Base de dados : MEDLINE Pesquisa : G05.360.340.024.340.137.232.459 [Categoria DeCS] Referências encontradas : 35 [refinar] Mostrando: 1 .. 10   no formato [Detalhado]

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[PMID]: 27008630 [Au] Autor: Sun L; Tabaka M; Hou S; Li L; Burdzy K; Aksimentiev A; Maffeo C; Zhang X; Holyst R [Ad] Endereço: Institute of Physical Chemistry PAS, Kasprzaka 44/52, 01-224, Warsaw, Poland. [Ti] Título: The Hinge Region Strengthens the Nonspecific Interaction between Lac-Repressor and DNA: A Computer Simulation Study. [So] Source: PLoS One;11(3):e0152002, 2016. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: LacI is commonly used as a model to study the protein-DNA interaction and gene regulation. The headpiece of the lac-repressor (LacI) protein is an ideal system for investigation of nonspecific binding of the whole LacI protein to DNA. The hinge region of the headpiece has been known to play a key role in the specific binding of LacI to DNA, whereas its role in nonspecific binding process has not been elucidated. Here, we report the results of explicit solvent molecular dynamics simulation and continuum electrostatic calculations suggesting that the hinge region strengthens the nonspecific interaction, accounting for up to 50% of the micro-dissociation free energy of LacI from DNA. Consequently, the rate of microscopic dissociation of LacI from DNA is reduced by 2~3 orders of magnitude in the absence of the hinge region. We find the hinge region makes an important contribution to the electrostatic energy, the salt dependence of electrostatic energy, and the number of salt ions excluded from binding of the LacI-DNA complex. [Mh] Termos MeSH primário: DNA/metabolismo Éxons Codificadores da Região de Dobradiça/fisiologia Repressores Lac/metabolismo [Mh] Termos MeSH secundário: Simulação por Computador Metabolismo Energético/fisiologia Escherichia coli/metabolismo Regulação da Expressão Gênica/fisiologia Ligações de Hidrogênio Eletricidade Estática [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Lac Repressors); 9007-49-2 (DNA) [Em] Mês de entrada: 1608 [Cu] Atualização por classe: 170220 [Lr] Data última revisão: 170220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160324 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0152002

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[PMID]: 25904551 [Au] Autor: Grevys A; Bern M; Foss S; Bratlie DB; Moen A; Gunnarsen KS; Aase A; Michaelsen TE; Sandlie I; Andersen JT [Ad] Endereço: Centre for Immune Regulation and Department of Biosciences, University of Oslo, 0316 Oslo, Norway; Centre for Immune Regulation and Department of Immunology, Oslo University Hospital, Rikshospitalet and University of Oslo, 0372 Oslo, Norway; [Ti] Título: Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions. [So] Source: J Immunol;194(11):5497-508, 2015 Jun 01. [Is] ISSN: 1550-6606 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Engineering of the constant Fc part of monoclonal human IgG1 (hIgG1) Abs is an approach to improve effector functions and clinical efficacy of next-generation IgG1-based therapeutics. A main focus in such development is tailoring of in vivo half-life and transport properties by engineering the pH-dependent interaction between IgG and the neonatal Fc receptor (FcRn), as FcRn is the main homeostatic regulator of hIgG1 half-life. However, whether such engineering affects binding to other Fc-binding molecules, such as the classical FcγRs and complement factor C1q, has not been studied in detail. These effector molecules bind to IgG1 in the lower hinge-CH2 region, structurally distant from the binding site for FcRn at the CH2-CH3 elbow region. However, alterations of the structural composition of the Fc may have long-distance effects. Indeed, in this study we show that Fc engineering of hIgG1 for altered binding to FcRn also influences binding to both the classical FcγRs and complement factor C1q, which ultimately results in alterations of cellular mechanisms such as Ab-dependent cell-mediated cytotoxicity, Ab-dependent cellular phagocytosis, and Ab-dependent complement-mediated cell lysis. Thus, engineering