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Pesquisa : D12.776.157.725.813.500.250 [Categoria DeCS]
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[PMID]:28460014
[Au] Autor:Wu X; Wang SH; Sun J; Krainer AR; Hua Y; Prior TW
[Ad] Endereço:Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China.
[Ti] Título:A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy.
[So] Source:Hum Mol Genet;26(14):2768-2780, 2017 07 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Spinal muscular atrophy (SMA) is a neuromuscular disease caused by reduced expression of survival of motor neuron (SMN), a protein expressed in humans by two paralogous genes, SMN1 and SMN2. These genes are nearly identical, except for 10 single-nucleotide differences and a 5-nucleotide insertion in SMN2. SMA is subdivided into four main types, with type I being the most severe. SMN2 copy number is a key positive modifier of the disease, but it is not always inversely correlated with clinical severity. We previously reported the c.859G > C variant in SMN2 exon 7 as a positive modifier in several patients. We have now identified A-44G as an additional positive disease modifier, present in a group of patients carrying 3 SMN2 copies but displaying milder clinical phenotypes than other patients with the same SMN2 copy number. One of the three SMN2 copies appears to have been converted from SMN1, but except for the C6T transition, no other changes were detected. Analyzed with minigenes, SMN1C6T displayed a ∼20% increase in exon 7 inclusion, compared to SMN2. Through systematic mutagenesis, we found that the improvement in exon 7 splicing is mainly attributable to the A-44G transition in intron 6. Using RNA-affinity chromatography and mass spectrometry, we further uncovered binding of the RNA-binding protein HuR to the -44 region, where it acts as a splicing repressor. The A-44G change markedly decreases the binding affinity of HuR, resulting in a moderate increase in exon 7 inclusion.
[Mh] Termos MeSH primário: Atrofia Muscular Espinal/genética
[Mh] Termos MeSH secundário: Animais
Células COS
Cercopithecus aethiops
Proteína Semelhante a ELAV 1/metabolismo
Éxons
Células HEK293
Células HeLa
Seres Humanos
Íntrons
Atrofia Muscular Espinal/metabolismo
Ligação Proteica
RNA/genética
Motivo de Reconhecimento de RNA
Processamento de RNA
Proteína 1 de Sobrevivência do Neurônio Motor/genética
Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo
Proteína 2 de Sobrevivência do Neurônio Motor/genética
Proteína 2 de Sobrevivência do Neurônio Motor/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 (ELAV-Like Protein 1); 0 (ELAVL1 protein, human); 0 (SMN1 protein, human); 0 (SMN2 protein, human); 0 (Survival of Motor Neuron 1 Protein); 0 (Survival of Motor Neuron 2 Protein); 63231-63-0 (RNA)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180225
[Lr] Data última revisão:
180225
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx166


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[PMID]:29225167
[Au] Autor:Jehung JP; Kitamura T; Yanagawa-Matsuda A; Kuroshima T; Towfik A; Yasuda M; Sano H; Kitagawa Y; Minowa K; Shindoh M; Higashino F
[Ad] Endereço:Department of Restorative Dentistry, Hokkaido University, Faculty of Dental Medicine, Graduate School of Dental Medicine, Sapporo, Japan.
[Ti] Título:Adenovirus infection induces HuR relocalization to facilitate virus replication.
[So] Source:Biochem Biophys Res Commun;495(2):1795-1800, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HuR is an RNA-binding protein of the embryonic lethal abnormal vision (ELAV) family, which binds to the AU-rich element (ARE) in the 3'-untranslated region (UTR) of certain mRNAs and is involved in the nucleo-cytoplasmic export and stabilization of ARE-mRNAs. The cytoplasmic relocalization of ARE-mRNAs with several proteins such as HuR and pp32 increases in cells transformed by the adenovirus oncogene product E4orf6. Additionally, these ARE-mRNAs were stabilized and acquired the potential to transform cells. Although, the relocalization of HuR and the stabilization of ARE-mRNAs are crucial for cell transformation, evidence regarding the relationship of HuR and ARE-mRNAs with adenovirus replication is lacking. In this report, we demonstrate that adenovirus infection induces the relocation of HuR to the cytoplasm of host cells. Analysis using the luciferase-ARE fusion gene and the tetracycline (tet)-off system revealed that the process of stabilizing ARE-mRNAs is activated in adenovirus-infected cells. Heat shock treatment or knockdown-mediated depletion of HuR reduced adenovirus production. Furthermore, expression of ARE-including viral IVa2 mRNA, decreased in HuR-depleted infected cells. These results indicate that HuR plays an important role in adenovirus replication, at least in part, by up-regulating IVa2 mRNA expression and that ARE-mRNA stabilization is required for both transformation and virus replication.
