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Pesquisa : D12.776.157.725.813.750.500 [Categoria DeCS]
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[PMID]:28756806
[Au] Autor:Huang WS; Xu FM; Zeng QZ; Liu XH; Gao XJ; Liu LX
[Ad] Endereço:Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, Guangzhou 510632, Guangdong, China.
[Ti] Título:ERK1/2-mediated Cytoplasmic Accumulation of hnRNPK Antagonizes TRAIL-induced Apoptosis through Upregulation of XIAP in H1299 Cells.
[So] Source:Biomed Environ Sci;30(7):473-481, 2017 Jul.
[Is] ISSN:0895-3988
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance greatly limits the clinical therapeutic efficacy of TRAIL. Elucidating the molecular mechanism underlying TRAIL resistance will be fundamental to resolving this problem. METHODS: Nuclear and cytoplasmic protein extraction and immuno?uorescence (IF) assay were used to detect changes in heterogeneous nuclear ribonucleoprotein K (hnRNPK) localization in H1299 cells. The evaluation of cell apoptosis in cells transfected with GFP-hnRNPK, GFP-hnRNPK S284/353A, or GFP-hnRNPK S284/353D mutant was performed using cleaved caspase-3 antibody. The gene expression of XIAP was tested by quantitative RT-PCR. RESULTS: Previously, we reported that hnRNPK antagonized TRAIL-induced apoptosis through inhibition of PKC-mediated GSK3ß phosphorylation. In this study, we further demonstrate that TRAIL treatment induces cytoplasmic accumulation of hnRNPK in H1299 cells. The hnRNPK localized in the cytoplasm has a higher capacity to antagonize TRAIL-induced apoptosis. Both ERK1/2 signaling inhibitor U0126 and ERK-phosphoacceptor-site mutant (GFP-hnRNPK S284/353A) diminish cytoplasmic accumulation of hnRNPK induced by TRAIL. Moreover, we show that XIAP is involved in hnRNPK-mediated TRAIL resistance in H1299 cells. CONCLUSION: Taken together, these results give new insights into the understanding of the molecular mechanism associated with TRAIL resistance in lung adenocarcinoma.
[Mh] Termos MeSH primário: Apoptose/fisiologia
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo
Proteína Quinase 1 Ativada por Mitógeno/metabolismo
Proteína Quinase 3 Ativada por Mitógeno/metabolismo
Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Regulação da Expressão Gênica/fisiologia
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética
Seres Humanos
Proteína Quinase 1 Ativada por Mitógeno/genética
Proteína Quinase 3 Ativada por Mitógeno/genética
Ligante Indutor de Apoptose Relacionado a TNF/genética
Regulação para Cima/fisiologia
Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heterogeneous-Nuclear Ribonucleoprotein K); 0 (TNF-Related Apoptosis-Inducing Ligand); 0 (TNFSF10 protein, human); 0 (X-Linked Inhibitor of Apoptosis Protein); 0 (XIAP protein, human); 146410-60-8 (HNRNPK protein, human); EC 2.7.11.24 (MAPK1 protein, human); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE
[do] DOI:10.3967/bes2017.063


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[PMID]:28592492
[Au] Autor:Kim HJ; Lee JJ; Cho JH; Jeong J; Park AY; Kang W; Lee KJ
[Ad] Endereço:From the Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.
[Ti] Título:Heterogeneous nuclear ribonucleoprotein K inhibits heat shock-induced transcriptional activity of heat shock factor 1.
[So] Source:J Biol Chem;292(31):12801-12812, 2017 Aug 04.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:When cells are exposed to heat shock and various other stresses, heat shock factor 1 (HSF1) is activated, and the heat shock response (HSR) is elicited. To better understand the molecular regulation of the HSR, we used 2D-PAGE-based proteome analysis to screen for heat shock-induced post-translationally modified cellular proteins. Our analysis revealed that two protein spots typically present on 2D-PAGE gels and containing heterogeneous nuclear ribonucleoprotein K (hnRNP K) with trioxidized Cys disappeared after the heat shock treatment and reappeared during recovery, but the total amount of hnRNP K protein remained unchanged. We next tested whether hnRNP K plays a role in HSR by regulating HSF1 and found that hnRNP K inhibits HSF1 activity, resulting in reduced expression of and mRNAs. hnRNP K also reduced binding affinity of HSF1 to the heat shock element by directly interacting with HSF1 but did not affect HSF1 phosphorylation-dependent activation or nuclear localization. hnRNP K lost its ability to induce these effects when its Cys was substituted with Ser, Asp, or Glu. These findings suggest that hnRNP K inhibits transcriptional activity of HSF1 by inhibiting its binding to heat shock element and that the oxidation status of Cys in hnRNP K is critical for this inhibition.