of the FcRn-IgG1 interaction may greatly influence effector functions, which has implications for the therapeutic efficacy and use of Fc-engineered hIgG1 variants. [Mh] Termos MeSH primário: Anticorpos Monoclonais/genética Complemento C1q/imunologia Antígenos de Histocompatibilidade Classe I/imunologia Imunoglobulina G/genética Receptores Fc/imunologia Receptores de IgG/imunologia [Mh] Termos MeSH secundário: Anticorpos Monoclonais/imunologia Afinidade de Anticorpos/genética Afinidade de Anticorpos/imunologia Citotoxicidade Celular Dependente de Anticorpos/imunologia Linhagem Celular Células HEK293 Éxons Codificadores da Região de Dobradiça/genética Antígenos de Histocompatibilidade Classe I/genética Seres Humanos Imunoglobulina G/imunologia Nitro-Hidroxi-Iodofenilacetato/imunologia Fagocitose/imunologia Engenharia de Proteínas Receptores Fc/genética Receptores de IgG/genética Ressonância de Plasmônio de Superfície [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antibodies, Monoclonal); 0 (Fc receptor, neonatal); 0 (Histocompatibility Antigens Class I); 0 (Immunoglobulin G); 0 (Receptors, Fc); 0 (Receptors, IgG); 2646-51-7 (Nitrohydroxyiodophenylacetate); 80295-33-6 (Complement C1q) [Em] Mês de entrada: 1508 [Cu] Atualização por classe: 151111 [Lr] Data última revisão: 151111 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 150424 [St] Status: MEDLINE [do] DOI: 10.4049/jimmunol.1401218

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[PMID]: 25848865 [Au] Autor: Übelhart R; Hug E; Bach MP; Wossning T; Dühren-von Minden M; Horn AH; Tsiantoulas D; Kometani K; Kurosaki T; Binder CJ; Sticht H; Nitschke L; Reth M; Jumaa H [Ad] Endereço: Institute of Immunology, University Hospital Ulm, Ulm, Germany. [Ti] Título: Responsiveness of B cells is regulated by the hinge region of IgD. [So] Source: Nat Immunol;16(5):534-43, 2015 May. [Is] ISSN: 1529-2916 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Mature B cells express immunoglobulin M (IgM)- and IgD-isotype B cell antigen receptors, but the importance of IgD for B cell function has been unclear. By using a cellular in vitro system and corresponding mouse models, we found that antigens with low valence activated IgM receptors but failed to trigger IgD signaling, whereas polyvalent antigens activated both receptor types. Investigations of the molecular mechanism showed that deletion of the IgD-specific hinge region rendered IgD responsive to monovalent antigen, whereas transferring the hinge to IgM resulted in responsiveness only to polyvalent antigen. Our data suggest that the increased IgD/IgM ratio on conventional B-2 cells is important for preferential immune responses to antigens in immune complexes, and that the increased IgM expression on B-1 cells is essential for B-1 cell homeostasis and function. [Mh] Termos MeSH primário: Linfócitos B/imunologia Imunoglobulina D/imunologia Imunoglobulina M/imunologia [Mh] Termos MeSH secundário: Animais Complexo Antígeno-Anticorpo/imunologia Antígenos/imunologia Sítios de Ligação de Anticorpos/imunologia Sinalização do Cálcio/genética Diferenciação Celular Linhagem Celular Éxons Codificadores da Região de Dobradiça/genética Homeostase/genética Imunidade Humoral/genética Imunoglobulina D/genética Imunoglobulina M/genética Camundongos Camundongos Knockout Engenharia de Proteínas Deleção de Sequência/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antigen-Antibody Complex); 0 (Antigens); 0 (Immunoglobulin D); 0 (Immunoglobulin M) [Em] Mês de entrada: 1507 [Cu] Atualização por classe: 170603 [Lr] Data última revisão: 170603 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150408 [St] Status: MEDLINE [do] DOI: 10.1038/ni.3141