[Mh] Termos MeSH primário: Infecções por Adenovirus Humanos/metabolismo
Infecções por Adenovirus Humanos/virologia
Proteína Semelhante a ELAV 1/metabolismo
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas
Elementos Ricos em Adenilato e Uridilato
Infecções por Adenovirus Humanos/genética
Adenovírus Humanos/genética
Adenovírus Humanos/fisiologia
Transformação Celular Viral/genética
Proteína Semelhante a ELAV 1/antagonistas & inibidores
Proteína Semelhante a ELAV 1/genética
Técnicas de Silenciamento de Genes
Células HeLa
Seres Humanos
Transporte Proteico
Estabilidade de RNA
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Proteínas Virais/genética
Replicação Viral/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (ELAV-Like Protein 1); 0 (ELAVL1 protein, human); 0 (RNA, Messenger); 0 (Viral Proteins); 0 (iva2 protein, adenovirus)
[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:171212
[St] Status:MEDLINE


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[PMID]:28744670
[Au] Autor:Lema I; Amazit L; Lamribet K; Fagart J; Blanchard A; Lombès M; Cherradi N; Viengchareun S
[Ad] Endereço:Inserm U1185, Faculté de Médecine Paris-Sud, Université Paris-Saclay, 63 rue Gabriel Peri, 94276, Le Kremlin-Bicêtre, France.
[Ti] Título:RNA-binding protein HuR enhances mineralocorticoid signaling in renal KC3AC1 cells under hypotonicity.
[So] Source:Cell Mol Life Sci;74(24):4587-4597, 2017 12.
[Is] ISSN:1420-9071
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Mineralocorticoid receptor (MR) mediates the sodium-retaining action of aldosterone in the distal nephron. Herein, we decipher mechanisms by which hypotonicity increases MR expression in renal principal cells. We identify HuR (human antigen R), an mRNA-stabilizing protein, as an important posttranscriptional regulator of MR expression. Hypotonicity triggers a rapid and reversible nuclear export of HuR in renal KC3AC1 cells, as quantified by high-throughput microscopy. We also identify a key hairpin motif in the 3'-untranslated region of MR transcript, pivotal for the interaction with HuR and its stabilizing function. Next, we show that hypotonicity increases MR recruitment onto Sgk1 promoter, a well-known MR target gene, thereby enhancing aldosterone responsiveness. Our data shed new light on the crucial role of HuR as a stabilizing factor for the MR transcript and provide evidence for a short autoregulatory loop in which expression of a nuclear receptor transcriptionally regulating water and sodium balance is controlled by osmotic tone.
[Mh] Termos MeSH primário: Proteína Semelhante a ELAV 1/metabolismo
Rim/metabolismo
Mineralocorticoides/metabolismo
Pressão Osmótica/fisiologia
Proteínas de Ligação a RNA/metabolismo
Receptores de Mineralocorticoides/metabolismo
Transdução de Sinais/fisiologia
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas/genética
Transporte Ativo do Núcleo Celular/genética
Aldosterona/metabolismo
Regulação da Expressão Gênica/genética
Células HEK293
Seres Humanos
Proteínas Imediatamente Precoces/metabolismo
Rim/fisiologia
Osmose/fisiologia
Regiões Promotoras Genéticas/genética
Proteínas Serina-Treonina Quinases/metabolismo
Processamento Pós-Transcricional do RNA/genética
RNA Mensageiro/metabolismo
Transcrição Genética/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (ELAV-Like Protein 1); 0 (ELAVL1 protein, human); 0 (Immediate-Early Proteins); 0 (Mineralocorticoids); 0 (RNA, Messenger); 0 (RNA-Binding Proteins); 0 (Receptors, Mineralocorticoid); 4964P6T9RB (Aldosterone); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (serum-glucocorticoid regulated kinase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:180131
[Lr] Data última revisão:
180131
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1007/s00018-017-2594-x


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[PMID]:28968471
[Au] Autor:Lin GL; Ting HJ; Tseng TC; Juang V; Lo YL
[Ad] Endereço:Department of Biological Sciences and Technology, National University of Tainan, Tainan, Taiwan.