[Mh] Termos MeSH primário: Proteínas de Ligação a DNA/antagonistas & inibidores
Regulação da Expressão Gênica
Proteínas de Choque Térmico HSP27/antagonistas & inibidores
Proteínas de Choque Térmico HSP70/antagonistas & inibidores
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo
Processamento de Proteína Pós-Traducional
Elementos de Resposta
Fatores de Transcrição/antagonistas & inibidores
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Linhagem Celular Tumoral
Cistina/metabolismo
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Perfilação da Expressão Gênica
Células HEK293
Proteínas de Choque Térmico HSP27/genética
Proteínas de Choque Térmico HSP27/metabolismo
Proteínas de Choque Térmico HSP70/genética
Proteínas de Choque Térmico HSP70/metabolismo
Fatores de Transcrição de Choque Térmico
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/antagonistas & inibidores
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética
Temperatura Alta/efeitos adversos
Seres Humanos
Camundongos
Mutação
Oxirredução
Interferência de RNA
RNA Mensageiro/metabolismo
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/metabolismo
Ribonucleoproteínas/antagonistas & inibidores
Ribonucleoproteínas/genética
Ribonucleoproteínas/metabolismo
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (HSF1 protein, human); 0 (HSP27 Heat-Shock Proteins); 0 (HSP70 Heat-Shock Proteins); 0 (HSPB1 protein, human); 0 (Heat Shock Transcription Factors); 0 (Heterogeneous-Nuclear Ribonucleoprotein K); 0 (RNA, Messenger); 0 (Recombinant Fusion Proteins); 0 (Ribonucleoproteins); 0 (Transcription Factors); 146410-60-8 (HNRNPK protein, human); 48TCX9A1VT (Cystine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170609
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.774992


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[PMID]:28426877
[Au] Autor:Wiesmann N; Strozynski J; Beck C; Zimmermann N; Mendler S; Gieringer R; Schmidtmann I; Brieger J
[Ad] Endereço:Molecular Tumor Biology, Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre of the Johannes Gutenberg University, 55131 Mainz, Germany and.
[Ti] Título:Knockdown of hnRNPK leads to increased DNA damage after irradiation and reduces survival of tumor cells.
[So] Source:Carcinogenesis;38(3):321-328, 2017 Mar 01.
[Is] ISSN:1460-2180
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Radiotherapy is an important treatment option in the therapy of multiple tumor entities among them head and neck squamous cell carcinoma (HNSCC). However, the success of radiotherapy is limited by the development of radiation resistances. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is a cofactor of p53 and represents a potential target for radio sensitization of tumor cells. In this study, we analyzed the impact of hnRNPK on the DNA damage response after gamma irradiation. By yH2AX foci analysis, we found that hnRNPK knockdown increases DNA damage levels in irradiated cells. Tumor cells bearing a p53 mutation showed increased damage levels and delayed repair. Knockdown of hnRNPK applied simultaneously with irradiation reduced colony-forming ability and survival of tumor cells. Taken together, our data shows that hnRNPK is a relevant modifier of DNA damage repair and tumor cell survival. We therefore recommend further studies to evaluate the potential of hnRNPK as a drug target for improvement of radiotherapy success.
