Base de dados : MEDLINE
Pesquisa : D12.776.543.750.725 [Categoria DeCS]
Referências encontradas : 7553 [refinar]
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[PMID]:28457750
[Au] Autor:Li L; Dong J; Yan L; Yong J; Liu X; Hu Y; Fan X; Wu X; Guo H; Wang X; Zhu X; Li R; Yan J; Wei Y; Zhao Y; Wang W; Ren Y; Yuan P; Yan Z; Hu B; Guo F; Wen L; Tang F; Qiao J
[Ad] Endereço:Beijing Advanced Innovation Center for Genomics (ICG), College of Life Sciences, Department of Obstetrics and Gynecology, Third Hospital, Peking University, Beijing 100871, China; Biomedical Institute for Pioneering Investigation via Convergence and Center for Reproductive Medicine, Ministry of Educ
[Ti] Título:Single-Cell RNA-Seq Analysis Maps Development of Human Germline Cells and Gonadal Niche Interactions.
[So] Source:Cell Stem Cell;20(6):858-873.e4, 2017 Jun 01.
[Is] ISSN:1875-9777
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human fetal germ cells (FGCs) are precursors to sperm and eggs and are crucial for maintenance of the species. However, the developmental trajectories and heterogeneity of human FGCs remain largely unknown. Here we performed single-cell RNA-seq analysis of over 2,000 FGCs and their gonadal niche cells in female and male human embryos spanning several developmental stages. We found that female FGCs undergo four distinct sequential phases characterized by mitosis, retinoic acid signaling, meiotic prophase, and oogenesis. Male FGCs develop through stages of migration, mitosis, and cell-cycle arrest. Individual embryos of both sexes simultaneously contain several subpopulations, highlighting the asynchronous and heterogeneous nature of FGC development. Moreover, we observed reciprocal signaling interactions between FGCs and their gonadal niche cells, including activation of the bone morphogenic protein (BMP) and Notch signaling pathways. Our work provides key insights into the crucial features of human FGCs during their highly ordered mitotic, meiotic, and gametogenetic processes in vivo.
[Mh] Termos MeSH primário: Divisão Celular/fisiologia
Células Germinativas Embrionárias/metabolismo
Feto/metabolismo
Gônadas/enzimologia
Transdução de Sinais/fisiologia
Nicho de Células-Tronco/fisiologia
[Mh] Termos MeSH secundário: Proteínas Morfogenéticas Ósseas/metabolismo
Células Germinativas Embrionárias/citologia
Feminino
Feto/citologia
Gônadas/citologia
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Masculino
Receptores Notch/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bone Morphogenetic Proteins); 0 (Receptors, Notch)
[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:170502
[St] Status:MEDLINE


  2 / 7553 MEDLINE  
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[PMID]:28465412
[Au] Autor:Severson E; Arnett KL; Wang H; Zang C; Taing L; Liu H; Pear WS; Shirley Liu X; Blacklow SC; Aster JC
[Ad] Endereço:Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
[Ti] Título:Genome-wide identification and characterization of Notch transcription complex-binding sequence-paired sites in leukemia cells.
[So] Source:Sci Signal;10(477), 2017 May 02.
[Is] ISSN:1937-9145
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Notch transcription complexes (NTCs) drive target gene expression by binding to two distinct types of genomic response elements, NTC monomer-binding sites and sequence-paired sites (SPSs) that bind NTC dimers. SPSs are conserved and have been linked to the Notch responsiveness of a few genes. To assess the overall contribution of SPSs to Notch-dependent gene regulation, we determined the DNA sequence requirements for NTC dimerization using a fluorescence resonance energy transfer (FRET) assay and applied insights from these in vitro studies to Notch-"addicted" T cell acute lymphoblastic leukemia (T-ALL) cells. We found that SPSs contributed to the regulation of about a third of direct Notch target genes. Although originally described in promoters, SPSs are present mainly in long-range enhancers, including an enhancer containing a newly described SPS that regulates expression. Our work provides a general method for identifying SPSs in genome-wide data sets and highlights the widespread role of NTC dimerization in Notch-transformed leukemia cells.
[Mh] Termos MeSH primário: Elementos Facilitadores Genéticos
Regulação Leucêmica da Expressão Gênica
Genoma Humano
Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética
Receptores Notch/metabolismo
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Animais
Perfilação da Expressão Gênica
Seres Humanos
Camundongos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo
Regiões Promotoras Genéticas
Ligação Proteica
Receptores Notch/genética
Transdução de Sinais
Fatores de Transcrição/genética
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Notch); 0 (Transcription Factors)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180303
[Lr] Data última revisão:
180303
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