[Ti] Título:Modulation of the mRNA-binding protein HuR as a novel reversal mechanism of epirubicin-triggered multidrug resistance in colorectal cancer cells.
[So] Source:PLoS One;12(10):e0185625, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HuR (ELAVL1), a RNA-binding protein, plays a key role in posttranscriptional regulation of multidrug resistance (MDR)-related genes. Among various HuR-regulated oncogenic transcripts, the activation of galectin-3/ß-catenin survival pathway is critical to induce transcription of cyclin D1, P-glycoprotein (P-gp) and/or multidrug resistance-associated proteins (MRPs). In this study, we aim to elucidate the HuR-regulating pathways related to epirubicin-mediated resistance in human colorectal carcinoma cells. The effects and mechanisms of epirubicin treatment on the expressions of upstream survival signals (e.g., ß-catenin) and downstream MDR transporters (e.g., P-gp) and anti-apoptotic pathways (e.g., Bcl-2) were assessed with or without HuR knockdown (siHuR) or overexpression (overHuR; ectopic HuR or pcDNA3/HA-HuR). Our results showed that siHuR decreased transcriptional expressions of galectin-3, ß-catenin, cyclin D1, Bcl-2, P-gp, MRP1, and MRP2 in epirubicin-treated colon cancer cells. Consistently, the co-treatment of epirubicin and siHuR diminished the expressions of galectin-3, ß-catenin, c-Myc, P-gp and MRP1. HuR silencing enhanced the intracellular accumulation of epirubicin in colon cancer cells. On the other hand, overHuR abolished such effects. Furthermore, siHuR significantly intensified epirubicin-mediated apoptosis via increasing reactive oxygen species and thus promoted the cytotoxic effect of epirubicin. The combined treatments of siHuR and epirubicin significantly reduced the expression of Bcl-2, but increased the expression of Bax, as well as activity and expression levels of caspase-3 and -9. In contrast, overHuR abrogated these effects. Our findings provide insight into the mechanisms by which siHuR potentiated epirubicin-induced cytotoxicity via inhibiting galectin-3/ß-catenin signaling, suppressing MDR transporters and provoking apoptosis. To our best knowledge, this is an innovative investigation linking the post-transcriptional control by HuR silencing to survival signaling repression, efflux transporter reversal and apoptosis induction. Our study thus provides a powerful regimen for circumventing MDR in colon cancer cells.
[Mh] Termos MeSH primário: Antibióticos Antineoplásicos/farmacologia
Neoplasias Colorretais/patologia
Resistência a Múltiplos Medicamentos/efeitos dos fármacos
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Proteína Semelhante a ELAV 1/fisiologia
Epirubicina/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Western Blotting
Linhagem Celular Tumoral
Neoplasias Colorretais/tratamento farmacológico
Neoplasias Colorretais/metabolismo
Proteína Semelhante a ELAV 1/genética
Inativação Gênica
Seres Humanos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética
Espécies Reativas de Oxigênio/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
Reação em Cadeia da Polimerase Via Transcriptase Reversa
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibiotics, Antineoplastic); 0 (ELAV-Like Protein 1); 0 (Multidrug Resistance-Associated Proteins); 0 (Reactive Oxygen Species); 3Z8479ZZ5X (Epirubicin)
[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:171003
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185625


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[PMID]:28965949
[Au] Autor:Pu J; Zhang X; Luo H; Xu L; Lu X; Lu J
[Ad] Endereço:Department of General Surgery, Tangdu Hospital of the Fourth Military Medical University, Xi'an 710038, PR China.
[Ti] Título:Adrenaline promotes epithelial-to-mesenchymal transition via HuR-TGFß regulatory axis in pancreatic cancer cells and the implication in cancer prognosis.