[Mh] Termos MeSH primário: Carcinoma de Células Escamosas/radioterapia
Neoplasias de Cabeça e Pescoço/radioterapia
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética
Tolerância a Radiação/genética
Proteína Supressora de Tumor p53/genética
[Mh] Termos MeSH secundário: Carcinoma de Células Escamosas/genética
Carcinoma de Células Escamosas/patologia
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos da radiação
Dano ao DNA/efeitos da radiação
Técnicas de Silenciamento de Genes
Neoplasias de Cabeça e Pescoço/genética
Neoplasias de Cabeça e Pescoço/patologia
Histonas/genética
Seres Humanos
Tolerância a Radiação/efeitos da radiação
Células-Tronco/efeitos da radiação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (H2AFX protein, human); 0 (Heterogeneous-Nuclear Ribonucleoprotein K); 0 (Histones); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); 146410-60-8 (HNRNPK protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.1093/carcin/bgx006


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[PMID]:28423633
[Au] Autor:Gong X; Siprashvili Z; Eminaga O; Shen Z; Sato Y; Kume H; Homma Y; Ogawa S; Khavari PA; Pollack JR; Brooks JD
[Ad] Endereço:Department of Urology, School of Medicine, Stanford University, Stanford, California, USA.
[Ti] Título:Novel lincRNA SLINKY is a prognostic biomarker in kidney cancer.
[So] Source:Oncotarget;8(12):18657-18669, 2017 Mar 21.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Clear cell renal cell carcinomas (ccRCC) show a broad range of clinical behavior, and prognostic biomarkers are needed to stratify patients for appropriate management. We sought to determine whether long intergenic non-coding RNAs (lincRNAs) might predict patient survival. Candidate prognostic lincRNAs were identified by mining The Cancer Genome Atlas (TCGA) transcriptome (RNA-seq) data on 466 ccRCC cases (randomized into discovery and validation sets) annotated for ~21,000 lncRNAs. A previously uncharacterized lincRNA, SLINKY (Survival-predictive LINcRNA in KidneY cancer), was the top-ranked prognostic lincRNA, and validated in an independent University of Tokyo cohort (P=0.004). In multivariable analysis, SLINKY expression predicted overall survival independent of tumor stage and grade [TCGA HR=3.5 (CI, 2.2-5.7), P < 0.001; Tokyo HR=8.4 (CI, 1.8-40.2), P = 0.007], and by decision tree, ROC and decision curve analysis, added independent prognostic value. In ccRCC cell lines, SLINKY knockdown reduced cancer cell proliferation (with cell-cycle G1 arrest) and induced transcriptome changes enriched for cell proliferation and survival processes. Notably, the genes affected by SLINKY knockdown in cell lines were themselves prognostic and correlated with SLINKY expression in the ccRCC patient samples. From a screen for binding partners, we identified direct binding of SLINKY to Heterogeneous Nuclear Ribonucleoprotein K (HNRNPK), whose knockdown recapitulated SLINKY knockdown phenotypes. Thus, SLINKY is a robust prognostic biomarker in ccRCC, where it functions possibly together with HNRNPK in cancer cell proliferation.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/genética
Carcinoma de Células Renais/patologia
Regulação Neoplásica da Expressão Gênica/genética
Neoplasias Renais/patologia
RNA Longo não Codificante/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Área Sob a Curva
Biomarcadores Tumorais/análise
Carcinoma de Células Renais/genética
Carcinoma de Células Renais/mortalidade
Proliferação Celular
Intervalo Livre de Doença
Feminino
Citometria de Fluxo
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo
Seres Humanos
Imunoprecipitação
Estimativa de Kaplan-Meier
Neoplasias Renais/genética
Neoplasias Renais/mortalidade
Masculino
Meia-Idade
Prognóstico
Modelos de Riscos Proporcionais
Análise Serial de Proteínas
Curva ROC
Sensibilidade e Especificidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Heterogeneous-Nuclear Ribonucleoprotein K); 0 (RNA, Long Noncoding); 0 (long non-coding RNA SLINKY, human); 146410-60-8 (HNRNPK protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15703


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[PMID]:28423622
[Au] Autor:He D; Huang C; Zhou Q; Liu D; Xiong L; Xiang H; Ma G; Zhang Z
[Ad] Endereço:Department of General Surgery, The Affiliated Baoan Hospital of Southern Medical University, Shenzhen, Guangdong, 518101, China.
[Ti] Título:HnRNPK/miR-223/FBXW7 feedback cascade promotes pancreatic cancer cell growth and invasion.
