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  1 / 12544 MEDLINE  
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[PMID]:29311697
[Au] Autor:Qureshi BM; Schmidt A; Behrmann E; Bürger J; Mielke T; Spahn CMT; Heck M; Scheerer P
[Ad] Endereço:Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, D-10117, Berlin, Germany.
[Ti] Título:Mechanistic insights into the role of prenyl-binding protein PrBP/δ in membrane dissociation of phosphodiesterase 6.
[So] Source:Nat Commun;9(1):90, 2018 01 08.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Isoprenylated proteins are associated with membranes and their inter-compartmental distribution is regulated by solubilization factors, which incorporate lipid moieties in hydrophobic cavities and thereby facilitate free diffusion during trafficking. Here we report the crystal structure of a solubilization factor, the prenyl-binding protein (PrBP/δ), at 1.81 Å resolution in its ligand-free apo-form. Apo-PrBP/δ harbors a preshaped, deep hydrophobic cavity, capacitating apo-PrBP/δ to readily bind its prenylated cargo. To investigate the molecular mechanism of cargo solubilization we analyzed the PrBP/δ-induced membrane dissociation of rod photoreceptor phosphodiesterase (PDE6). The results suggest that PrBP/δ exclusively interacts with the soluble fraction of PDE6. Depletion of soluble species in turn leads to dissociation of membrane-bound PDE6, as both are in equilibrium. This "solubilization by depletion" mechanism of PrBP/δ differs from the extraction of prenylated proteins by the similar folded solubilization factor RhoGDI, which interacts with membrane bound cargo via an N-terminal structural element lacking in PrBP/δ.
[Mh] Termos MeSH primário: Proteínas de Transporte/metabolismo
Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo
Neopreno/metabolismo
Células Fotorreceptoras Retinianas Bastonetes/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteínas de Transporte/química
Bovinos
Cristalografia por Raios X
Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/química
Modelos Moleculares
Complexos Multiproteicos/química
Complexos Multiproteicos/metabolismo
Neopreno/química
Ligação Proteica
Domínios Proteicos
Prenilação de Proteína
Subunidades Proteicas/química
Subunidades Proteicas/metabolismo
Inibidores da Dissociação do Nucleotídeo Guanina rho-Específico/química
Inibidores da Dissociação do Nucleotídeo Guanina rho-Específico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Multiprotein Complexes); 0 (Protein Subunits); 0 (prenyl); 0 (rho-Specific Guanine Nucleotide Dissociation Inhibitors); 9010-98-4 (Neoprene); EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 6)
[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:180110
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02569-y


  2 / 12544 MEDLINE  
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[PMID]:28470612
[Au] Autor:Berger I; Jiang Q; Schulze RJ; Collinson I; Schaffitzel C
[Ad] Endereço:The School of Biochemistry, University Walk, University of Bristol, Clifton, BS8 1TD, UK. imre.berger@bristol.ac.uk.
[Ti] Título:Multiprotein Complex Production in E. coli: The SecYEG-SecDFYajC-YidC Holotranslocon.
[So] Source:Methods Mol Biol;1586:279-290, 2017.
[Is] ISSN:1940-6029
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A modular approach for balanced overexpression of recombinant multiprotein complexes in E. coli is described, with the prokaryotic protein secretase/insertase complex, the SecYEG-SecDFYajC-YidC holotranslocon (HTL), used as an example. This procedure has been implemented here in the ACEMBL system. The protocol details the design principles of the monocistronic or polycistronic DNA constructs, the expression and purification of functional HTL and its association with translating ribosome nascent chain (RNC) complexes into a RNC-HTL supercomplex.