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[PMID]: 25185680 [Au] Autor: Pinheiro A; Woof JM; Almeida T; Abrantes J; Alves PC; Gortázar C; Esteves PJ [Ad] Endereço: CIBIO Centro de Investigação em Biodiversidade e Recursos Genéticos, InBio Laboratório Associado, Universidade do Porto, Campus Agrário de Vairão, Vairão 4485-661, Portugal Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, Porto 4169-007, Portugal SaBio IREC (CSIC-UCLM-JCCM), R [Ti] Título: Leporid immunoglobulin G shows evidence of strong selective pressure on the hinge and CH3 domains. [So] Source: Open Biol;4(9):140088, 2014 Sep. [Is] ISSN: 2046-2441 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Immunoglobulin G (IgG) is the predominant serum immunoglobulin and has the longest serum half-life of all the antibody classes. The European rabbit IgG has been of significant importance in immunological research, and is therefore well characterized. However, the IgG of other leporids has been disregarded. To evaluate the evolution of this gene in leporids, we sequenced the complete IGHG for six other genera: Bunolagus, Brachylagus, Lepus, Pentalagus, Romerolagus and Sylvilagus. The newly sequenced leporid IGHG gene has an organization and structure similar to that of the European rabbit IgG. A gradient in leporid IgG constant domain diversity was observed, with the CH1 being the most conserved and the CH3 the most variable domain. Positive selection was found to be acting on all constant domains, but with a greater incidence in the CH3 domain, where a cluster of three positively selected sites was identified. In the hinge region, only three polymorphic positions were observed. The same hinge length was observed for all leporids. Unlike the variation observed for the European rabbit, all 11 Lepus species studied share exactly the same hinge motif, suggesting its maintenance as a result of an advantageous structure or conformation. [Mh] Termos MeSH primário: Evolução Molecular Lebres/classificação Lebres/genética Éxons Codificadores da Região de Dobradiça Imunoglobulina G/química Imunoglobulina G/genética [Mh] Termos MeSH secundário: Animais Variação Genética Lebres/imunologia Filogenia Estrutura Terciária de Proteína Coelhos Seleção Genética Análise de Sequência de DNA Especificidade da Espécie [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Immunoglobulin G) [Em] Mês de entrada: 1505 [Cu] Atualização por classe: 150804 [Lr] Data última revisão: 150804 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 140905 [St] Status: MEDLINE

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[PMID]: 22123056 [Au] Autor: Brezski RJ; Oberholtzer A; Strake B; Jordan RE [Ad] Endereço: Biologics Research; Centocor R&D Inc., Radnor, PA, USA. rbrezski@its.jnj.com [Ti] Título: The in vitro resistance of IgG2 to proteolytic attack concurs with a comparative paucity of autoantibodies against peptide analogs of the IgG2 hinge. [So] Source: MAbs;3(6):558-67, 2011 Nov-Dec. [Is] ISSN: 1942-0870 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The mammalian antibody repertoire comprises immunoglobulin (Ig) molecules of multiple isotypes and subclasses with varying functional properties. Among the four subclasses of the human IgG isotype, we found that IgG2 exhibits a particular resistance to human and bacterial proteases that readily cleave the IgG1 hinge region in vitro. Autoantibodies (IgGs) that recognize points of proteolytic cleavage in the IgG1 hinge are widespread in the healthy human population, suggesting that IgG1 fragmentation and the generation of cryptic antigens for host immune surveillance commonly occur in vivo. We previously reported that autoantibodies to cleaved IgG1s can restore Fc-mediated effector functions that are lost following proteolytic cleavage of the hinge. In contrast, it was not possible to demonstrate an analogous cohort of autoantibodies to IgG2 hinge epitope analogs, and there appeared to be no functional component in human serum with the ability to reconstitute Fc effector functions to a cell-bound IgG2 fragment. Thus, the results indicate that among the IgG subclasses, human IgG2 is uniquely resistant to a number of known pathological proteases and that autoimmune recognition to potential cleavage points in the IgG2 hinge appears to be absent in human circulation. [Mh] Termos MeSH primário: Anticorpos Monoclonais/imunologia Autoanticorpos/imunologia Éxons Codificadores da Região de Dobradiça Imunoglobulina G/imunologia Imunoglobulina G/metabolismo Peptídeo Hidrolases/metabolismo Peptídeos/imunologia [Mh] Termos MeSH secundário: Sequência de Aminoácidos Anticorpos Monoclonais/química Citotoxicidade Celular Dependente de Anticorpos Proteínas do Sistema Complemento/imunologia Proteínas do Sistema Complemento/metabolismo Seres Humanos Imunoglobulina G/química Macrófagos/imunologia Dados de Sequência Molecular Peptídeos/química Fagocitose [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antibodies, Monoclonal); 0 (Autoantibodies); 0 (Immunoglobulin G); 0 (Peptides); 9007-36-7 (Complement System Proteins); EC 3.4.