  3 / 7553 MEDLINE  
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[PMID]:28456747
[Au] Autor:He Q; Gao S; Lv J; Li W; Liu F
[Ad] Endereço:State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.
[Ti] Título:BLOS2 maintains hematopoietic stem cells in the fetal liver via repressing Notch signaling.
[So] Source:Exp Hematol;51:1-6.e2, 2017 07.
[Is] ISSN:1873-2399
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:During development, hematopoietic stem cells (HSCs) undergo a rapid expansion in the fetal liver (FL) after their emergence in the aorta-gonad-mesonephros (AGM) region. We recently reported that the endolysosomal trafficking factor BLOS2, encoded by the Bloc1s2 gene, regulates HSC/hematopoietic progenitor cell emergence in the AGM region; however, whether it plays a role in the FL remains unknown. Here, we show that BLOS2 plays an essential role in the regulation of HSC proliferation and differentiation in the FL. Bloc1s2 depletion leads to elevated Notch signaling, with an increased frequency but weakened self-renewal ability of FL HSCs. Functional assays show that Bloc1s2 FL HSCs harbor impaired lymphoid and myeloid differentiation abilities. These findings reveal that balanced control of Notch signaling by BLOS2 is required for HSC homeostasis during FL hematopoiesis.
[Mh] Termos MeSH primário: Diferenciação Celular/fisiologia
Proliferação Celular/fisiologia
Feto/embriologia
Células-Tronco Hematopoéticas/metabolismo
Fígado/embriologia
Proteínas/metabolismo
Receptores Notch/metabolismo
[Mh] Termos MeSH secundário: Animais
Feto/citologia
Hematopoese Extramedular/fisiologia
Células-Tronco Hematopoéticas/citologia
Seres Humanos
Fígado/citologia
Camundongos
Camundongos Knockout
Proteínas/genética
Receptores Notch/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (BLOS2 protein, mouse); 0 (Proteins); 0 (Receptors, Notch)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180224
[Lr] Data última revisão:
180224
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE


  4 / 7553 MEDLINE  
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[PMID]:28468863
[Au] Autor:Liu Z; Sanders AJ; Liang G; Song E; Jiang WG; Gong C
[Ad] Endereço:Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
[Ti] Título:Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment.
[So] Source:Mol Cancer Ther;16(5):775-786, 2017 May.
[Is] ISSN:1538-8514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hairy and Enhancer-of-split related with YRPW motif (Hey) transcription factors are important regulators of stem cell embryogenesis. Clinical relevance shows that they are also highly expressed in malignant carcinoma. Recent studies have highlighted functions for the Hey factors in tumor metastasis, the maintenance of cancer cell self-renewal, as well as proliferation and the promotion of tumor angiogenesis. Pathways that regulate gene expression, such as Notch and TGFß signaling, are frequently aberrant in numerous cancers. In addition, Hey factors control downstream targets via recruitment of histone deacetylases (HDAC). Targeting these signaling pathways or HDACs may reverse tumor progression and provide clinical benefit for cancer patients. Thus, some small molecular inhibitors or monoclonal antibodies of each of these signaling pathways have been studied in clinical trials. This review focuses on the involvement of Hey proteins in malignant carcinoma progression and provides valuable therapeutic information for anticancer treatment. .
[Mh] Termos MeSH primário: Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética
Carcinogênese/genética
Carcinoma/genética
Proteínas de Ciclo Celular/genética
[Mh] Termos MeSH secundário: Carcinoma/patologia
Proliferação Celular/genética
Histona Desacetilases/genética
Seres Humanos
Metástase Neoplásica
Receptores Notch/genética
Transdução de Sinais/genética
Fator de Crescimento Transformador beta/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Cell Cycle Proteins); 0 (HEY1 protein, human); 0 (Receptors, Notch); 0 (Transforming Growth Factor beta); EC 3.5.1.98 (Histone Deacetylases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1158/1535-7163.MCT-16-0576


