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Pesquisa : G03.143.700 [Categoria DeCS]
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  1 / 45414 MEDLINE  
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[PMID]:28467418
[Au] Autor:Khare S; Nick JA; Zhang Y; Galeano K; Butler B; Khoshbouei H; Rayaprolu S; Hathorn T; Ranum LPW; Smithson L; Golde TE; Paucar M; Morse R; Raff M; Simon J; Nordenskjöld M; Wirdefeldt K; Rincon-Limas DE; Lewis J; Kaczmarek LK; Fernandez-Funez P; Nick HS; Waters MF
[Ad] Endereço:Department of Neurology, University of Florida, Gainesville, FL, United States of America.
[Ti] Título:A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking.
[So] Source:PLoS One;12(5):e0173565, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The autosomal dominant spinocerebellar ataxias (SCAs) are a diverse group of neurological disorders anchored by the phenotypes of motor incoordination and cerebellar atrophy. Disease heterogeneity is appreciated through varying comorbidities: dysarthria, dysphagia, oculomotor and/or retinal abnormalities, motor neuron pathology, epilepsy, cognitive impairment, autonomic dysfunction, and psychiatric manifestations. Our study focuses on SCA13, which is caused by several allelic variants in the voltage-gated potassium channel KCNC3 (Kv3.3). We detail the clinical phenotype of four SCA13 kindreds that confirm causation of the KCNC3R423H allele. The heralding features demonstrate congenital onset with non-progressive, neurodevelopmental cerebellar hypoplasia and lifetime improvement in motor and cognitive function that implicate compensatory neural mechanisms. Targeted expression of human KCNC3R423H in Drosophila triggers aberrant wing veins, maldeveloped eyes, and fused ommatidia consistent with the neurodevelopmental presentation of patients. Furthermore, human KCNC3R423H expression in mammalian cells results in altered glycosylation and aberrant retention of the channel in anterograde and/or endosomal vesicles. Confirmation of the absence of plasma membrane targeting was based on the loss of current conductance in cells expressing the mutant channel. Mechanistically, genetic studies in Drosophila, along with cellular and biophysical studies in mammalian systems, demonstrate the dominant negative effect exerted by the mutant on the wild-type (WT) protein, which explains dominant inheritance. We demonstrate that ocular co-expression of KCNC3R423H with Drosophila epidermal growth factor receptor (dEgfr) results in striking rescue of the eye phenotype, whereas KCNC3R423H expression in mammalian cells results in aberrant intracellular retention of human epidermal growth factor receptor (EGFR). Together, these results indicate that the neurodevelopmental consequences of KCNC3R423H may be mediated through indirect effects on EGFR signaling in the developing cerebellum. Our results therefore confirm the KCNC3R423H allele as causative for SCA13, through a dominant negative effect on KCNC3WT and links with EGFR that account for dominant inheritance, congenital onset, and disease pathology.
[Mh] Termos MeSH primário: Receptor do Fator de Crescimento Epidérmico/metabolismo
Canais de Potássio Shaw/genética
Degenerações Espinocerebelares/genética
[Mh] Termos MeSH secundário: Animais
Células CHO
Cricetinae
Cricetulus
Drosophila melanogaster
Feminino
Seres Humanos
Masculino
Linhagem
Transporte Proteico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KCNC3 protein, human); 0 (Shaw Potassium Channels); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180311
[Lr] Data última revisão:
180311
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173565


  2 / 45414 MEDLINE  
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[PMID]:29381770
[Au] Autor:Lin CY; Lin LY
[Ad] Endereço:Institute of Molecular and Cellular Biology and Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan, ROC.
[Ti] Título:The conserved basic residues and the charged amino acid residues at the α-helix of the zinc finger motif regulate the nuclear transport activity of triple C2H2 zinc finger proteins.