[Mh] Termos MeSH primário: Escherichia coli/genética
Complexos Multiproteicos/genética
Canais de Translocação SEC/genética
[Mh] Termos MeSH secundário: Clonagem Molecular/métodos
DNA Recombinante/genética
Proteínas de Escherichia coli/genética
Proteínas de Membrana Transportadoras/genética
Plasmídeos/genética
Proteínas Recombinantes/genética
Ribossomos/genética
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Recombinant); 0 (Escherichia coli Proteins); 0 (Membrane Transport Proteins); 0 (Multiprotein Complexes); 0 (Recombinant Proteins); 0 (SEC Translocation Channels); 0 (SecD protein, E coli); 0 (YIDC protein, E coli)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1007/978-1-4939-6887-9_18


  3 / 12544 MEDLINE  
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[PMID]:29372961
[Au] Autor:Mazina MY; Derevyanko PK; Kocheryzhkina EV; Nikolenko YV; Krasnov AN; Vorobyeva NE
[Ti] Título:[Coactivator complexes participate in different stages of the Drosophila melanogaster hsp70 gene transcription].
[So] Source:Genetika;53(2):155-64, 2017 Feb.
[Is] ISSN:0016-6758
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:The objective of this study was to identify transcriptional coactivators participating in transcription elongation of the hsp70 gene induced by heat shock. We found that all investigated coactivator complexes participate in transcription of this gene, as significant level of them were present at the gene promoter in its active state. For most of the coactivators (except for p300/CBP, Set2, and Mediator complex), we also observed a considerable increase of their binding level at the coding region of the gene after activation of its transcription by heat shock. We assume that coactivators CHD1, ISWI, Brm, Kismet-L, INO80, Mi-2, Gcn5, Lid/KDM5, Set1, DART1, DART4, SSRP1, PAF1, and Fs(1)h/Brd4 bind to the promoter of the active hsp70 gene and migrate to its coding region together with elongating RNA polymerase II. It can be suggested that some of these coactivators play an important role in stimulating the transition of the RNA polymerase II complex from transcription initiation to elongation stage.
[Mh] Termos MeSH primário: Proteínas de Drosophila/metabolismo
Proteínas de Choque Térmico HSP70/biossíntese
Complexos Multiproteicos/metabolismo
RNA Polimerase II/metabolismo
Transcrição Genética/fisiologia
[Mh] Termos MeSH secundário: Animais
Proteínas de Drosophila/genética
Drosophila melanogaster
Proteínas de Choque Térmico HSP70/genética
Complexos Multiproteicos/genética
RNA Polimerase II/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (HSP70 Heat-Shock Proteins); 0 (Multiprotein Complexes); EC 2.7.7.- (RNA Polymerase II)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180127
[St] Status:MEDLINE


  4 / 12544 MEDLINE  
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[PMID]:29321179
[Au] Autor:Reginato G; Cannavo E; Cejka P
[Ad] Endereço:Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland.
[Ti] Título:Physiological protein blocks direct the Mre11-Rad50-Xrs2 and Sae2 nuclease complex to initiate DNA end resection.
[So] Source:Genes Dev;31(23-24):2325-2330, 2017 12 01.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DNA double-strand break repair by homologous recombination is initiated by DNA end resection, which is commenced by the Mre11-Rad50-Xrs2 complex and Sae2 in yeast. Here we report that the nonhomologous end joining factor Ku limits the exonuclease activity of Mre11 and promotes its endonuclease to cleave 5'-terminated DNA strands at break sites. Following initial endonucleolytic cleavage past the obstacle, Exo1 specifically extends the resection track, leading to the generation of long 3' overhangs that are required for homologous recombination. These experiments provide mechanistic insights into how short-range and long-range DNA end resection enzymes overcome obstacles near broken DNA ends to initiate recombination.