  5 / 7553 MEDLINE  
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[PMID]:29224781
[Au] Autor:Seegar TCM; Killingsworth LB; Saha N; Meyer PA; Patra D; Zimmerman B; Janes PW; Rubinstein E; Nikolov DB; Skiniotis G; Kruse AC; Blacklow SC
[Ad] Endereço:Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
[Ti] Título:Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10.
[So] Source:Cell;171(7):1638-1648.e7, 2017 Dec 14.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cleavage of membrane-anchored proteins by ADAM (a disintegrin and metalloproteinase) endopeptidases plays a key role in a wide variety of biological signal transduction and protein turnover processes. Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic α-secretase cleavage of the Alzheimer's precursor protein (APP). We present here the X-ray crystal structure of the ADAM10 ectodomain, which, together with biochemical and cellular studies, reveals how access to the enzyme active site is regulated. The enzyme adopts an unanticipated architecture in which the C-terminal cysteine-rich domain partially occludes the enzyme active site, preventing unfettered substrate access. Binding of a modulatory antibody to the cysteine-rich domain liberates the catalytic domain from autoinhibition, enhancing enzymatic activity toward a peptide substrate. Together, these studies reveal a mechanism for regulation of ADAM activity and offer a roadmap for its modulation.
[Mh] Termos MeSH primário: Proteína ADAM10/química
Secretases da Proteína Precursora do Amiloide/química
Proteínas de Membrana/química
Proteólise
[Mh] Termos MeSH secundário: Proteína ADAM10/metabolismo
Secretases da Proteína Precursora do Amiloide/metabolismo
Cristalografia por Raios X
Seres Humanos
Proteínas de Membrana/metabolismo
Modelos Moleculares
Receptores Notch/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Membrane Proteins); 0 (Receptors, Notch); EC 3.4.- (Amyloid Precursor Protein Secretases); EC 3.4.24.81 (ADAM10 Protein); EC 3.4.24.81 (ADAM10 protein, human)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180120
[Lr] Data última revisão:
180120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE


  6 / 7553 MEDLINE  
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[PMID]:29198839
[Au] Autor:Ma Q; Wang Y; Zhang T; Zuo W
[Ad] Endereço:School of Medicine, Tongji University, Shanghai 200433, China.
[Ti] Título:Notch-mediated Sox9 cell activation contributes to kidney repair after partial nephrectomy.
[So] Source:Life Sci;193:104-109, 2018 Jan 15.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Partial nephrectomy is a surgical technique as an alternative for traditional radical nephrectomy. The advantage of partial nephrectomy technique is nephron-sparing, however, whether the remaining kidney tissue could regenerate the lost nephron is still unknown. The current work is to investigate the kidney tissue repair process and the related cellular and molecular mechanism. MAIN METHODS: We used a novel unilateral partial nephrectomy mouse model to study kidney repair, and focused on a population of Sox9 progenitor cells to study their pivotal role in the regenerative process. Kidney function after nephrectomy was measured using creatinine and urea nitrogen assay kit. Wound healing was assessed by Masson Trichrome Staining. Tissue regeneration was tested by Sox9 cells immunofluorescence staining. The differentiation potential of Sox9 cells were assessed by immunoanalysis with various tubular cell markers. Notch activation was determined by qPCR and Western blotting. KEY FINDINGS: After partial nephrectomy, we found that massive Sox9 cells emerged one day after the surgery and lasted for up to 20days. The Sox9 cells had proliferative capacity and could give rise to epithelial cells of proximal tubule, Henle's loop, distal tubule, collecting duct, and the parietal layer of glomerulus. We also found that the activation of Sox9 cells was mediated by Notch signaling pathway. SIGNIFICANCE: The current study reveals that Notch-mediated Sox9 cell activation can contribute to kidney tubule regeneration after unilateral partial nephrectomy in mice.
[Mh] Termos MeSH primário: Rim/metabolismo
Nefrectomia/métodos
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular
Creatinina/metabolismo
Células Epiteliais/metabolismo
Rim/fisiologia
Túbulos Renais
Túbulos Renais Proximais/fisiologia
Camundongos
Camundongos Endogâmicos C57BL
Nefrectomia/reabilitação
Néfrons
Receptores Notch/metabolismo
Regeneração/fisiologia
Fatores de Transcrição SOX9/genética
Fatores de Transcrição SOX9/metabolismo
Transdução de Sinais
Cicatrização/genética
Cicatrização/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Notch); 0 (SOX9 Transcription Factor); 0 (SOX9 protein, human); AYI8EX34EU (Creatinine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE


  7 / 7553 MEDLINE  
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[PMID]:29206870
[Au] Autor:Williams E; Villar-Prados A; Bowser J; Broaddus R; Gladden AB
[Ad] Endereço:Department of Genetics, University of Texas, MD Anderson Cancer Center, Houston, TX, United States of America.
[Ti] Título:Loss of polarity alters proliferation and differentiation in low-grade endometrial cancers by disrupting Notch signaling.
[So] Source:PLoS One;12(12):e0189081, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cell adhesion and apicobasal polarity together maintain epithelial tissue organization and homeostasis. Loss of adhesion has been described as a prerequisite for the epithelial to mesenchymal transition. However, what role misregulation of apicobasal polarity promotes tumor initiation and/or early progression remains unclear. We find that human low-grade endometrial cancers are associated with disrupted localization of the apical polarity protein Par3 and Ezrin while, the adhesion molecule E-cadherin remains unchanged, accompanied by decreased Notch signaling, and altered Notch receptor localization. Depletion of Par3 or Ezrin, in a cell-based model, results in loss of epithelial architecture, differentiation, increased proliferation, migration and decreased Notch signaling. Re-expression of Par3 in endometrial cancer cell lines with disrupted Par3 protein levels blocks proliferation and reduces migration in a Notch dependent manner. These data uncover a function for apicobasal polarity independent of cell adhesion in regulating Notch-mediated differentiation signals in endometrial epithelial cells.
[Mh] Termos MeSH primário: Diferenciação Celular
Polaridade Celular/fisiologia
Proliferação Celular
Neoplasias do Endométrio/patologia
Receptores Notch/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Cães
Feminino
Seres Humanos
Células Madin Darby de Rim Canino
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Notch)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189081


  8 / 7553 MEDLINE  
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[PMID]:29176671
[Au] Autor:Schneider M; Kumar V; Nordstrøm LU; Feng L; Takeuchi H; Hao H; Luca VC; Garcia KC; Stanley P; Wu P; Haltiwanger RS
[Ad] Endereço:Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA.
[Ti] Título:Inhibition of Delta-induced Notch signaling using fucose analogs.
[So] Source:Nat Chem Biol;14(1):65-71, 2018 Jan.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Notch is a cell-surface receptor that controls cell-fate decisions and is regulated by O-glycans attached to epidermal growth factor-like (EGF) repeats in its extracellular domain. Protein O-fucosyltransferase 1 (Pofut1) modifies EGF repeats with O-fucose and is essential for Notch signaling. Constitutive activation of Notch signaling has been associated with a variety of human malignancies. Therefore, tools that inhibit Notch activity are being developed as cancer therapeutics. To this end, we screened L-fucose analogs for their effects on Notch signaling. Two analogs, 6-alkynyl and 6-alkenyl fucose, were substrates of Pofut1 and were incorporated directly into Notch EGF repeats in cells. Both analogs were potent inhibitors of binding to and activation of Notch1 by Notch ligands Dll1 and Dll4, but not by Jag1. Mutagenesis and modeling studies suggest that incorporation of the analogs into EGF8 of Notch1 markedly reduces the ability of Delta ligands to bind and activate Notch1.
[Mh] Termos MeSH primário: Família de Proteínas EGF/metabolismo
Fucose/análogos & derivados
Fucose/farmacologia
Fucosiltransferases/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Proteínas de Membrana/metabolismo
Receptores Notch/antagonistas & inibidores
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Fucose/química
Fucose/genética
Fucosiltransferases/genética
Células HEK293
Seres Humanos
Ligantes
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (EGF Family of Proteins); 0 (Intracellular Signaling Peptides and Proteins); 0 (Ligands); 0 (Membrane Proteins); 0 (Receptors, Notch); 0 (delta protein); 28RYY2IV3F (Fucose); EC 2.4.1.- (Fucosyltransferases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171225
[Lr] Data última revisão:
171225
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.2520