[So] Source:PLoS One;13(1):e0191971, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Zinc finger (ZF) motifs on proteins are frequently recognized as a structure for DNA binding. Accumulated reports indicate that ZF motifs contain nuclear localization signal (NLS) to facilitate the transport of ZF proteins into nucleus. We investigated the critical factors that facilitate the nuclear transport of triple C2H2 ZF proteins. Three conserved basic residues (hot spots) were identified among the ZF sequences of triple C2H2 ZF proteins that reportedly have NLS function. Additional basic residues can be found on the α-helix of the ZFs. Using the ZF domain (ZFD) of Egr-1 as a template, various mutants were constructed and expressed in cells. The nuclear transport activity of various mutants was estimated by analyzing the proportion of protein localized in the nucleus. Mutation at any hot spot of the Egr-1 ZFs reduced the nuclear transport activity. Changes of the basic residues at the α-helical region of the second ZF (ZF2) of the Egr-1 ZFD abolished the NLS activity. However, this activity can be restored by substituting the acidic residues at the homologous positions of ZF1 or ZF3 with basic residues. The restored activity dropped again when the hot spots at ZF1 or the basic residues in the α-helix of ZF3 were mutated. The variations in nuclear transport activity are linked directly to the binding activity of the ZF proteins with importins. This study was extended to other triple C2H2 ZF proteins. SP1 and KLF families, similar to Egr-1, have charged amino acid residues at the second (α2) and the third (α3) positions of the α-helix. Replacing the amino acids at α2 and α3 with acidic residues reduced the NLS activity of the SP1 and KLF6 ZFD. The reduced activity can be restored by substituting the α3 with histidine at any SP1 and KLF6 ZFD. The results show again the interchangeable role of ZFs and charge residues in the α-helix in regulating the NLS activity of triple C2H2 ZF proteins.
[Mh] Termos MeSH primário: Aminoácidos/metabolismo
Núcleo Celular/metabolismo
Dedos de Zinco
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Transporte Proteico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amino Acids)
[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:180131
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191971


  3 / 45414 MEDLINE  
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[PMID]:28456783
[Au] Autor:Cai S; Li Y; Bai JY; Zhang ZQ; Wang Y; Qiao YB; Zhou XZ; Yang B; Tian Y; Cao C
[Ad] Endereço:Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
[Ti] Título:Gαi3 nuclear translocation causes irradiation resistance in human glioma cells.
[So] Source:Oncotarget;8(21):35061-35068, 2017 May 23.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have previously shown that Gαi3 is elevated in human glioma, mediating Akt activation and cancer cell proliferation. Here, we imply that Gαi3 could also be important for irradiation resistance. In A172 human glioma cells, Gαi3 knockdown (by targeted shRNAs) or dominant-negative mutation significantly potentiated irradiation-induced cell apoptosis. Reversely, forced over-expression of wild-type or constitutively-active Gαi3 inhibited irradiation-induced A172 cell apoptosis. Irradiation in A172 cells induced Gαi3 translocation to cell nuclei and association with local protein DNA-dependent protein kinase (DNA-PK) catalytic subunit. This association was important for DNA damage repair. Gαi3 knockdown, depletion (using Gαi3 knockout MEFs) or dominant-negative mutation potentiated irradiation-induced DNA damages. On the other hand, expression of the constitutively-active Gαi3 in A172 cells inhibited DNA damage by irradiation. Together, these results indicate a novel function of Gαi3 in irradiation-resistance in human glioma cells.
[Mh] Termos MeSH primário: Neoplasias Encefálicas/metabolismo
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo
Glioma/metabolismo
Tolerância a Radiação
[Mh] Termos MeSH secundário: Neoplasias Encefálicas/genética
Neoplasias Encefálicas/radioterapia
Linhagem Celular Tumoral
Núcleo Celular/metabolismo
Dano ao DNA
Proteína Quinase Ativada por DNA/metabolismo
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética
Regulação Neoplásica da Expressão Gênica/efeitos da radiação
Glioma/genética
Glioma/radioterapia
Seres Humanos
Transporte Proteico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.11.1 (DNA-Activated Protein Kinase); EC 3.6.5.1 (GNAI3 protein, human); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go)
[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:170501
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.17043


  4 / 45414 MEDLINE  
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[PMID]:28471021
[Au] Autor:Spessott WA; Sanmillan ML; Kulkarni VV; McCormick ME; Giraudo CG
[Ad] Endereço:Department of Pathology and Laboratory Medicine, University of Pennsylvania - The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
[Ti] Título:Syntaxin 4 mediates endosome recycling for lytic granule exocytosis in cytotoxic T-lymphocytes.