[Mh] Termos MeSH primário: Reparo do DNA por Junção de Extremidades
Endonucleases/metabolismo
Exonucleases/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/fisiologia
[Mh] Termos MeSH secundário: Animais
Clivagem do DNA
Proteínas de Ligação a DNA/metabolismo
Endodesoxirribonucleases/metabolismo
Ativação Enzimática/genética
Exodesoxirribonucleases/metabolismo
Complexos Multiproteicos/metabolismo
Saccharomyces cerevisiae/enzimologia
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/genética
Células Sf9
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (Multiprotein Complexes); 0 (RAD50 protein, S cerevisiae); 0 (SAE2 protein, S cerevisiae); 0 (Saccharomyces cerevisiae Proteins); 0 (XRS2 protein, S cerevisiae); 0 (high affinity DNA-binding factor, S cerevisiae); EC 3.1.- (Endodeoxyribonucleases); EC 3.1.- (Endonucleases); EC 3.1.- (Exodeoxyribonucleases); EC 3.1.- (Exonucleases); EC 3.1.- (MRE11 protein, S cerevisiae); EC 3.1.11.1 (exodeoxyribonuclease I)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.1101/gad.308254.117


  5 / 12544 MEDLINE  
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[PMID]:29321177
[Au] Autor:Wang W; Daley JM; Kwon Y; Krasner DS; Sung P
[Ad] Endereço:Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
[Ti] Título:Plasticity of the Mre11-Rad50-Xrs2-Sae2 nuclease ensemble in the processing of DNA-bound obstacles.
[So] Source:Genes Dev;31(23-24):2331-2336, 2017 12 01.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The budding yeast Mre11-Rad50-Xrs2 (MRX) complex and Sae2 function together in DNA end resection during homologous recombination. Here we show that the Ku complex shields DNA ends from exonucleolytic digestion but facilitates endonucleolytic scission by MRX with a dependence on ATP and Sae2. The incision site is enlarged into a DNA gap via the exonuclease activity of MRX, which is stimulated by Sae2 without ATP being present. RPA renders a partially resected or palindromic DNA structure susceptible to MRX-Sae2, and internal protein blocks also trigger DNA cleavage. We present models for how MRX-Sae2 creates entry sites for the long-range resection machinery.
[Mh] Termos MeSH primário: Reparo do DNA por Junção de Extremidades
Reparo do DNA/fisiologia
Endonucleases/metabolismo
Exonucleases/metabolismo
Complexos Multienzimáticos/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/fisiologia
[Mh] Termos MeSH secundário: Clivagem do DNA
Proteínas de Ligação a DNA/metabolismo
Endodesoxirribonucleases/metabolismo
Ativação Enzimática/genética
Exodesoxirribonucleases/metabolismo
Complexos Multiproteicos/metabolismo
Saccharomyces cerevisiae/enzimologia
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (Multienzyme Complexes); 0 (Multiprotein Complexes); 0 (RAD50 protein, S cerevisiae); 0 (SAE2 protein, S cerevisiae); 0 (Saccharomyces cerevisiae Proteins); 0 (XRS2 protein, S cerevisiae); 0 (high affinity DNA-binding factor, S cerevisiae); EC 3.1.- (Endodeoxyribonucleases); EC 3.1.- (Endonucleases); EC 3.1.- (Exodeoxyribonucleases); EC 3.1.- (Exonucleases); EC 3.1.- (MRE11 protein, S cerevisiae); EC 3.1.11.1 (exodeoxyribonuclease I)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.1101/gad.307900.117


  6 / 12544 MEDLINE  
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[PMID]:28450306
[Au] Autor:Xiao M; Wang Y; Tao C; Wang Z; Yang J; Chen Z; Zou Z; Li M; Liu A; Jia C; Huang B; Yan B; Lai P; Ding C; Cai D; Xiao G; Jiang Y; Bai X
[Ad] Endereço:State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences and.
[Ti] Título:Osteoblasts support megakaryopoiesis through production of interleukin-9.