- (Peptide Hydrolases) [Em] Mês de entrada: 1206 [Cu] Atualização por classe: 150129 [Lr] Data última revisão: 150129 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 111130 [St] Status: MEDLINE [do] DOI: 10.4161/mabs.3.6.18119

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[PMID]: 21623461 [Au] Autor: Brezski RJ; Knight DM; Jordan RE [Ad] Endereço: Biologics Research, Centocor R&D Inc., Radnor, PA, USA. rbrezski@its.jnj.com [Ti] Título: The origins, specificity, and potential biological relevance of human anti-IgG hinge autoantibodies. [So] Source: ScientificWorldJournal;11:1153-67, 2011 May 26. [Is] ISSN: 1537-744X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Human anti-IgG hinge (HAH) autoantibodies constitute a class of immunoglobulins that recognize cryptic epitopes in the hinge region of antibodies exposed after proteolytic cleavage, but do not bind to the intact IgG counterpart. Detailed molecular characterizations of HAH autoantibodies suggest that they are, in some cases, distinct from natural autoantibodies that arise independent of antigenic challenge. Multiple studies have attempted to define the specificity of HAH autoantibodies, which were originally detected as binding to fragments possessing C-terminal amino acid residues exposed in either the upper or lower hinge regions of IgGs. Numerous investigators have provided information on the isotype profiles of the HAH autoantibodies, as well as correlations among protease cleavage patterns and HAH autoantibody reactivity. Several biological functions have been attributed to HAH autoantibodies, ranging from house-cleaning functions to an immunosuppressive role to restoring function to cleaved IgGs. In this review, we discuss both the historic and current literature regarding HAH autoantibodies in terms of their origins, specificity, and proposed biological relevance. [Mh] Termos MeSH primário: Anticorpos Anti-Idiotípicos/fisiologia Autoanticorpos/fisiologia Modelos Imunológicos [Mh] Termos MeSH secundário: Anticorpos Anti-Idiotípicos/imunologia Autoanticorpos/imunologia Linfócitos B/imunologia Linfócitos B/fisiologia Éxons Codificadores da Região de Dobradiça/imunologia Seres Humanos Fragmentos Fab das Imunoglobulinas/imunologia Imunoglobulina G/química Imunoglobulina G/imunologia Imunoglobulina G/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Antibodies, Anti-Idiotypic); 0 (Autoantibodies); 0 (Immunoglobulin Fab Fragments); 0 (Immunoglobulin G); 0 (anti-IgG) [Em] Mês de entrada: 1201 [Cu] Atualização por classe: 110530 [Lr] Data última revisão: 110530 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 110531 [St] Status: MEDLINE [do] DOI: 10.1100/tsw.2011.107

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[PMID]: 20400859 [Au] Autor: Brezski RJ; Jordan RE [Ad] Endereço: Biologics Research, Centocor R&D Inc., Radnor, PA, USA. rbrezski@its.jnj.com [Ti] Título: Cleavage of IgGs by proteases associated with invasive diseases: an evasion tactic against host immunity? [So] Source: MAbs;2(3):212-20, 2010 May-Jun. [Is] ISSN: 1942-0870 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The effective functioning of immunoglobulins and IgG mAbs in removing pathological cells requires that the antigen binding regions and the Fc (effector) domain act in concert. The hinge region that connects these domains itself presents motifs that engage Fc receptors on immune effector cells to achieve cell lysis. In addition, sequences in the lower hinge/CH2 and further down the CH2 region are involved in C1q binding and complement-mediated cell killing. Proteolytic enzymes of little relevance to human physiology were successfully used for decades to generate fragments of IgGs for reagent and therapeutic use. It was