[So] Source:Traffic;18(7):442-452, 2017 Jul.
[Is] ISSN:1600-0854
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Adaptive and innate immunity utilize the perforin-killing pathway to eliminate virus-infected or cancer cells. Cytotoxic T-lymphocytes (CTLs) and natural killer cells mediate this process by releasing toxic proteins at the contact area with target cells known as immunological synapse (IS). Formation of a stable IS and exocytosis of toxic proteins requires persistent fusion of Rab11a recycling endosomes with the plasma membrane (PM) that may assure the delivery of key effector proteins. Despite the importance of the recycling endosomal compartment, the membrane fusion proteins that control this process at the IS remain elusive. Here, by performing knockdown experiments we found that syntaxin 4 (STX4) is necessary for cytotoxic activity and CD107a degranulation against target cells in a similar fashion to syntaxin 11, which is involved in lytic granule (LG) exocytosis and immunodeficiency when it is mutated. Using total internal reflection fluorescent microscopy we identified that STX4 mediates fusion of EGFP-Rab11a vesicles at the IS. Immunoprecipitation experiments in lysates of activated CTLs indicate that endogenous STX4 may drive this fusion step by interacting with cognate proteins: Munc18-3/SNAP23/VAMP7 and/or VAMP8. These results reveal the role of STX4 in mediating fusion of Rab11a endosomes upstream of lytic granules (LGs) exocytosis and further demonstrate the importance of this pathway in controlling CTL-mediated cytotoxicity.
[Mh] Termos MeSH primário: Grânulos Citoplasmáticos/metabolismo
Endossomos/metabolismo
Exocitose/imunologia
Proteínas Qa-SNARE/metabolismo
Linfócitos T Citotóxicos/metabolismo
[Mh] Termos MeSH secundário: Degranulação Celular
Linhagem Celular
Grânulos Citoplasmáticos/imunologia
Citotoxicidade Imunológica
Técnicas de Silenciamento de Genes
Seres Humanos
Proteína 1 de Membrana Associada ao Lisossomo/metabolismo
Transporte Proteico
Proteínas Qa-SNARE/genética
Linfócitos T Citotóxicos/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lysosomal-Associated Membrane Protein 1); 0 (Qa-SNARE Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1111/tra.12490


  5 / 45414 MEDLINE  
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[PMID]:28455168
[Au] Autor:Cummings CS; Fein K; Murata H; Ball RL; Russell AJ; Whitehead KA
[Ad] Endereço:Center for Polymer-based Protein Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, United States; Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, United States.
[Ti] Título:ATRP-grown protein-polymer conjugates containing phenylpiperazine selectively enhance transepithelial protein transport.
[So] Source:J Control Release;255:270-278, 2017 Jun 10.
[Is] ISSN:1873-4995
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Despite its patient-friendliness, the oral route is not yet a viable strategy for the delivery of biomacromolecular therapeutics. This is, in part, due to the large size of proteins, which greatly limits their absorption across the intestinal epithelium. Although chemical permeation enhancers can improve macromolecular transport, their positive impact is often accompanied by toxicity. One element potentially contributing to this toxicity is the lack of co-localization of the enhancer with the protein drug, which can result in non-specific permeation of the intestine as well as enhancer overdosing in some areas due to non-uniform distribution. To circumvent these issues, this study describes a new way of increasing protein permeability via a polymer conjugation process that co-localizes permeation enhancer with the protein. Based on previous reports demonstrating the utility of 1-phenylpiperazine as an intestinal permeation enhancer, we synthesized protein-polymer conjugates with a phenylpiperazine-containing polymer using polymer-based protein engineering. A novel phenylpiperazine acrylamide monomer was synthesized and chain extended using atom transfer radical polymerization from the model protein bovine serum albumin (BSA). At non-cytotoxic doses, the protein-polymer conjugates induced a dose dependent reduction in the trans-epithelial electrical resistance of Caco-2 monolayers and an impressive ~30-fold increase in BSA permeability. Furthermore, this permeability increase was selective, as the permeability of the small molecule calcein co-incubated with the protein-polymer conjugate increased only 5-fold. Together, these data represent an important first step in the development of protein polymer conjugates that facilitate selective protein transport across membranes that are typically impermeable to macromolecules.