[So] Source:Blood;129(24):3196-3209, 2017 06 15.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Severe thrombocytopenia is a significant challenge in patients undergoing myelosuppressive chemotherapy for malignancies. Understanding the biology of platelet-producing megakaryocytes development in the bone marrow microenvironment may facilitate the development of novel therapies to stimulate platelet production and prevent thrombocytopenia. We report here that osteoblasts supported megakaryopoiesis by secreting interleukin-9 (IL-9), which stimulated IL-9 receptor (IL-9R)/Stat3 signaling in promoting megakaryopoiesis. IL-9 production in osteoblasts was negatively regulated by the mechanistic target of rapamycin complex 1 (mTORC1) signaling in a NF-κB-dependent manner. Constitutive activation of mTORC1 inhibited IL-9 production in osteoblasts and suppressed megakaryocytic cells expansion, whereas mTORC1 inactivation increased IL-9 production and enhanced megakaryocyte and platelet numbers in mice. In mouse models, we showed that IL-9 administration stimulated megakaryopoiesis, whereas neutralizing endogenous IL-9 or IL-9R depletion inhibited the process. Importantly, we found that low doses of IL-9 efficiently prevented chemotherapy-induced thrombocytopenia (CIT) and accelerated platelet recovery after CIT. These data indicate that IL-9 is an essential regulator of megakaryopoiesis and a promising therapeutic agent for treatment of thrombocytopenia such as CIT.
[Mh] Termos MeSH primário: Interleucina-9/metabolismo
Megacariócitos/metabolismo
Osteoblastos/metabolismo
Transdução de Sinais/fisiologia
Trombopoese/fisiologia
[Mh] Termos MeSH secundário: Animais
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Alvo Mecanístico do Complexo 1 de Rapamicina
Megacariócitos/citologia
Camundongos
Complexos Multiproteicos/metabolismo
Osteoblastos/citologia
Células RAW 264.7
Receptores de Interleucina-9/metabolismo
Fator de Transcrição STAT3/metabolismo
Serina-Treonina Quinases TOR/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (IL9 protein, human); 0 (IL9R protein, human); 0 (Il9r protein, mouse); 0 (Interleukin-9); 0 (Multiprotein Complexes); 0 (Receptors, Interleukin-9); 0 (STAT3 Transcription Factor); 0 (STAT3 protein, human); 0 (Stat3 protein, mouse); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180113
[Lr] Data última revisão:
180113
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-11-749838


  7 / 12544 MEDLINE  
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[PMID]:29223159
[Au] Autor:Baleva MV; Meyer M; Entelis N; Tarassov I; Kamenski P; Masquida B
[Ad] Endereço:GMGM, CNRS - University of Strasbourg, UMR 7156, Strasbourg, 67081, France. b.masquida@unistra.fr.
[Ti] Título:Factors beyond Enolase 2 and Mitochondrial Lysyl-tRNA Synthetase Precursor Are Required for tRNA Import into Yeast Mitochondria.
[So] Source:Biochemistry (Mosc);82(11):1324-1335, 2017 Nov.
[Is] ISSN:1608-3040
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In yeast, the import of tRNA with CUU anticodon (tRK1) relies on a complex mechanism where interaction with enolase 2 (Eno2p) dictates a deep conformational change of the tRNA. This event is believed to mask the tRNA from the cytosolic translational machinery to re-direct it towards the mitochondria. Once near the mitochondrial outer membrane, the precursor of the mitochondrial lysyl-tRNA synthetase (preMsk1p) takes over enolase to carry the tRNA within the mitochondrial matrix, where it is supposed to participate in translation following correct refolding. Biochemical data presented in this report focus on the role of enolase. They show that despite the inability of Eno2p alone to form a complex with tRK1, mitochondrial import can be recapitulated in vitro using fractions of yeast extracts sharing either recombinant or endogenous yeast Eno2p as one of the main components. Taken together, our data suggest the existence of a protein complex containing Eno2p that is involved in RNA mitochondrial import.