subsequently noted that tumor-related and microbial proteases also cleaved human IgG specifically in the hinge region. We have shown previously that the "nick" of just one of the lower hinge heavy chains of IgG unexpectedly prevented many effector functions without impacting antigen binding. Of interest, related single-cleaved IgG breakdown products were detected in breast carcinoma extracts. This suggested a pathway by which tumors might avoid host immune surveillance under a cloak of proteolytically-generated, dysfunctional antibodies that block competent IgG binding. The host immune system cannot be blind to this pathway since there exists a widespread, low-titer incidence of anti-hinge (cleavage-site) antibodies in the healthy population. The prevalence of anti-hinge reactivity may reflect an ongoing immune recognition of normal IgG catabolism. Tumor growth and bacterial infections potentially generate hostile proteolytic environments that may pose harsh challenges to host immunity. Recent findings involving physiologically-relevant proteases suggest that the potential loss of key effector functions of host IgGs may result from subtle and limited proteolytic cleavage of IgGs and that such events may facilitate the incursion of invasive cells in local proteolytic settings. [Mh] Termos MeSH primário: Infecções Bacterianas/enzimologia Infecções Bacterianas/imunologia Evasão da Resposta Imune Imunoglobulina G/metabolismo Neoplasias/enzimologia Neoplasias/imunologia Peptídeo Hidrolases/metabolismo Evasão Tumoral [Mh] Termos MeSH secundário: Sequência de Aminoácidos Animais Anticorpos Monoclonais/metabolismo Autoanticorpos/imunologia Infecções Bacterianas/terapia Proteínas de Bactérias/metabolismo Éxons Codificadores da Região de Dobradiça/genética Éxons Codificadores da Região de Dobradiça/imunologia Seres Humanos Imunoglobulina G/imunologia Dados de Sequência Molecular Neoplasias/terapia [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Antibodies, Monoclonal); 0 (Autoantibodies); 0 (Bacterial Proteins); 0 (Immunoglobulin G); EC 3.4.- (Peptide Hydrolases) [Em] Mês de entrada: 1012 [Cu] Atualização por classe: 141203 [Lr] Data última revisão: 141203 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 100420 [St] Status: MEDLINE

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[PMID]: 19850673 [Au] Autor: Stubenrauch K; Wessels U; Regula JT; Kettenberger H; Schleypen J; Kohnert U [Ad] Endereço: Departments of Bioanalytics, Pharma Research Penzberg, Roche Diagnostics, Nonnenwald 2, 82377 Penzberg, Germany. kay-gunnar.stubenrauch@roche.com [Ti] Título: Impact of molecular processing in the hinge region of therapeutic IgG4 antibodies on disposition profiles in cynomolgus monkeys. [So] Source: Drug Metab Dispos;38(1):84-91, 2010 Jan. [Is] ISSN: 1521-009X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The IgG4 isotype antibody is a potential candidate for immunotherapy when reduced effector functions are desirable. However, antigen binding fragment (Fab) arm exchange leads to functional monovalency with potentially reduced therapeutic efficacy. Mutagenesis studies suggested that the CH3 domain and not the core hinge is dominantly involved in in vivo molecular processing. This work investigated whether stabilization of the core hinge of a therapeutic IgG4 antibody by mutation of Ser228 to Pro (S228P) would be sufficient to prevent in vivo Fab arm exchange. In vitro experiments evaluated the influence of different levels of oxidation-reduction conditions in buffer and serum on Fab arm exchange (swapping) of wild-type (WT) IgG4 and IgG1 and of IgG4 S228P, which included a sterically neutral second mutation (Leu235 replaced by Glu). The objective of single-dose pharmacokinetic experiments in cynomolgus monkeys was to determine whether the mutation reduced IgG4 swapping in vivo. The results indicated that S228P mutation did not completely prevent Fab arm exchange in vitro in buffer under reducing conditions relative to IgG4 WT. The immunoassay findings were confirmed by mass spectrometry measurements. Results of the in vivo studies suggested that the therapeutic IgG4 WT antibody exchanged Fab arms with endogenous