  9 / 7553 MEDLINE  
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[PMID]:29195077
[Au] Autor:Langridge PD; Struhl G
[Ad] Endereço:Department of Genetics and Development, Columbia University, New York, NY, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, New York, NY, USA. Electronic address: pl2266@columbia.edu.
[Ti] Título:Epsin-Dependent Ligand Endocytosis Activates Notch by Force.
[So] Source:Cell;171(6):1383-1396.e12, 2017 Nov 30.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DSL ligands activate Notch by inducing proteolytic cleavage of the receptor ectodomain, an event that requires ligand to be endocytosed in signal-sending cells by the adaptor protein Epsin. Two classes of explanation for this unusual requirement are (1) recycling models, in which the ligand must be endocytosed to be modified or repositioned before it binds Notch and (2) pulling models, in which the ligand must be endocytosed after it binds Notch to exert force that exposes an otherwise buried site for cleavage. We demonstrate in vivo that ligands that cannot enter the Epsin pathway nevertheless bind Notch but fail to activate the receptor because they cannot exert sufficient force. This argues against recycling models and in favor of pulling models. Our results also suggest that once ligand binds receptor, activation depends on a competition between Epsin-mediated ligand endocytosis, which induces cleavage, and transendocytosis of the ligand by the receptor, which aborts the incipient signal.
[Mh] Termos MeSH primário: Proteínas de Drosophila/metabolismo
Drosophila/citologia
Drosophila/metabolismo
Endocitose
Transdução de Sinais
Proteínas de Transporte Vesicular/metabolismo
Asas de Animais/metabolismo
[Mh] Termos MeSH secundário: Animais
Drosophila/crescimento & desenvolvimento
Discos Imaginais/metabolismo
Ligantes
Receptores Notch/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (Ligands); 0 (Lqf protein, Drosophila); 0 (Receptors, Notch); 0 (Vesicular Transport Proteins)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171222
[Lr] Data última revisão:
171222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171202
[St] Status:MEDLINE


  10 / 7553 MEDLINE  
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[PMID]:27770818
[Au] Autor:Altmann C; Vasic V; Hardt S; Heidler J; Häussler A; Wittig I; Schmidt MH; Tegeder I
[Ad] Endereço:Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
[Ti] Título:Progranulin promotes peripheral nerve regeneration and reinnervation: role of notch signaling.
[So] Source:Mol Neurodegener;11(1):69, 2016 10 22.
[Is] ISSN:1750-1326
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Peripheral nerve injury is a frequent cause of lasting motor deficits and chronic pain. Although peripheral nerves are capable of regrowth they often fail to re-innervate target tissues. RESULTS: Using newly generated transgenic mice with inducible neuronal progranulin overexpression we show that progranulin accelerates axonal regrowth, restoration of neuromuscular synapses and recovery of sensory and motor functions after injury of the sciatic nerve. Oppositely, progranulin deficient mice have long-lasting deficits in motor function tests after nerve injury due to enhanced losses of motor neurons and stronger microglia activation in the ventral horn of the spinal cord. Deep proteome and gene ontology (GO) enrichment analysis revealed that the proteins upregulated in progranulin overexpressing mice were involved in 'regulation of transcription' and 'response to insulin' (GO terms). Transcription factor prediction pointed to activation of Notch signaling and indeed, co-immunoprecipitation studies revealed that progranulin bound to the extracellular domain of Notch receptors, and this was functionally associated with higher expression of Notch target genes in the dorsal root ganglia of transgenic mice with neuronal progranulin overexpression. Functionally, these transgenic mice recovered normal gait and running, which was not achieved by controls and was stronger impaired in progranulin deficient mice. CONCLUSION: We infer that progranulin activates Notch signaling pathways, enhancing thereby the regenerative capacity of partially injured neurons, which leads to improved motor function recovery.
[Mh] Termos MeSH primário: Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
Regeneração Nervosa/fisiologia
Traumatismos dos Nervos Periféricos/metabolismo
Receptores Notch/metabolismo
Transdução de Sinais/fisiologia
[Mh] Termos MeSH secundário: Animais
Western Blotting
Modelos Animais de Doenças
Ensaio de Imunoadsorção Enzimática
Feminino
Imunoprecipitação
Hibridização in Situ Fluorescente
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Reação em Cadeia da Polimerase em Tempo Real
Recuperação de Função Fisiológica/fisiologia
Nervo Isquiático/lesões
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Grn protein, mouse); 0 (Intercellular Signaling Peptides and Proteins); 0 (Receptors, Notch)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171211
[Lr] Data última revisão:
171211
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE



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BIREME/OPAS/OMS - Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde