[PMID]:28464919
[Au] Autor:Toth C; Funke S; Nitsche V; Liverts A; Zlachevska V; Gasis M; Wiek C; Hanenberg H; Mahotka C; Schirmacher P; Heikaus S
[Ad] Endereço:Institute of Pathology, Heinrich Heine University Hospital, Medical Faculty, Moorenstrasse 5, 40225, Düsseldorf, Germany. csaba.toth@med.uni-heidelberg.de.
[Ti] Título:The role of apoptosis repressor with a CARD domain (ARC) in the therapeutic resistance of renal cell carcinoma (RCC): the crucial role of ARC in the inhibition of extrinsic and intrinsic apoptotic signalling.
[So] Source:Cell Commun Signal;15(1):16, 2017 May 02.
[Is] ISSN:1478-811X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Renal cell carcinomas (RCCs) display broad resistance against conventional radio- and chemotherapies, which is due at least in part to impairments in both extrinsic and intrinsic apoptotic pathways. One important anti-apoptotic factor that is strongly overexpressed in RCCs and known to inhibit both apoptotic pathways is ARC (apoptosis repressor with a CARD domain). METHODS: Expression and subcellular distribution of ARC in RCC tissue samples and RCC cell lines were determined by immunohistochemistry and fluorescent immunohistochemistry, respectively. Extrinsic and intrinsic apoptosis signalling were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT-263 or topotecan. ARC knock-down was performed in clearCa-12 cells using lentiviral transduction of pGIPZ. shRNAmir constructs. Extrinsic respectively intrinsic apoptosis were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT263 or topotecan. Potential synergistic effects were tested by pre-treatment with topotecan and subsequent treatment with ABT263. Activation of different caspases and mitochondrial depolarisation (JC-1 staining) were analysed by flow cytometry. Protein expression of Bcl-2 family members and ARC in RCC cell lines was measured by Western blotting. Statistical analysis was performed by Student's t-test. RESULTS: Regarding the extrinsic pathway, ARC knockdown strongly enhanced TRAIL-induced apoptosis by increasing the activation level of caspase-8. Regarding the intrinsic pathway, ARC, which was only weakly expressed in the nuclei of RCCs in vivo, exerted its anti-apoptotic effect by impairing mitochondrial activation rather than inhibiting p53. Topotecan- and ABT-263-induced apoptosis was strongly enhanced following ARC knockdown in RCC cell lines. In addition, topotecan pre-treatment enhanced ABT-263-induced apoptosis and this effect was amplified in ARC-knockdown cells. CONCLUSION: Taken together, our results are the first to demonstrate the importance of ARC protein in the inhibition of both the extrinsic and intrinsic pathways of apoptosis in RCCs. In this context, ARC cooperates with anti-apoptotic Bcl-2 family members to exert its strong anti-apoptotic effects and is therefore an important factor not only in the therapeutic resistance but also in future therapy strategies (i.e., Bcl-2 inhibitors) in RCC. In sum, targeting of ARC may enhance the therapeutic response in combination therapy protocols.
[Mh] Termos MeSH primário: Proteínas Reguladoras de Apoptose/metabolismo
Apoptose/efeitos dos fármacos
Carcinoma de Células Renais/patologia
Resistência a Medicamentos Antineoplásicos
Neoplasias Renais/patologia
Proteínas Musculares/metabolismo
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/efeitos dos fármacos
Compostos de Anilina/farmacologia
Proteínas Reguladoras de Apoptose/deficiência
Proteínas Reguladoras de Apoptose/genética
Linhagem Celular Tumoral
Núcleo Celular/efeitos dos fármacos
Núcleo Celular/metabolismo
Citoplasma/efeitos dos fármacos
Citoplasma/metabolismo
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Técnicas de Silenciamento de Genes
Seres Humanos
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/patologia
Terapia de Alvo Molecular
Proteínas Musculares/deficiência
Proteínas Musculares/genética
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Sulfonamidas/farmacologia
Topotecan/farmacologia
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aniline Compounds); 0 (Apoptosis Regulatory Proteins); 0 (Muscle Proteins); 0 (NOL3 protein, human); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Sulfonamides); 0 (Tumor Suppressor Protein p53); 7M7YKX2N15 (Topotecan); XKJ5VVK2WD (navitoclax)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1186/s12964-017-0170-5


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[PMID]:29326041
[Au] Autor:Xiao C; Yu Q; Zhang B; Li J; Zhang D; Li M
[Ad] Endereço:Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin 300071, China.
[Ti] Título:Role of the mRNA export factor Sus1 in oxidative stress tolerance in Candida albicans.
[So] Source:Biochem Biophys Res Commun;496(2):253-259, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In eukaryotes, the nuclear export of mRNAs is essential for gene expression. However, little is known about the role of mRNA nuclear export in the important fungal pathogen, Candida albicans. In this study, we identified C. albicans Sus1, a nucleus-localized protein that is required for mRNA export. Interestingly, the sus1Δ/Δ displayed hyper-sensitivity to extracellular oxidative stress, enhanced ROS accumulation and severe oxidative stress-related cell death. More strikingly, although the mutant exhibited normal activation of the expression of oxidative stress response (OSR) genes, it had attenuated activity of ROS scavenging system, which may be attributed to the defect in OSR mRNA export in this mutant. In addition, the virulence of the sus1Δ/Δ was seriously attenuated. Taken together, our findings provide evidence that the mRNA export factor Sus1 plays an important role in oxidative stress tolerance and pathogenesis.
[Mh] Termos MeSH primário: Candida albicans/genética
Candida albicans/patogenicidade
Regulação Fúngica da Expressão Gênica
Proteínas Nucleares/genética
Estresse Oxidativo/genética
Proteínas de Ligação a RNA/genética
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular
Candida albicans/metabolismo
Núcleo Celular/metabolismo
Deleção de Genes
Viabilidade Microbiana
Proteínas Nucleares/metabolismo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Proteínas de Ligação a RNA/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Estresse Fisiológico
Virulência
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Nuclear Proteins); 0 (RNA, Messenger); 0 (RNA-Binding Proteins); 0 (Reactive Oxygen Species)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180113
[St] Status:MEDLINE



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