Asunto(s)
Diversidad de Anticuerpos/genética , ADN/historia , Reordenamiento Génico de Cadena Pesada de Linfocito B , Cadenas Pesadas de Inmunoglobulina/historia , Cadenas J de Inmunoglobulina/historia , Región Variable de Inmunoglobulina/historia , Secuencia de Aminoácidos , Animales , Secuencia de Bases , ADN/genética , Historia del Siglo XX , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas J de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Datos de Secuencia MolecularRESUMEN
Plasma cells are cellular factories devoted entirely to the manufacture and export of a single product: soluble immunoglobulin (Ig). As the final mediators of a humoral response, plasma cells play a critical role in adaptive immunity. Although intense effort has been devoted to studying the regulation and requirements for early B cell development, little information has been available on plasma cells. However, more recent work-including studies on genetically altered mice and data from microarray analyses-has begun to identify the regulatory cascades that initiate and maintain the plasma cell phenotype. This review will summarize our current understanding of the molecules that regulate commitment to a plasma cell fate and those that mediate plasma cell function.
Asunto(s)
Linfocitos B/inmunología , Células Plasmáticas/inmunología , Animales , Antígenos de Diferenciación de Linfocitos B/metabolismo , Diferenciación Celular , Linaje de la Célula , Inmunoglobulinas/biosíntesis , Memoria Inmunológica , Ratones , Modelos Inmunológicos , Receptores de Quimiocina/metabolismo , Bazo/inmunología , Factores de Transcripción/fisiologíaRESUMEN
Representational difference analysis (RDA) cloning has identified transcriptional intermediary factor 1 beta (TIF1beta) as a gene inducibly expressed early during myeloid differentiation of the promyelocytic cell lines HL-60 and U937. To assess the role of TIF1beta, U937 cell lines were made that expressed antisense-hammerhead ribozymes targeted specifically against TIF1beta mRNA. These cells failed to differentiate into macrophages, as determined by several criteria: a nonadherent morphology, a failure to arrest cell cycle, lowered levels of macrophage-specific cell surface markers, resistance to Legionella pneumophila infection, a loss of the ability to phagocytose and chemotax, and decreased expression of chemokine mRNAs. One way TIF1beta acts in macrophage differentiation is to augment C/EBPbeta transcriptional activity. Furthermore, we show by EMSA supershifts and coimmunoprecipitation that C/EBPbeta and TIF1beta physically interact. Although TIF1beta is necessary for macrophage differentiation of U937 cells, it is not sufficient, based on the inability of ectopically expressed TIF1beta to induce or augment phorbol ester-induced macrophage differentiation. We conclude that TIF1beta plays an important role in the terminal differentiation program of macrophages, which involves the coactivation of C/EBPbeta and induction of C/EBPbeta-responsive myeloid genes.
Asunto(s)
Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/fisiología , Proteínas Represoras/metabolismo , Proteínas Represoras/fisiología , Sitios de Unión , Northern Blotting , Western Blotting , Ciclo Celular/efectos de los fármacos , Diferenciación Celular , Línea Celular , Núcleo Celular/metabolismo , Separación Celular , Quimiocina CCL5/metabolismo , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Células HL-60 , Humanos , Legionella pneumophila/metabolismo , Macrófagos/citología , Macrófagos/metabolismo , Fagocitosis , Plásmidos/metabolismo , Pruebas de Precipitina , Unión Proteica , ARN Catalítico/metabolismo , ARN Mensajero/metabolismo , Retroviridae/genética , Ribonucleasas/metabolismo , Transcripción Genética , Transducción Genética , Transfección , Proteína 28 que Contiene Motivos Tripartito , Células U937Asunto(s)
Linfocitos B/citología , Proteínas de Unión al ADN/fisiología , Células Plasmáticas/citología , Factores de Transcripción/fisiología , Animales , Formación de Anticuerpos , Linfocitos B/inmunología , Diferenciación Celular , Quimera , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Factores Reguladores del Interferón , Ratones , Factor de Transcripción PAX5 , Células Plasmáticas/inmunología , Factores de Transcripción del Factor Regulador X , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
The importance of c-myc as a target of the Blimp-1 repressor has been studied in BCL-1 cells, in which Blimp-1 is sufficient to trigger terminal B-cell differentiation. Our data show that Blimp-1-dependent repression of c-myc is required for BCL-1 differentiation, since constitutive expression of c-Myc blocked differentiation. Furthermore, ectopic expression of cyclin E mimicked the effects of c-Myc on both proliferation and differentiation, indicating that the ability of c-Myc to drive proliferation is responsible for blocking BCL-1 differentiation. However, inhibition of c-Myc by a dominant negative form was not sufficient to drive BCL-1 differentiation. Thus, during Blimp-1-dependent plasma cell differentiation, repression of c-myc is necessary but not sufficient, demonstrating the existence of additional Blimp-1 target genes.