[So] Source:Biochem Biophys Res Commun;493(3):1273-1279, 2017 Nov 25.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Psychological stress has recently been described as a risk factor in the development of pancreatic cancer. Here, we reported that increased neurotransmitter adrenaline was associated with the poor survival in pancreatic cancer patients. Moreover, in the cell model study, we found adrenaline promoted pancreatic cell PANC-1 migration in a dose dependent manner. Block of the ß2-adrenoreceptor with ICI118,551, significantly reduced cell migration. Further study found that adrenaline induced a cytoplasmic translocation of RNA binding protein HuR, which in turn activated TGFß, as shown by the SBE luciferase assay and phosphorylation of Smad2/3. Either HuR knockdown or TGFß inhibition reduced cell migration induced by adrenaline. Taken together, our study here revealed that adrenaline-HuR-TGFß regulatory axis at least partially contributes to the psychological stress induced metastasis in PANC-1 cells, shedding light on therapeutic targeting psychological stress in improving the prognosis of pancreatic cancer.
[Mh] Termos MeSH primário: Proteína Semelhante a ELAV 1/metabolismo
Epinefrina/metabolismo
Neoplasias Pancreáticas/metabolismo
Neoplasias Pancreáticas/patologia
Fator de Crescimento Transformador beta/metabolismo
[Mh] Termos MeSH secundário: Antagonistas Adrenérgicos beta/farmacologia
Idoso
Linhagem Celular Tumoral
Movimento Celular
Proteína Semelhante a ELAV 1/genética
Epinefrina/sangue
Transição Epitelial-Mesenquimal/fisiologia
Feminino
Seres Humanos
Estimativa de Kaplan-Meier
Masculino
Meia-Idade
Neoplasias Pancreáticas/mortalidade
Propanolaminas/farmacologia
Receptores Adrenérgicos beta 2/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adrenergic beta-Antagonists); 0 (ELAV-Like Protein 1); 0 (ELAVL1 protein, human); 0 (Propanolamines); 0 (Receptors, Adrenergic, beta-2); 0 (Transforming Growth Factor beta); 46OL1UC10R (ICI 118551); YKH834O4BH (Epinephrine)
[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:171003
[St] Status:MEDLINE


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[PMID]:28934484
[Au] Autor:Lal P; Cerofolini L; D'Agostino VG; Zucal C; Fuccio C; Bonomo I; Dassi E; Giuntini S; Di Maio D; Vishwakarma V; Preet R; Williams SN; Fairlamb MS; Munk R; Lehrmann E; Abdelmohsen K; Elezgarai SR; Luchinat C; Novellino E; Quattrone A; Biasini E; Manzoni L; Gorospe M; Dixon DA; Seneci P; Marinelli L; Fragai M; Provenzani A
[Ad] Endereço:Centre for Integrative Biology, CIBIO, University of Trento, Trento 38122, Italy.
[Ti] Título:Regulation of HuR structure and function by dihydrotanshinone-I.
[So] Source:Nucleic Acids Res;45(16):9514-9527, 2017 Sep 19.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The Human antigen R protein (HuR) is an RNA-binding protein that recognizes U/AU-rich elements in diverse RNAs through two RNA-recognition motifs, RRM1 and RRM2, and post-transcriptionally regulates the fate of target RNAs. The natural product dihydrotanshinone-I (DHTS) prevents the association of HuR and target RNAs in vitro and in cultured cells by interfering with the binding of HuR to RNA. Here, we report the structural determinants of the interaction between DHTS and HuR and the impact of DHTS on HuR binding to target mRNAs transcriptome-wide. NMR titration and Molecular Dynamics simulation identified the residues within RRM1 and RRM2 responsible for the interaction between DHTS and HuR. RNA Electromobility Shifts and Alpha Screen Assays showed that DHTS interacts with HuR through the same binding regions as target RNAs, stabilizing HuR in a locked conformation that hampers RNA binding competitively. HuR ribonucleoprotein immunoprecipitation followed by microarray (RIP-chip) analysis showed that DHTS treatment of HeLa cells paradoxically enriched HuR binding to mRNAs with longer 3'UTR and with higher density of U/AU-rich elements, suggesting that DHTS inhibits the association of HuR to weaker target mRNAs. In vivo, DHTS potently inhibited xenograft tumor growth in a HuR-dependent model without systemic toxicity.