[Mh] Termos MeSH primário: Lisina-tRNA Ligase/fisiologia
Mitocôndrias/metabolismo
Fosfopiruvato Hidratase/fisiologia
RNA de Transferência de Lisina/metabolismo
Saccharomyces cerevisiae/enzimologia
Saccharomyces cerevisiae/ultraestrutura
[Mh] Termos MeSH secundário: Transporte Biológico
Proteínas de Transporte de Cátions/metabolismo
Mitocôndrias/enzimologia
Complexos Multiproteicos/química
Complexos Multiproteicos/fisiologia
Fosfopiruvato Hidratase/metabolismo
RNA de Transferência/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Proteínas de Saccharomyces cerevisiae/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cation Transport Proteins); 0 (Multiprotein Complexes); 0 (RNA, Transfer, Lys); 0 (Saccharomyces cerevisiae Proteins); 136956-54-2 (TRK1 protein, S cerevisiae); 9014-25-9 (RNA, Transfer); EC 4.2.1.11 (Phosphopyruvate Hydratase); EC 6.1.1.6 (Lysine-tRNA Ligase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180103
[Lr] Data última revisão:
180103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171211
[St] Status:MEDLINE
[do] DOI:10.1134/S0006297917110104


  8 / 12544 MEDLINE  
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[PMID]:28468873
[Au] Autor:Vink EI; Smiley JR; Mohr I
[Ad] Endereço:Department of Microbiology, New York University School of Medicine, New York, New York, USA.
[Ti] Título:Subversion of Host Responses to Energy Insufficiency by Us3 Supports Herpes Simplex Virus 1 Replication during Stress.
[So] Source:J Virol;91(14), 2017 Jul 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cellular stress responses to energy insufficiency can impact virus reproduction. In particular, activation of the host AMP-activated protein kinase (AMPK) by low energy could limit protein synthesis by inhibiting mTORC1. Although many herpesviruses, including herpes simplex virus 1 (HSV-1), stimulate mTORC1, how HSV-1-infected cells respond to energy availability, a physiological indicator regulating mTORC1, has not been investigated. In addition, the impact of low-energy stress on productive HSV-1 growth and viral genetic determinants potentially enabling replication under physiological stress remains undefined. Here, we demonstrate that mTORC1 activity in HSV-1-infected cells is largely insensitive to stress induced by simulated energy insufficiency. Furthermore, resistance of mTORC1 activity to low-energy-induced stress, while not significantly influenced by the HSV-1 UL46-encoded phosphatidylinositol 3-kinase (PI3K)-Akt activator, was dependent upon the Ser/Thr kinase activity of Us3. A Us3-deficient virus was hypersensitive to low-energy-induced stress as infected cell protein synthesis and productive replication were reduced compared to levels in cells infected with a Us3-expressing virus. Although Us3 did not detectably prevent energy stress-induced AMPK activation, it enforced mTORC1 activation despite the presence of activated AMPK. In the absence of applied low-energy stress, AMPK activity in infected cells was restricted in a Us3-dependent manner. This establishes that the Us3 kinase not only activated mTORC1 but also enabled sustained mTORC1 signaling during simulated energy insufficiency that would otherwise restrict protein synthesis and virus replication. Moreover, it identifies the alphaherpesvirus-specific Us3 kinase as an mTORC1 activator that subverts the host cell energy-sensing program to support viral productive growth irrespective of physiological stress. Like all viruses, herpes simplex virus type 1 (HSV-1) reproduction relies upon numerous host energy-intensive processes, the most demanding of which is protein synthesis. In response to low energy, the cellular AMP-activated protein kinase (AMPK) triggers a physiological stress response that antagonizes mTORC1, a multisubunit host kinase that controls protein synthesis. This could restrict virus protein production and growth. Here, we establish that the HSV-1 Us3 protein kinase subverts the normal response to low-energy-induced stress. While Us3 does not prevent AMPK activation by low energy, it enforces mTORC1 activation and overrides a physiological response that couples energy availability and protein synthesis. These results help explain how reproduction of HSV-1, a ubiquitous, medically significant human pathogen causing a spectrum of diseases ranging from the benign to the life threatening, occurs during physiological stress. This is important because HSV-1 reproduction triggered by physiological stress is characteristic of reactivation of lifelong latent infections.