Asunto(s)
Linfocitos B/citología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Diferenciación Celular , Ciclina E/metabolismo , Citocinas/farmacología , Regulación de la Expresión Génica , Antígenos de Histocompatibilidad Clase II/metabolismo , Inmunoglobulina M/metabolismo , Glicoproteínas de Membrana/metabolismo , Modelos Biológicos , Mutación , Células Plasmáticas/citología , Proteoglicanos/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , ARN Mensajero/biosíntesis , Sindecanos , Factores de Transcripción/genéticaRESUMEN
B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor that is sufficient to trigger terminal differentiation in the B cell lymphoma BCL-1. In this study, we have determined the expression pattern of Blimp-1 in vivo in primary and secondary lymphoid organs of humans and immunized mice. Blimp-1 is expressed in plasma cells derived from either a T-independent or T-dependent response in plasma cells that have undergone isotype switching and those resulting from secondary immunization. Blimp-1 is also present in long-lived plasma cells residing in the bone marrow. However, Blimp-1 was not detected in memory B cells. This expression pattern provides further evidence of a critical role for Blimp-1 in plasma cell development, supporting earlier studies in cultured lines. Significantly, Blimp-1 was also found in a fraction (4-15%) of germinal center B cells in murine spleen and human tonsils. Blimp-1 expression in the germinal center is associated with an interesting subset of cells with a phenotype intermediate between germinal center B cells and plasma cells. In the mouse, Blimp-1(+) germinal center B cells peak at day 12 postimmunization and disappear soon thereafter. They are not apoptotic, some are proliferating, they express germinal center markers peanut agglutinin or CD10 but not Bcl-6, and most express CD138 (syndecan-1), IRF4, and cytoplasmic Ig. Together, these data support a model in which B cell fate decisions occur within the germinal center and Blimp-1 expression is critical for commitment to a plasma cell, rather than a memory cell, fate.
Asunto(s)
Subgrupos de Linfocitos B/citología , Subgrupos de Linfocitos B/metabolismo , Ficoll/análogos & derivados , Células Plasmáticas/citología , Células Plasmáticas/metabolismo , Proteínas Represoras , Factores de Transcripción/biosíntesis , Animales , Antígenos T-Independientes/inmunología , Subgrupos de Linfocitos B/inmunología , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Diferenciación Celular/inmunología , Linaje de la Célula/inmunología , Ficoll/administración & dosificación , Ficoll/inmunología , Centro Germinal/citología , Haptenos/administración & dosificación , Haptenos/inmunología , Hemocianinas/administración & dosificación , Hemocianinas/inmunología , Humanos , Inmunización Secundaria , Memoria Inmunológica , Inmunofenotipificación , Inyecciones Intraperitoneales , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Nitrofenoles/administración & dosificación , Nitrofenoles/inmunología , Fenilacetatos , Células Plasmáticas/inmunología , Factor 1 de Unión al Dominio 1 de Regulación PositivaRESUMEN
Transformation of 3T3 fibroblasts by the v-Abl tyrosine kinase replaces mitogenic and adhesion signals normally required for cell cycle progression. A 3T3 cell line conditionally transformed with v-Abl has been used to study v-Abl's effects on cell cycle in the context of either serum depletion or absence of adhesion signals. We show that E2F-dependent mRNAs, encoding proteins required for cell cycle progression, are induced by v-Abl. In addition, we identify two previously unknown targets of v-Abl signaling: (1) cyclin D1 and D2 mRNAs are induced upon v-Abl activation; and (2) the CDK inhibitor p27 is decreased upon v-Abl activation.
Asunto(s)
Proteínas Portadoras , Proteínas de Ciclo Celular , Proteínas de Unión al ADN , Fibroblastos/citología , Regulación Neoplásica de la Expresión Génica , Proteínas Asociadas a Microtúbulos/fisiología , Proteínas Oncogénicas v-abl/fisiología , Transducción de Señal , Factores de Transcripción/fisiología , Proteínas Supresoras de Tumor , Células 3T3/citología , Animales , Transformación Celular Neoplásica , Medio de Cultivo Libre de Suero , Ciclina A/biosíntesis , Ciclina A/genética , Ciclina D1/biosíntesis , Ciclina D1/metabolismo , Ciclina D2 , Ciclina D3 , Ciclina E/biosíntesis , Ciclina E/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Ciclinas/biosíntesis , Ciclinas/metabolismo , Factores de Transcripción E2F , Fase G1 , Genes abl , Ratones , ARN Mensajero/biosíntesis , Proteínas Recombinantes de Fusión/fisiología , Proteína 1 de Unión a Retinoblastoma , Ribonucleótido Reductasas/biosíntesis , Ribonucleótido Reductasas/genética , Fase S , Tetrahidrofolato Deshidrogenasa/biosíntesis , Tetrahidrofolato Deshidrogenasa/genética , Factor de Transcripción DP1RESUMEN
B-lymphocyte-induced maturation protein (Blimp-1) is a transcriptional repressor that is considered to be a master regulator of terminal B-cell development because it is sufficient to trigger differentiation in the BCL(1)-cell model. Transcription of the c-myc gene is repressed by Blimp-1 during B-cell differentiation. In this study, we have explored the mechanism by which Blimp-1 represses transcription by using Gal4-fusion protein assays and assays in which Blimp-1 represses the natural c-myc promoter. The results show that Blimp-1 represses the c-myc promoter by an active mechanism that is independent of the adjacently bound activator YY1. Blimp-1 contains two regions that independently associate with histone deacetylase (HDAC) and endogenous Blimp-1 in nuclear extracts binds in vitro to the c-myc Blimp-1 site in a complex containing HDAC. The functional importance of recruiting HDAC for Blimp-1-dependent repression of c-myc transcription is supported by two experiments. First, the HDAC inhibitor tricostatin A inhibits Blimp-1-dependent repression in cotransfection assays. Second, a chromatin immunoprecipitation assay shows that expression of Blimp-1 causes deacetylation of histone H3 associated with the c-myc promoter, and this deacetylation depends on the Blimp-1 binding site in the c-myc promoter.