[Mh] Termos MeSH primário: Proteína Semelhante a ELAV 1/química
Fenantrenos/química
Fenantrenos/farmacologia
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas
Elementos Ricos em Adenilato e Uridilato
Animais
Antineoplásicos Fitogênicos/química
Antineoplásicos Fitogênicos/farmacologia
Proteína Semelhante a ELAV 1/antagonistas & inibidores
Proteína Semelhante a ELAV 1/genética
Proteína Semelhante a ELAV 1/metabolismo
Seres Humanos
Espectroscopia de Ressonância Magnética
Camundongos Mutantes Neurológicos
Simulação de Dinâmica Molecular
Fenantrenos/metabolismo
Mutação Puntual
Conformação Proteica
Domínios Proteicos
RNA Mensageiro/metabolismo
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (15,16-dihydrotanshinone I); 0 (3' Untranslated Regions); 0 (Antineoplastic Agents, Phytogenic); 0 (ELAV-Like Protein 1); 0 (ELAVL1 protein, human); 0 (Phenanthrenes); 0 (RNA, Messenger)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx623


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[PMID]:28790173
[Au] Autor:Filippova N; Yang X; Ananthan S; Sorochinsky A; Hackney JR; Gentry Z; Bae S; King P; Nabors LB
[Ad] Endereço:From the Departments of Neurology.
[Ti] Título:Hu antigen R (HuR) multimerization contributes to glioma disease progression.
[So] Source:J Biol Chem;292(41):16999-17010, 2017 Oct 13.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Among primary brain cancers, gliomas are the most deadly and most refractory to current treatment modalities. Previous reports overwhelmingly support the role of the RNA-binding protein Hu antigen R (HuR) as a positive regulator of glioma disease progression. HuR expression is consistently elevated in tumor tissues, and a cytoplasmic localization appears essential for HuR-dependent oncogenic transformation. Here, we report HuR aggregation (multimerization) in glioma and the analysis of this tumor-specific HuR protein multimerization in clinical brain tumor samples. Using a split luciferase assay, a bioluminescence resonance energy transfer technique, and site-directed mutagenesis, we examined the domains involved in HuR multimerization. Results obtained with the combination of the split HuR luciferase assay with the bioluminescence resonance energy transfer technique suggested that multiple (at least three) HuR molecules come together during HuR multimerization in glioma cells. Using these data, we developed a model of HuR multimerization in glioma cells. We also demonstrate that exposing glioma cells to the HuR inhibitor tanshinone group compound 15,16-dihydrotanshinone-I or to the newly identified compound 5 disrupts HuR multimerization modules and reduces tumor cell survival and proliferation. In summary, our findings provide new insights into HuR multimerization in glioma and highlight possible pharmacological approaches for targeting HuR domains involved in cancer cell-specific multimerization.
[Mh] Termos MeSH primário: Transformação Celular Neoplásica/metabolismo
Proteína Semelhante a ELAV 1/metabolismo
Glioma/metabolismo
Proteínas de Neoplasias/metabolismo
Agregação Patológica de Proteínas/metabolismo
[Mh] Termos MeSH secundário: Neoplasias Encefálicas
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Proliferação Celular/genética
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/genética
Transformação Celular Neoplásica/efeitos dos fármacos
Transformação Celular Neoplásica/genética
Transformação Celular Neoplásica/patologia
Proteína Semelhante a ELAV 1/antagonistas & inibidores
Proteína Semelhante a ELAV 1/genética
Glioma/tratamento farmacológico
Glioma/genética
Glioma/patologia
Seres Humanos
Proteínas de Neoplasias/antagonistas & inibidores
Proteínas de Neoplasias/genética
Fenantrenos/farmacologia
Agregação Patológica de Proteínas/tratamento farmacológico
Agregação Patológica de Proteínas/genética
Agregação Patológica de Proteínas/patologia
Domínios Proteicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (15,16-dihydrotanshinone I); 0 (ELAV-Like Protein 1); 0 (ELAVL1 protein, human); 0 (Neoplasm Proteins); 0 (Phenanthrenes)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.797878


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[PMID]:28687616
[Au] Autor:Chand SN; Zarei M; Schiewer MJ; Kamath AR; Romeo C; Lal S; Cozzitorto JA; Nevler A; Scolaro L; Londin E; Jiang W; Meisner-Kober N; Pishvaian MJ; Knudsen KE; Yeo CJ; Pascal JM; Winter JM; Brody JR
[Ad] Endereço:Department of Surgery, The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
[Ti] Título:Posttranscriptional Regulation of mRNA by HuR Facilitates DNA Repair and Resistance to PARP Inhibitors.