[Mh] Termos MeSH primário: Herpesvirus Humano 1/fisiologia
Interações Hospedeiro-Patógeno
Complexos Multiproteicos/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
Serina-Treonina Quinases TOR/metabolismo
Proteínas Virais/metabolismo
Replicação Viral
[Mh] Termos MeSH secundário: Células Cultivadas
Seres Humanos
Alvo Mecanístico do Complexo 1 de Rapamicina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Multiprotein Complexes); 0 (Viral Proteins); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (US3 protein, Human herpesvirus 1)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171226
[Lr] Data última revisão:
171226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE


  9 / 12544 MEDLINE  
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[PMID]:28465529
[Au] Autor:Hasan MK; Yu J; Chen L; Cui B; Widhopf Ii GF; Rassenti L; Shen Z; Briggs SP; Kipps TJ
[Ad] Endereço:Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
[Ti] Título:Wnt5a induces ROR1 to complex with HS1 to enhance migration of chronic lymphocytic leukemia cells.
[So] Source:Leukemia;31(12):2615-2622, 2017 Dec.
[Is] ISSN:1476-5551
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:ROR1 (receptor tyrosine kinase-like orphan receptor 1) is a conserved, oncoembryonic surface antigen expressed in chronic lymphocytic leukemia (CLL). We found that ROR1 associates with hematopoietic-lineage-cell-specific protein 1 (HS1) in freshly isolated CLL cells or in CLL cells cultured with exogenous Wnt5a. Wnt5a also induced HS1 tyrosine phosphorylation, recruitment of ARHGEF1, activation of RhoA and enhanced chemokine-directed migration; such effects could be inhibited by cirmtuzumab, a humanized anti-ROR1 mAb. We generated truncated forms of ROR1 and found its extracellular cysteine-rich domain or kringle domain was necessary for Wnt5a-induced HS1 phosphorylation. Moreover, the cytoplamic, and more specifically the proline-rich domain (PRD), of ROR1 was required for it to associate with HS1 and allow for F-actin polymerization in response to Wnt5a. Accordingly, we introduced single amino acid substitutions of proline (P) to alanine (A) in the ROR1 PRD at positions 784, 808, 826, 841 or 850 in potential SH3-binding motifs. In contrast to wild-type ROR1, or other ROR1 mutants, ROR1 had impaired capacity to recruit HS1 and ARHGEF1 to ROR1 in response to Wnt5a. Moreover, Wnt5a could not induce cells expressing ROR1 to phosphorylate HS1 or activate ARHGEF1, and was unable to enhance CLL-cell motility. Collectively, these studies indicate HS1 plays an important role in ROR1-dependent Wnt5a-enhanced chemokine-directed leukemia-cell migration.
[Mh] Termos MeSH primário: Proteínas Sanguíneas/metabolismo
Movimento Celular/imunologia
Leucemia Linfocítica Crônica de Células B/imunologia
Leucemia Linfocítica Crônica de Células B/metabolismo
Complexos Multiproteicos/metabolismo
Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo
Proteína Wnt-5a/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Proteínas Sanguíneas/química
Quimiocinas/metabolismo
Seres Humanos
Fosforilação
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/química
Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo
Células Tumorais Cultivadas
Proteína rhoA de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ARHGEF1 protein, human); 0 (Blood Proteins); 0 (Chemokines); 0 (HCLS1 protein, human); 0 (Multiprotein Complexes); 0 (Rho Guanine Nucleotide Exchange Factors); 0 (WNT5A protein, human); 0 (Wnt-5a Protein); EC 2.7.10.1 (ROR1 protein, human); EC 2.7.10.1 (Receptor Tyrosine Kinase-like Orphan Receptors); EC 3.6.5.2 (rhoA GTP-Binding Protein)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171215
[Lr] Data última revisão:
171215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1038/leu.2017.133


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[PMID]:28300280
[Au] Autor:Zeng Q; Qin S; Zhang H; Liu B; Qin J; Wang X; Zhang R; Liu C; Dong X; Zhang S; Huang S; Chen L
[Ad] Endereço:Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, PR China.