cynomolgus monkey IgG4, resulting in bispecific IgG4 antibodies with monovalency for the therapeutic target. In contrast, serum from cynomolgus monkeys dosed with the IgG4 mutant was virtually free of swapped IgG4. In conclusion, the results indicated that IgG4 swapping in vivo was markedly attenuated by S228P mutation. [Mh] Termos MeSH primário: Anticorpos Monoclonais/metabolismo Anticorpos Monoclonais/farmacocinética Éxons Codificadores da Região de Dobradiça/genética Imunoglobulina G/metabolismo Imunoglobulina G/uso terapêutico Proteínas Recombinantes/farmacocinética [Mh] Termos MeSH secundário: Substituição de Aminoácidos/genética Substituição de Aminoácidos/imunologia Animais Anticorpos Biespecíficos/imunologia Anticorpos Biespecíficos/metabolismo Anticorpos Biespecíficos/farmacocinética Anticorpos Monoclonais/genética Anticorpos Monoclonais/uso terapêutico Tampões (Química) Ensaio de Imunoadsorção Enzimática Feminino Seres Humanos Fragmentos Fab das Imunoglobulinas/imunologia Fragmentos Fab das Imunoglobulinas/metabolismo Imunoglobulina G/genética Macaca fascicularis Masculino Camundongos Ligante OX40/imunologia Oxirredução Ratos Receptores de Interleucina-1/imunologia Receptores de Interleucina-13/imunologia Proteínas Recombinantes/genética Proteínas Recombinantes/imunologia Proteínas Recombinantes/metabolismo Substâncias Redutoras/metabolismo Soro/imunologia Soro/metabolismo Espectrometria de Massas por Ionização por Electrospray [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antibodies, Bispecific); 0 (Antibodies, Monoclonal); 0 (Buffers); 0 (Immunoglobulin Fab Fragments); 0 (Immunoglobulin G); 0 (OX40 Ligand); 0 (Receptors, Interleukin-1); 0 (Receptors, Interleukin-13); 0 (Recombinant Proteins); 0 (Reducing Agents) [Em] Mês de entrada: 1003 [Cu] Atualização por classe: 091216 [Lr] Data última revisão: 091216 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 091024 [St] Status: MEDLINE [do] DOI: 10.1124/dmd.109.029751

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[PMID]: 19114667 [Au] Autor: Li F; Eckhardt LA [Ad] Endereço: Hunter College and Graduate Center of the City University of New York, New York, NY 10065, USA. [Ti] Título: A role for the IgH intronic enhancer E mu in enforcing allelic exclusion. [So] Source: J Exp Med;206(1):153-67, 2009 Jan 16. [Is] ISSN: 1540-9538 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The intronic enhancer (E mu) of the immunoglobulin heavy chain (IgH) locus is critical for V region gene assembly. To determine E mu's subsequent functions, we created an Igh allele with assembled V(H) gene but with E mu removed. In mice homozygous for this E mu-deficient allele, B cell development was normal and indistinguishable from that of mice with the same V(H) knockin and E mu intact. In mice heterozygous for the E mu-deficient allele, however, allelic exclusion was severely compromised. Surprisingly, this was not a result of reduced suppression of V-DJ assembly on the second allele. Rather, the striking breakdown in allelic exclusion took place at the pre-B to immature B cell transition. These findings reveal both an important role for E mu in influencing the fate of newly arising B cells and a second checkpoint for allelic exclusion. [Mh] Termos MeSH primário: Alelos Elementos Facilitadores Genéticos/genética Genes de Cadeia Pesada de Imunoglobulina/genética Cadeias mu de Imunoglobulina/genética [Mh] Termos MeSH secundário: Animais Subpopulações de Linfócitos B/química Subpopulações de Linfócitos B/citologia Subpopulações de Linfócitos B/metabolismo Linfócitos B/citologia Linfócitos B/metabolismo Células da Medula Óssea/citologia Células da Medula Óssea/metabolismo Diferenciação Celular/genética Diferenciação Celular/imunologia Expressão Gênica/genética Rearranjo Gênico de Cadeia Pesada de Linfócito B/genética Éxons Codificadores da Região de Dobradiça/genética Proteínas de Homeodomínio/genética Imunoglobulina D/análise Cadeias Pesadas de Imunoglobulinas/genética Cadeias Pesadas de Imunoglobulinas/metabolismo Imunoglobulina M/análise Imunoglobulina M/genética Cadeias kappa de Imunoglobulina/genética Cadeias kappa de Imunoglobulina/metabolismo Cadeias