[So] Source:Cancer Res;77(18):5011-5025, 2017 Sep 15.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The majority of pancreatic ductal adenocarcinomas (PDAC) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here, we show that CRISPR-Cas9-mediated silencing of the HuR locus increases the relative sensitivity of PDAC cells to PARP inhibitors (PARPi). PDAC cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, poly (ADP-ribose) glycohydrolase ( ) mRNA, by binding a unique sequence embedded in its 3' untranslated region. HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to inhibit HuR directly promoted DNA damage accumulation, inefficient PAR removal, and persistent PARP-1 residency on chromatin (PARP-1 trapping). Immunoprecipitation assays demonstrated that the PARP-1 protein binds and posttranslationally modifies HuR in PARPi-treated PDAC cells. In a mouse xenograft model of human PDAC, PARPi monotherapy combined with targeted silencing of HuR significantly reduced tumor growth compared with PARPi therapy alone. Our results highlight the HuR-PARG axis as an opportunity to enhance PARPi-based therapies. .
[Mh] Termos MeSH primário: Reparo do DNA/genética
Resistência a Medicamentos Antineoplásicos/genética
Proteína Semelhante a ELAV 1/metabolismo
Glicosídeo Hidrolases/genética
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Poli(ADP-Ribose) Polimerases/química
Processamento Pós-Transcricional do RNA
RNA Mensageiro/genética
[Mh] Termos MeSH secundário: Animais
Apoptose
Biomarcadores Tumorais/genética
Biomarcadores Tumorais/metabolismo
Carcinoma Ductal Pancreático/genética
Carcinoma Ductal Pancreático/metabolismo
Carcinoma Ductal Pancreático/patologia
Núcleo Celular/efeitos dos fármacos
Núcleo Celular/genética
Proliferação Celular
Dano ao DNA/efeitos dos fármacos
Dano ao DNA/genética
Reparo do DNA/efeitos dos fármacos
Proteína Semelhante a ELAV 1/antagonistas & inibidores
Proteína Semelhante a ELAV 1/genética
Feminino
Seres Humanos
Camundongos
Camundongos Nus
Neoplasias Pancreáticas/genética
Neoplasias Pancreáticas/metabolismo
Neoplasias Pancreáticas/patologia
Células Tumorais Cultivadas
Regulação para Cima
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (ELAV-Like Protein 1); 0 (ELAVL1 protein, human); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 0 (RNA, Messenger); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases); EC 3.2.1.- (Glycoside Hydrolases); EC 3.2.1.143 (poly ADP-ribose glycohydrolase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170709
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-16-2704


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[PMID]:28684423
[Au] Autor:Chen J; Martindale JL; Cramer C; Gorospe M; Atasoy U; Drew PD; Yu S
[Ad] Endereço:From the Arkansas Biosciences Institute, Department of Biological Sciences, Arkansas State University, Jonesboro, Arkansas 72467, jing.chen@jefferson.edu.
[Ti] Título:The RNA-binding protein HuR contributes to neuroinflammation by promoting C-C chemokine receptor 6 (CCR6) expression on Th17 cells.
[So] Source:J Biol Chem;292(35):14532-14543, 2017 Sep 01.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In both multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), the C-C chemokine receptor 6 (CCR6) is critical for pathogenic T helper 17 (Th17) cell migration to the central nervous system (CNS). Whereas many cytokines and their receptors are potently regulated via post-transcriptional mechanisms in response to various stimuli, how CCR6 expression is post-transcriptionally regulated in Th17 cells is unknown. Here, using RNA-binding protein HuR conditional knock-out (KO) and wild-type (WT) mice, we present evidence that HuR post-transcriptionally regulates CCR6 expression by binding to and stabilizing mRNA and by promoting CCR6 translation. We also found that HuR down-regulates several microRNA expressions, which could target the 3'-UTR of Ccr6 mRNA for decay. Accordingly, knock-out of HuR reduced CCR6 expression on Th17 cells and impaired their migration to CNS compared with the response of WT Th17 cells and thereby ameliorated EAE. Together, these findings highlight how HuR contributes to Th17 cell-mediated autoimmune neuroinflammation and support the notion that targeting HuR might be a potential therapeutic intervention for managing autoimmune disorders of the CNS.