[Mh] Termos MeSH primário: Piperazinas/administração & dosagem
Soroalbumina Bovina/administração & dosagem
[Mh] Termos MeSH secundário: Células CACO-2
Sobrevivência Celular/efeitos dos fármacos
Seres Humanos
Absorção Intestinal
Permeabilidade
Piperazinas/química
Polimerização
Transporte Proteico
Soroalbumina Bovina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Piperazines); 27432CM55Q (Serum Albumin, Bovine); J9225CBI7D (phenylpiperazine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


  6 / 45414 MEDLINE  
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[PMID]:29402931
[Au] Autor:Bianchi F; Syga L; Moiset G; Spakman D; Schavemaker PE; Punter CM; Seinen AB; van Oijen AM; Robinson A; Poolman B
[Ad] Endereço:Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9700AB, Groningen, The Netherlands.
[Ti] Título:Steric exclusion and protein conformation determine the localization of plasma membrane transporters.
[So] Source:Nat Commun;9(1):501, 2018 02 05.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The plasma membrane (PM) of Saccharomyces cerevisiae contains membrane compartments, MCC/eisosomes and MCPs, named after the protein residents Can1 and Pma1, respectively. Using high-resolution fluorescence microscopy techniques we show that Can1 and the homologous transporter Lyp1 are able to diffuse into the MCC/eisosomes, where a limited number of proteins are conditionally trapped at the (outer) edge of the compartment. Upon addition of substrate, the immobilized proteins diffuse away from the MCC/eisosomes, presumably after taking a different conformation in the substrate-bound state. Our data indicate that the mobile fraction of all integral plasma membrane proteins tested shows extremely slow Brownian diffusion through most of the PM. We also show that proteins with large cytoplasmic domains, such as Pma1 and synthetic chimera of Can1 and Lyp1, are excluded from the MCC/eisosomes. We hypothesize that the distinct localization patterns found for these integral membrane proteins in S. cerevisiae arises from a combination of slow lateral diffusion, steric exclusion, and conditional trapping in membrane compartments.
[Mh] Termos MeSH primário: Sistemas de Transporte de Aminoácidos Básicos/química
Membrana Celular/metabolismo
ATPases Translocadoras de Prótons/química
Proteínas de Saccharomyces cerevisiae/química
Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: Sistemas de Transporte de Aminoácidos Básicos/metabolismo
Membrana Celular/ultraestrutura
Difusão
Recuperação de Fluorescência Após Fotodegradação
Cinética
Microdomínios da Membrana
Conformação Proteica
Transporte Proteico
ATPases Translocadoras de Prótons/metabolismo
Saccharomyces cerevisiae/ultraestrutura
Proteínas de Saccharomyces cerevisiae/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amino Acid Transport Systems, Basic); 0 (CAN1 protein, S cerevisiae); 0 (LYP1 protein, S cerevisiae); 0 (Saccharomyces cerevisiae Proteins); EC 3.6.1.- (PMA1 protein, S cerevisiae); EC 3.6.3.14 (Proton-Translocating ATPases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180207
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-018-02864-2


  7 / 45414 MEDLINE  
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[PMID]:28461452
[Au] Autor:Bosserman RE; Champion PA
[Ad] Endereço:Department of Biological Sciences, Eck Institute for Global Health, Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, Indiana, USA.
[Ti] Título:Esx Systems and the Mycobacterial Cell Envelope: What's the Connection?
[So] Source:J Bacteriol;199(17), 2017 09 01.
[Is] ISSN:1098-5530
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mycobacterial 6-kDa early secreted antigenic target (ESAT-6) system (ESX) exporters transport proteins across the cytoplasmic membrane. Many proteins transported by ESX systems are then translocated across the mycobacterial cell envelope and secreted from the cell. Although the mechanism underlying protein transport across the mycolate outer membrane remains elusive, the ESX systems are closely connected with and localize to the cell envelope. Links between ESX-associated proteins, cell wall synthesis, and the maintenance of cell envelope integrity have been reported. Genes encoding the ESX systems and those required for biosynthesis of the mycobacterial envelope are coregulated. Here, we review the interplay between ESX systems and the mycobacterial cell envelope.