[So] Source:Oncotarget;8(12):20165-20178, 2017 Mar 21.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Several studies have identified miR-223 critically involved in various types of cancer, including pancreatic ductal adenocarcinoma (PDAC). However, its action and regulatory mechanisms in PDAC remains largely unclear. In this study, we found that the expression levels of miR-223 were increased in clinical samples with PDAC (81.6%). The upregulation of miR-223 increases the proliferation, migration, and invasive abilities of PDAC cells in vitro and in vivo. Mechanistically, miR-223 directly targeted FBXW7 and overexpression of FBXW7 reverted miR-223- induced drastic proliferation in PDAC cells. Interestingly, miR-223 promoter was found to form a coprecipitable complex with hnRNPK, and siRNA knockdown of hnRNPK in PDAC cells reduced the levels of miR-223. These results show that hnRNPK is a cellular protein that binds and affects the accumulation of miR-223 in PDAC. Furthermore, FBXW7 interacts with hnRNPK and promotes its degradation, which requires phosphorylation of hnRNPK at threonine 1695 by GSK3. Consistently, we observed an inverse expression pattern between FBXW7 and miR-223, whereas a positive expression pattern between miR-223 and hnRNPK was found in human PDAC tissues. These data unveiled an important new miR-223/FBXW7/HnRNPK feedback cascade in human PDAC.
[Mh] Termos MeSH primário: Proteínas de Ciclo Celular/metabolismo
Movimento Celular
Proliferação Celular
Proteínas F-Box/metabolismo
Retroalimentação Fisiológica
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo
MicroRNAs/metabolismo
Neoplasias Pancreáticas/patologia
Ubiquitina-Proteína Ligases/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose
Biomarcadores Tumorais/genética
Biomarcadores Tumorais/metabolismo
Carcinoma Ductal Pancreático/genética
Carcinoma Ductal Pancreático/metabolismo
Carcinoma Ductal Pancreático/patologia
Estudos de Casos e Controles
Proteínas de Ciclo Celular/genética
Proteínas F-Box/genética
Proteína 7 com Repetições F-Box-WD
Feminino
Seguimentos
Regulação Neoplásica da Expressão Gênica
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Nus
MicroRNAs/genética
Meia-Idade
Gradação de Tumores
Invasividade Neoplásica
Estadiamento de Neoplasias
Neoplasias Pancreáticas/genética
Neoplasias Pancreáticas/metabolismo
Prognóstico
Taxa de Sobrevida
Células Tumorais Cultivadas
Ubiquitina-Proteína Ligases/genética
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Cell Cycle Proteins); 0 (F-Box Proteins); 0 (F-Box-WD Repeat-Containing Protein 7); 0 (FBXW7 protein, human); 0 (Heterogeneous-Nuclear Ribonucleoprotein K); 0 (MIRN223 microRNA, human); 0 (MicroRNAs); 146410-60-8 (HNRNPK protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases)
[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:170421
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15529


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[PMID]:28335083
[Au] Autor:Zhu XH; Wang JM; Yang SS; Wang FF; Hu JL; Xin SN; Men H; Lu GF; Lan XL; Zhang D; Wang XY; Liao WT; Ding YQ; Liang L
[Ad] Endereço:Department of Pathology, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China.
[Ti] Título:Down-regulation of DAB2IP promotes colorectal cancer invasion and metastasis by translocating hnRNPK into nucleus to enhance the transcription of MMP2.
[So] Source:Int J Cancer;141(1):172-183, 2017 Jul 01.