[Mh] Termos MeSH primário: Proteína Semelhante a ELAV 1/metabolismo
Regulação da Expressão Gênica
RNA Mensageiro/metabolismo
Receptores CCR6/agonistas
Linfócitos T Auxiliares-Indutores/metabolismo
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas
Animais
Doenças Autoimunes do Sistema Nervoso/imunologia
Doenças Autoimunes do Sistema Nervoso/metabolismo
Doenças Autoimunes do Sistema Nervoso/patologia
Linhagem Celular
Movimento Celular
Células Cultivadas
Sistema Nervoso Central/imunologia
Sistema Nervoso Central/metabolismo
Sistema Nervoso Central/patologia
Proteína Semelhante a ELAV 1/antagonistas & inibidores
Proteína Semelhante a ELAV 1/genética
Encefalomielite/imunologia
Encefalomielite/metabolismo
Encefalomielite/patologia
Seres Humanos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Camundongos Transgênicos
MicroRNAs/metabolismo
Biossíntese de Proteínas
Interferência de RNA
Estabilidade de RNA
Receptores CCR6/antagonistas & inibidores
Receptores CCR6/genética
Receptores CCR6/metabolismo
Linfócitos T Auxiliares-Indutores/citologia
Linfócitos T Auxiliares-Indutores/imunologia
Linfócitos T Auxiliares-Indutores/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (CCR6 protein, mouse); 0 (ELAV-Like Protein 1); 0 (ELAVL1 protein, human); 0 (Elavl1 protein, mouse); 0 (MicroRNAs); 0 (RNA, Messenger); 0 (Receptors, CCR6)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.782771


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[PMID]:28652247
[Au] Autor:Zarei M; Lal S; Parker SJ; Nevler A; Vaziri-Gohar A; Dukleska K; Mambelli-Lisboa NC; Moffat C; Blanco FF; Chand SN; Jimbo M; Cozzitorto JA; Jiang W; Yeo CJ; Londin ER; Seifert EL; Metallo CM; Brody JR; Winter JM
[Ad] Endereço:Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
[Ti] Título:Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells.
[So] Source:Cancer Res;77(16):4460-4471, 2017 Aug 15.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine ( = 107) with elevated serum glucose levels (HgbA1C > 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled by either nutrient withdrawal or gemcitabine treatment, but depriving PDAC cells of nutrients before gemcitabine treatment attenuated this effect. Mechanistic investigations based on RNAi or CRISPR approaches implicated the RNA binding protein HuR in preserving survival under nutrient withdrawal, with or without gemcitabine. Notably, RNA deep sequencing and functional analyses in HuR-deficient PDAC cell lines identified isocitrate dehydrogenase 1 (IDH1) as the sole antioxidant enzyme under HuR regulation. HuR-deficient PDAC cells lacked the ability to engraft successfully in immunocompromised mice, but IDH1 overexpression in these cells was sufficient to fully restore chemoresistance under low nutrient conditions. Overall, our findings highlight the HuR-IDH1 regulatory axis as a critical, actionable therapeutic target in pancreatic cancer. .
[Mh] Termos MeSH primário: Proteína Semelhante a ELAV 1/metabolismo
Isocitrato Desidrogenase/metabolismo
Neoplasias Pancreáticas/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Proliferação Celular/fisiologia
Estudos de Coortes
Desoxicitidina/análogos & derivados
Desoxicitidina/farmacologia
Resistência a Medicamentos Antineoplásicos
Proteína Semelhante a ELAV 1/genética
Seres Humanos
Isocitrato Desidrogenase/genética
Camundongos
Camundongos Nus
Compostos Organoplatínicos/farmacologia
Neoplasias Pancreáticas/tratamento farmacológico
Neoplasias Pancreáticas/genética
Neoplasias Pancreáticas/patologia
Fenótipo
Processamento de Proteína Pós-Traducional
Análise de Sobrevida
Ativação Transcricional
Transfecção
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ELAV-Like Protein 1); 0 (Organoplatinum Compounds); 04ZR38536J (oxaliplatin); 0W860991D6 (Deoxycytidine); B76N6SBZ8R (gemcitabine); EC 1.1.1.41 (Isocitrate Dehydrogenase); EC 1.1.1.42. (IDH1 protein, human)
[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:170628
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-17-0015



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