[Mh] Termos MeSH primário: Parede Celular/metabolismo
Mycobacterium/metabolismo
Sistemas de Secreção Tipo VII/metabolismo
[Mh] Termos MeSH secundário: Regulação Bacteriana da Expressão Gênica
Modelos Biológicos
Mycobacterium/genética
Transporte Proteico
Sistemas de Secreção Tipo VII/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Type VII Secretion Systems)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


  8 / 45414 MEDLINE  
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[PMID]:28449947
[Au] Autor:Bahouth SW; Nooh MM
[Ad] Endereço:Department of Pharmacology, The University of Tennessee Health Sciences Center, 71 S. Manassas, Memphis, TN 38103, USA. Electronic address: sbahouth@uthsc.edu.
[Ti] Título:Barcoding of GPCR trafficking and signaling through the various trafficking roadmaps by compartmentalized signaling networks.
[So] Source:Cell Signal;36:42-55, 2017 Aug.
[Is] ISSN:1873-3913
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Proper signaling by G protein coupled receptors (GPCR) is dependent on the specific repertoire of transducing, enzymatic and regulatory kinases and phosphatases that shape its signaling output. Activation and signaling of the GPCR through its cognate G protein is impacted by G protein-coupled receptor kinase (GRK)-imprinted "barcodes" that recruit ß-arrestins to regulate subsequent desensitization, biased signaling and endocytosis of the GPCR. The outcome of agonist-internalized GPCR in endosomes is also regulated by sequence motifs or "barcodes" within the GPCR that mediate its recycling to the plasma membrane or retention and eventual degradation as well as its subsequent signaling in endosomes. Given the vast number of diverse sequences in GPCR, several trafficking mechanisms for endosomal GPCR have been described. The majority of recycling GPCR, are sorted out of endosomes in a "sequence-dependent pathway" anchored around a type-1 PDZ-binding module found in their C-tails. For a subset of these GPCR, a second "barcode" imprinted onto specific GPCR serine/threonine residues by compartmentalized kinase networks was required for their efficient recycling through the "sequence-dependent pathway". Mutating the serine/threonine residues involved, produced dramatic effects on GPCR trafficking, indicating that they played a major role in setting the trafficking itinerary of these GPCR. While endosomal SNX27, retromer/WASH complexes and actin were required for efficient sorting and budding of all these GPCR, additional proteins were required for GPCR sorting via the second "barcode". Here we will review recent developments in GPCR trafficking in general and the human ß -adrenergic receptor in particular across the various trafficking roadmaps. In addition, we will discuss the role of GPCR trafficking in regulating endosomal GPCR signaling, which promote biochemical and physiological effects that are distinct from those generated by the GPCR signal transduction pathway in membranes.
[Mh] Termos MeSH primário: Transporte Proteico
Receptores Acoplados a Proteínas-G/metabolismo
[Mh] Termos MeSH secundário: Animais
Endossomos/metabolismo
Retroalimentação Fisiológica
Seres Humanos
Processamento de Proteína Pós-Traducional
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, G-Protein-Coupled)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE


  9 / 45414 MEDLINE  
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[PMID]:28460472
[Au] Autor:Å Urga S; Nanut MP; Kos J; Sabotic J
[Ad] Endereço:Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia.
[Ti] Título:Fungal lectin MpL enables entry of protein drugs into cancer cells and their subcellular targeting.