[Is] ISSN:1097-0215
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DOC-2/DAB2 interacting protein (DAB2IP) is a RasGAP protein that shows a suppressive effect on cancer progression. Our previous study showed the involvement of transcription regulation of DAB2IP in metastasis of colorectal cancer (CRC). However, the molecular mechanisms of DAB2IP in regulating the progression of CRC need to be further explored. Here, we identified heterogeneous nuclear ribonucleoprotein K (hnRNPK) and matrix metalloproteinase 2 (MMP2) as vital downstream targets of DAB2IP in CRC cells by two-dimensional fluorescence difference gel electrophoresis and cDNA microassay, respectively. Mechanistically, down-regulation of DAB2IP increased the level of hnRNPK through MAPK/ERK signaling pathway. Subsequently, translocation of hnRNPK into nucleus enhanced the transcription activity of MMP2, and therefore promoted invasion and metastasis of CRC. Down-regulation of DAB2IP correlated negatively with hnRNPK and MMP2 expressions in CRC tissues. In conclusion, our study elucidates a novel mechanism of the DAB2IP/hnRNPK/MMP2 axis in the regulation of CRC invasion and metastasis, which may be a potential therapeutic target.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/genética
Neoplasias Colorretais/genética
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética
Metaloproteinase 2 da Matriz/genética
Proteínas Ativadoras de ras GTPase/genética
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Núcleo Celular/genética
Neoplasias Colorretais/patologia
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Invasividade Neoplásica/genética
Invasividade Neoplásica/patologia
Metástase Neoplásica
Transdução de Sinais
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (DAB2IP protein, human); 0 (Heterogeneous-Nuclear Ribonucleoprotein K); 0 (ras GTPase-Activating Proteins); 146410-60-8 (HNRNPK protein, human); EC 3.4.24.24 (MMP2 protein, human); EC 3.4.24.24 (Matrix Metalloproteinase 2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1002/ijc.30701


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[PMID]:28334913
[Au] Autor:Moujalled D; Grubman A; Acevedo K; Yang S; Ke YD; Moujalled DM; Duncan C; Caragounis A; Perera ND; Turner BJ; Prudencio M; Petrucelli L; Blair I; Ittner LM; Crouch PJ; Liddell JR; White AR
[Ad] Endereço:Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
[Ti] Título:TDP-43 mutations causing amyotrophic lateral sclerosis are associated with altered expression of RNA-binding protein hnRNP K and affect the Nrf2 antioxidant pathway.
[So] Source:Hum Mol Genet;26(9):1732-1746, 2017 May 01.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:TAR DNA binding protein 43 (TDP-43) is a major disease-associated protein involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Our previous studies found a direct association between TDP-43 and heterogeneous nuclear ribonucleoprotein K (hnRNP K). In this study, utilizing ALS patient fibroblasts harboring a TDP-43M337V mutation and NSC-34 motor neuronal cell line expressing TDP-43Q331K mutation, we show that hnRNP K expression is impaired in urea soluble extracts from mutant TDP-43 cell models. This was confirmed in vivo using TDP-43Q331K and inducible TDP-43A315T murine ALS models. We further investigated the potential pathological effects of mutant TDP-43-mediated changes to hnRNP K metabolism by RNA binding immunoprecipitation analysis. hnRNP K protein was bound to antioxidant NFE2L2 transcripts encoding Nrf2 antioxidant transcription factor, with greater enrichment in TDP-43M337V patient fibroblasts compared to healthy controls. Subsequent gene expression profiling revealed an increase in downstream antioxidant transcript expression of Nrf2 signaling in the spinal cord of TDP-43Q331K mice compared to control counterparts, yet the corresponding protein expression was not up-regulated in transgenic mice. Despite the elevated expression of antioxidant transcripts, we observed impaired levels of glutathione (downstream Nrf2 antioxidant) in TDP-43M337V patient fibroblasts and astrocyte cultures from TDP-43Q331K mice, indicative of elevated oxidative stress and failure of some upregulated antioxidant genes to be translated into protein. Our findings indicate that further exploration of the interplay between hnRNP K (or other hnRNPs) and Nrf2-mediated antioxidant signaling is warranted and may be an important driver for motor neuron degeneration in ALS.
[Mh] Termos MeSH primário: Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética
[Mh] Termos MeSH secundário: Esclerose Amiotrófica Lateral/genética
Esclerose Amiotrófica Lateral/metabolismo
Animais
Antioxidantes
Linhagem Celular
Demência Frontotemporal/metabolismo
Degeneração Lobar Frontotemporal/genética
Fator de Transcrição de Proteínas de Ligação GA/genética
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo
Ribonucleoproteínas Nucleares Heterogêneas/genética
Seres Humanos
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Neurônios Motores/metabolismo
Mutação
Fator 2 Relacionado a NF-E2/metabolismo
RNA/metabolismo
Medula Espinal/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (DNA-Binding Proteins); 0 (GA-Binding Protein Transcription Factor); 0 (Heterogeneous-Nuclear Ribonucleoprotein K); 0 (Heterogeneous-Nuclear Ribonucleoproteins); 0 (NF-E2-Related Factor 2); 0 (NFE2L2 protein, human); 0 (TDP-43 protein, human); 63231-63-0 (RNA)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx093


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[PMID]:28324005
[Au] Autor:Ghosh A; Abdo S; Zhao S; Wu CH; Shi Y; Lo CS; Chenier I; Alquier T; Filep JG; Ingelfinger JR; Zhang SL; Chan JSD
[Ad] Endereço:Department of Medicine, Université de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
[Ti] Título:Insulin Inhibits Nrf2 Gene Expression via Heterogeneous Nuclear Ribonucleoprotein F/K in Diabetic Mice.