lambda de Imunoglobulina/genética Cadeias lambda de Imunoglobulina/metabolismo Cadeias mu de Imunoglobulina/metabolismo Camundongos Camundongos Endogâmicos C57BL Camundongos Knockout Camundongos Transgênicos Receptores de Antígenos de Linfócitos B/análise Receptores de Antígenos de Linfócitos B/genética Baço/citologia Éxons VDJ/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (Homeodomain Proteins); 0 (Immunoglobulin D); 0 (Immunoglobulin Heavy Chains); 0 (Immunoglobulin M); 0 (Immunoglobulin kappa-Chains); 0 (Immunoglobulin lambda-Chains); 0 (Immunoglobulin mu-Chains); 0 (Receptors, Antigen, B-Cell); 128559-51-3 (RAG-1 protein) [Em] Mês de entrada: 0902 [Cu] Atualização por classe: 161122 [Lr] Data última revisão: 161122 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 081231 [St] Status: MEDLINE [do] DOI: 10.1084/jem.20081202

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[PMID]: 17567731 [Au] Autor: Xia J; Kemper B [Ad] Endereço: Department of Cell and Development Biology, University of Illinois at Urbana-Champaign, 524 Burrill Hall, 407 S. Goodwin Ave., Urbana, IL 61801, USA. [Ti] Título: Subcellular trafficking signals of constitutive androstane receptor: evidence for a nuclear export signal in the DNA-binding domain. [So] Source: Drug Metab Dispos;35(9):1489-94, 2007 Sep. [Is] ISSN: 0090-9556 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Translocation of constitutive androstane receptor (CAR) from the cytoplasm to the nucleus is induced by phenobarbital-like drugs. Nuclear localization signals (NLSs) and a sequence [xenochemical response signal (XRS)] required for xenobiotic-induced nuclear translocation have been defined in rat and human CAR, but a nuclear export signal (NES) has not been identified. To identify cellular localization signals of CAR, the localization of fragments and mutants of mouse CAR expressed in mouse hepatocytes in vivo was examined. Consistent with other studies, an NLS in the hinge region, a diffuse NLS in the ligand-binding domain, and a cytoplasmic retention sequence were identified, and mutation of the XRS blocked nuclear accumulation both in phenobarbital-treated mice in vivo and in untreated HepG2 cells. Fusing the simian virus 40 NLS to the mutant proteins reversed the localization defect resulting from mutation of the hinge NLS but not that from mutation of the XRS, indicating that the XRS is not simply a novel phenobarbital-responsive NLS. In the DNA-binding domain, a sequence in CAR is conserved with an NES identified in other nuclear receptors. Mutation of two conserved phenylalanines in this sequence resulted in increased nuclear localization of both full-length CAR and a CAR fragment containing the DNA-binding domain. The DNA-binding domain sequence, therefore, may contain an NES, which is consistent with nucleocytoplasmic shuttling of CAR. The results demonstrate that regulation of the cellular localization of CAR is complex, with multiple sequences mediating nuclear import and export and retention in the cytoplasm. [Mh] Termos MeSH primário: Transporte Ativo do Núcleo Celular/fisiologia DNA/metabolismo Receptores Citoplasmáticos e Nucleares/fisiologia Transdução de Sinais/fisiologia Frações Subcelulares/metabolismo Fatores de Transcrição/fisiologia [Mh] Termos MeSH secundário: Animais Proteínas de Transporte/metabolismo Linhagem Celular Linhagem Celular Tumoral Proteínas de Fluorescência Verde/metabolismo Hepatócitos/efeitos dos fármacos Hepatócitos/metabolismo Éxons Codificadores da Região de Dobradiça/genética Seres Humanos Ligantes Camundongos Mutação/genética Proteínas Nucleares/metabolismo Plasmídeos/genética Ratos [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (Carrier Proteins); 0 (Ligands); 0 (Mybbp1a protein, mouse); 0 (Nuclear Proteins); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Transcription Factors); 0 (constitutive androstane receptor); 147336-22-9 (Green Fluorescent Proteins); 9007-49-2 (DNA) [Em] Mês de entrada: 0712 [Cu] Atualização por classe: 070822 [Lr] Data última revisão: 070822 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 070615 [St] Status: MEDLINE

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