[So] Source:Oncotarget;8(16):26896-26910, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lectins have been recognized as promising carrier molecules for targeted drug delivery. They specifically bind carbohydrate moieties on cell membranes and trigger cell internalization. Fungal lectin MpL (Macrolepiota procera lectin) does not provoke cancer cell cytotoxicity but is able to bind aminopeptidase N (CD13) and integrin α3ß1, two glycoproteins that are overexpressed on the membrane of tumor cells. Upon binding, MpL is endocytosed in a clathrin-dependent manner and accumulates initially in the Golgi apparatus and, finally, in the lysosomes. For effective binding and internalization a functional binding site on the α-repeat is needed. To test the potential of MpL as a carrier for delivering protein drugs to cancer cells we constructed fusion proteins consisting of MpL and the cysteine peptidase inhibitors cystatin C and clitocypin. The fused proteins followed the same endocytic route as the unlinked MpL. Peptidase inhibitor-MpL fusions impaired both the intracellular degradation of extracellular matrix and the invasiveness of cancer cells. MpL is thus shown in vitro to be a lectin that can enable protein drugs to enter cancer cells, enhance their internalization and sort them to lysosomes and the Golgi apparatus.
[Mh] Termos MeSH primário: Portadores de Fármacos
Proteínas Fúngicas/metabolismo
Lectinas/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Membrana Celular/metabolismo
Colágeno Tipo IV/metabolismo
Endocitose
Glicoproteínas/metabolismo
Seres Humanos
Espaço Intracelular/metabolismo
Ligação Proteica
Transporte Proteico
Proteólise
Proteínas Recombinantes de Fusão/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Collagen Type IV); 0 (Drug Carriers); 0 (Fungal Proteins); 0 (Glycoproteins); 0 (Lectins); 0 (Recombinant Fusion Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15849


  10 / 45414 MEDLINE  
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[PMID]:28460457
[Au] Autor:Trivedi T; Zheng Y; Fournier PGJ; Murthy S; John S; Schillo S; Dunstan CR; Mohammad KS; Zhou H; Seibel MJ; Guise TA
[Ad] Endereço:Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia.
[Ti] Título:The vitamin D receptor is involved in the regulation of human breast cancer cell growth via a ligand-independent function in cytoplasm.
[So] Source:Oncotarget;8(16):26687-26701, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Vitamin D has pleiotropic effects on multiple tissues, including malignant tumors. Vitamin D inhibits breast cancer growth through activation of the vitamin D receptor (VDR) and via classical nuclear signaling pathways. Here, we demonstrate that the VDR can also function in the absence of its ligand to control behaviour of human breast cancer cells both outside and within the bone microenvironment. Stable shRNA expression was used to knock down VDR expression in MCF-7 cells, generating two VDR knockdown clonal lines. In ligand-free culture, knockdown of VDR in MCF-7 cells significantly reduced proliferation and increased apoptosis, suggesting that the VDR plays a ligand-independent role in cancer cell growth. Implantation of these VDR knockdown cells into the mammary fat pad of nude mice resulted in reduced tumor growth in vivo compared with controls. In the intra-tibial xenograft model, VDR knockdown greatly reduced the ability of the cells to form tumors in the bone microenvironment. The in vitro growth of VDR knockdown cells was rescued by the expression of a mutant form of VDR which is unable to translocate to the nucleus and hence accumulates in the cytoplasm. Thus, our data indicate that in the absence of ligand, the VDR promotes breast cancer growth both in vitro and in vivo and that cytoplasmic accumulation of VDR is sufficient to produce this effect in vitro. This new mechanism of VDR action in breast cancer cells contrasts the known anti-proliferative nuclear actions of the VDR-vitamin D ligand complex.
[Mh] Termos MeSH primário: Neoplasias da Mama/metabolismo
Receptores de Calcitriol/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose/genética
Neoplasias Ósseas/genética
Neoplasias Ósseas/metabolismo
Neoplasias Ósseas/patologia
Neoplasias da Mama/genética
Linhagem Celular Tumoral
Proliferação Celular
Citoplasma/metabolismo
Modelos Animais de Doenças
Feminino
Expressão Gênica
Técnicas de Silenciamento de Genes
Xenoenxertos
Seres Humanos
Ligantes
Camundongos
Mutação
Osteosclerose/genética
Osteosclerose/metabolismo
Transporte Proteico
Receptores de Calcitriol/genética
Vitamina D/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Receptors, Calcitriol); 0 (VDR protein, human); 1406-16-2 (Vitamin D)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15803



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