[So] Source:Endocrinology;158(4):903-919, 2017 04 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Oxidative stress induces endogenous antioxidants via nuclear factor erythroid 2-related factor 2 (Nrf2), potentially preventing tissue injury. We investigated whether insulin affects renal Nrf2 expression in type 1 diabetes (T1D) and studied its underlying mechanism. Insulin normalized hyperglycemia, hypertension, oxidative stress, and renal injury; inhibited renal Nrf2 and angiotensinogen (Agt) gene expression; and upregulated heterogeneous nuclear ribonucleoprotein F and K (hnRNP F and hnRNP K) expression in Akita mice with T1D. In immortalized rat renal proximal tubular cells, insulin suppressed Nrf2 and Agt but stimulated hnRNP F and hnRNP K gene transcription in high glucose via p44/42 mitogen-activated protein kinase signaling. Transfection with small interfering RNAs of p44/42 MAPK, hnRNP F, or hnRNP K blocked insulin inhibition of Nrf2 gene transcription. Insulin curbed Nrf2 promoter activity via a specific DNA-responsive element that binds hnRNP F/K, and hnRNP F/K overexpression curtailed Nrf2 promoter activity. In hyperinsulinemic-euglycemic mice, renal Nrf2 and Agt expression was downregulated, whereas hnRNP F/K expression was upregulated. Thus, the beneficial actions of insulin in diabetic nephropathy appear to be mediated, in part, by suppressing renal Nrf2 and Agt gene transcription and preventing Nrf2 stimulation of Agt expression via hnRNP F/K. These findings identify hnRNP F/K and Nrf2 as potential therapeutic targets in diabetes.
[Mh] Termos MeSH primário: Angiotensinogênio/genética
Diabetes Mellitus Tipo 1/genética
Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/genética
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética
Insulina/farmacologia
Fator 2 Relacionado a NF-E2/genética
Transcrição Genética/efeitos dos fármacos
[Mh] Termos MeSH secundário: Angiotensinogênio/metabolismo
Animais
Diabetes Mellitus Tipo 1/tratamento farmacológico
Diabetes Mellitus Tipo 1/metabolismo
Nefropatias Diabéticas/tratamento farmacológico
Nefropatias Diabéticas/genética
Nefropatias Diabéticas/metabolismo
Expressão Gênica/efeitos dos fármacos
Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/metabolismo
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo
Insulina/uso terapêutico
Rim/efeitos dos fármacos
Rim/metabolismo
Masculino
Camundongos
Camundongos Transgênicos
Proteínas Quinases Ativadas por Mitógeno/metabolismo
Fator 2 Relacionado a NF-E2/metabolismo
Regiões Promotoras Genéticas/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heterogeneous-Nuclear Ribonucleoprotein Group F-H); 0 (Heterogeneous-Nuclear Ribonucleoprotein K); 0 (Insulin); 0 (NF-E2-Related Factor 2); 0 (Nfe2l2 protein, mouse); 11002-13-4 (Angiotensinogen); EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170719
[Lr] Data última revisão:
170719
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE
[do] DOI:10.1210/en.2016-1576


  9 / 304 MEDLINE  
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[PMID]:27897116
[Au] Autor:Lu J; Gao FH
[Ti] Título:The Molecular Mechanisms and the Role of hnRNP K Protein Post- Translational Modification in DNA Damage Repair.
[So] Source:Curr Med Chem;24(6):614-621, 2017.
[Is] ISSN:1875-533X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:DNA damage repair is a kind of cellular self-protection mechanism in which some relevant proteins are activated when DNA damage response occurs in order to maintain the intracellular function stability and structure integrity. Post-translational modifications (PTMs) of proteins can rapidly confer to them more complicated structure and sophisticated function by covalently combining different small molecules with target proteins, which in turn plays an important regulatory role in DNA damage repair. It was reported that heterogeneous nuclear ribonucleoprotein K (hnRNP K) could be involved in DNA damage repair process under the regulation of its many post-translational modifications, including methylation, ubiquitination, sumoylation and phosphorylation. Here, we reviewed molecular mechanisms of hnRNP K protein post-translational modifications and their role in DNA damage repair, which will promote our understanding of how hnRNP K participating in the repair process to maintain the normal operation of biological activities in the cells.