[Ti] Título:Rapamycin attenuates BAFF-extended proliferation and survival via disruption of mTORC1/2 signaling in normal and neoplastic B-lymphoid cells.
[So] Source:J Cell Physiol;233(1):516-529, 2018 Jan.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:B cell activating factor from the TNF family (BAFF) stimulates B-cell proliferation and survival, but excessive BAFF promotes the development of aggressive B cells leading to malignant and autoimmune diseases. Recently, we have reported that rapamycin, a macrocyclic lactone, attenuates human soluble BAFF (hsBAFF)-stimulated B-cell proliferation/survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway. Here, we show that the inhibitory effect of rapamycin on hsBAFF-promoted B cell proliferation/survival is also related to blocking hsBAFF-stimulated phosphorylation of Akt, S6K1, and 4E-BP1, as well as expression of survivin in normal and B-lymphoid (Raji and Daudi) cells. It appeared that both mTORC1 and mTORC2 were involved in the inhibitory activity of rapamycin, as silencing raptor or rictor enhanced rapamycin's suppression of hsBAFF-induced survivin expression and proliferation/viability in B cells. Also, PP242, an mTORC1/2 kinase inhibitor, repressed survivin expression, and cell proliferation/viability more potently than rapamycin (mTORC1 inhibitor) in B cells in response to hsBAFF. Of interest, ectopic expression of constitutively active Akt (myr-Akt) or constitutively active S6K1 (S6K1-ca), or downregulation of 4E-BP1 conferred resistance to rapamycin's attenuation of hsBAFF-induced survivin expression and B-cell proliferation/viability, whereas overexpression of dominant negative Akt (dn-Akt) or constitutively hypophosphorylated 4E-BP1 (4EBP1-5A), or downregulation of S6K1, or co-treatment with Akt inhibitor potentiated the inhibitory effects of rapamycin. The findings indicate that rapamycin attenuates excessive hsBAFF-induced cell proliferation/survival via blocking mTORC1/2 signaling in normal and neoplastic B-lymphoid cells. Our data underscore that rapamycin may be a potential agent for preventing excessive BAFF-evoked aggressive B-cell malignancies and autoimmune diseases.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Fator Ativador de Células B/metabolismo
Linfócitos B/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Linfoma de Células B/tratamento farmacológico
Complexos Multiproteicos/metabolismo
Transdução de Sinais/efeitos dos fármacos
Sirolimo/farmacologia
Serina-Treonina Quinases TOR/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/genética
Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Linfócitos B/enzimologia
Linfócitos B/patologia
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Linfoma de Células B/genética
Linfoma de Células B/patologia
Alvo Mecanístico do Complexo 1 de Rapamicina
Alvo Mecanístico do Complexo 2 de Rapamicina
Fosfoproteínas/genética
Fosfoproteínas/metabolismo
Fosforilação
Proteínas Proto-Oncogênicas c-akt/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
Interferência de RNA
Proteínas Quinases S6 Ribossômicas 70-kDa/genética
Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Antineoplastic Agents); 0 (B-Cell Activating Factor); 0 (EIF4EBP1 protein, human); 0 (Multiprotein Complexes); 0 (Phosphoproteins); 0 (TNFSF13B protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa); EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1); W36ZG6FT64 (Sirolimus)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171212
[Lr] Data última revisão:
171212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170317
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.25913



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