[Mh] Termos MeSH primário: Dano ao DNA
Reparo do DNA
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/química
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo
Processamento de Proteína Pós-Traducional
[Mh] Termos MeSH secundário: Seres Humanos
Metilação
Fosforilação
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Heterogeneous-Nuclear Ribonucleoprotein K)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170615
[Lr] Data última revisão:
170615
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161130
[St] Status:MEDLINE
[do] DOI:10.2174/0929867323666161129124122


  10 / 304 MEDLINE  
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[PMID]:27793696
[Au] Autor:Eder S; Arndt A; Lamkowski A; Daskalaki W; Rump A; Priller M; Genze F; Wardelmann E; Port M; Steinestel K
[Ad] Endereço:Bundeswehr Institute of Radiobiology Affiliated to the University of Ulm, Neuherbergstrasse 11, 80937 Munich, Germany. Electronic address: stefanfriedricheder@bundeswehr.org.
[Ti] Título:Baseline MAPK signaling activity confers intrinsic radioresistance to KRAS-mutant colorectal carcinoma cells by rapid upregulation of heterogeneous nuclear ribonucleoprotein K (hnRNP K).
[So] Source:Cancer Lett;385:160-167, 2017 01 28.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is overexpressed in malignant tumors and involved in DNA damage response upon ionizing radiation (IR). Here, we investigate its role in radioresistance of colorectal carcinoma (CRC) and evaluate a pharmacological approach to enhance CRC radiosensitivity via downregulation of hnRNP K. We show that hnRNP K is overexpressed in CRC tissue specimens and upregulated in response to IR in vitro, which occurs faster in KRAS-mutant CRC cells. HnRNP K knockdown impairs cell survival, cell cycle progression and KRAS-dependent radioresistance and increases apoptosis. Using the chicken chorioallantoic membrane assay, a decrease in xenograft tumor growth and radioresistance upon hnRNP K depletion could be verified in vivo, and comparable effects were achieved by suppression of hnRNP K expression using the MEK inhibitor MEK162 (Binimetinib). In summary, KRAS-mutant CRC shows intrinsic radioresistance along with rapid upregulation of hnRNP K in response to IR that can effectively be targeted by MEK inhibition. Our results point towards a possible use of MAPK pathway inhibitors to decrease radioresistance of KRAS-mutant CRC via downregulation of hnRNP K.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/genética
Neoplasias Colorretais/radioterapia
MAP Quinase Quinase Quinases/metabolismo
Mutação
Proteínas Proto-Oncogênicas p21(ras)/genética
Tolerância a Radiação/genética
Ribonucleoproteínas/metabolismo
Transdução de Sinais/efeitos da radiação
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Animais
Apoptose/efeitos da radiação
Ciclo Celular/efeitos da radiação
Linhagem Celular Tumoral
Embrião de Galinha
Membrana Corioalantoide/irrigação sanguínea
Neoplasias Colorretais/enzimologia
Neoplasias Colorretais/genética
Neoplasias Colorretais/patologia
Relação Dose-Resposta à Radiação
Feminino
Regulação Neoplásica da Expressão Gênica
Predisposição Genética para Doença
Ribonucleoproteínas Nucleares Heterogêneas Grupo K
Seres Humanos
MAP Quinase Quinase Quinases/antagonistas & inibidores
Masculino
Meia-Idade
Fenótipo
Inibidores de Proteínas Quinases/farmacologia
Interferência de RNA
Tolerância a Radiação/efeitos dos fármacos
Ribonucleoproteínas/genética
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
Transfecção
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Heterogeneous-Nuclear Ribonucleoprotein K); 0 (KRAS protein, human); 0 (Protein Kinase Inhibitors); 0 (Ribonucleoproteins); 146410-60-8 (HNRNPK protein, human); EC 2.7.11.25 (MAP Kinase Kinase Kinases); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161030
[St] Status:MEDLINE



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