Asunto(s)
Histona Desacetilasas/metabolismo , Proteínas Represoras/metabolismo , Proteínas de Saccharomyces cerevisiae , Factores de Transcripción/metabolismo , Acetilación , Línea Celular , Cromatina/metabolismo , Proteínas de Unión al ADN/genética , Inhibidores Enzimáticos/farmacología , Factores de Unión al ADN Específico de las Células Eritroides , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulación de la Expresión Génica , Genes Reporteros , Histonas/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Pruebas de Precipitina , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Recombinantes de Fusión/metabolismo , Factores de Transcripción/genética , Transfección , Factor de Transcripción YY1RESUMEN
Blimp-1 is a transcriptional repressor that is both required and sufficient to trigger terminal differentiation of B lymphocytes and monocyte/macrophages. Here we report the organization of the mouse Blimp-1 gene, an analysis of Blimp-1 homologs in different species, the characterization of Blimp-1 mRNA isoforms and initial studies on the transcription of Blimp-1. The murine Blimp-1 gene covers approximately 23 kb and contains eight exons. There are Blimp-1 homologs in species evolutionarily distant from mouse (Caenorhabditis elegans and Drosophila melanogaster) but no homolog was found in the unicellular yeast Saccharomyces cerevisiae. The three major Blimp-1 mRNA isoforms result from the use of different polyadenylation sites and do not encode different proteins. Run-on transcription analyses were used to show that the developmentally regulated expression of Blimp-1 mRNA in B cells is determined by transcription initiation. Multiple Blimp-1 transcription initiates sites were mapped near an initiator element and a region conferring basal promoter activity has been identified.
Asunto(s)
Empalme Alternativo/genética , Regiones Promotoras Genéticas/genética , Proteínas Represoras , Factores de Transcripción/genética , Secuencia de Aminoácidos , Animales , Linfocitos B/citología , Linfocitos B/metabolismo , Secuencia de Bases , Diferenciación Celular , Línea Celular , Clonación Molecular , ARN Polimerasas Dirigidas por ADN/metabolismo , Evolución Molecular , Exones/genética , Regulación del Desarrollo de la Expresión Génica , Genes Reporteros/genética , Humanos , Ratones , Datos de Secuencia Molecular , Ensayos de Protección de Nucleasas , Poli A/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Isoformas de Proteínas/genética , ARN Mensajero/análisis , ARN Mensajero/genética , TATA Box/genética , Factores de Transcripción/química , Transcripción Genética/genética , TransfecciónRESUMEN
Class II transactivator (CIITA), a coactivator required for class II major histocompatibility complex (MHC) transcription, is expressed in B cells but extinguished in plasma cells. This report identifies B lymphocyte-induced maturation protein I (BLIMP-I), a transcriptional repressor that is capable of triggering plasma cell differentiation, as a developmentally regulated repressor of CIITA transcription. BLIMP-I represses the B cell-specific promoter of the human gene that encodes CIITA (MHC2TA) in a binding site-dependent manner. Decreased CIITA correlates with increased BLIMP-I during plasma cell differentiation in cultured cells. Ectopic expression of BLIMP-I represses endogenous mRNA for CIITA and the CIITA targets, class II MHC, invariant chain and H2-DM (the murine equivalent of HLA-DM) in primary splenic B cells as well as 18-81 pre-B cells. Thus, the BLIMP-I program of B cell differentiation includes loss of antigen presentation via extinction of CIITA expression.
Asunto(s)
Proteínas Nucleares , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Proteínas Represoras , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Animales , Presentación de Antígeno , Linfocitos B/citología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Secuencia de Bases , Diferenciación Celular , Línea Celular , ADN/genética , Cartilla de ADN/genética , Antígenos HLA-DR/genética , Cadenas alfa de HLA-DR , Humanos , Células Híbridas , Ratones , Modelos Biológicos , Datos de Secuencia Molecular , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transactivadores/genética , Factores de Transcripción/genéticaRESUMEN
B lymphocyte-induced maturation protein-1 (BLIMP-1 or PRDI-BF1) is induced when bone marrow-derived progenitors differentiate in response to macrophage-colony stimulating factor (M-CSF) and is present in peripheral blood monocytes and granulocytes. BLIMP-1 is also induced during differentiation of U937 and HL-60 cells into macrophages or granulocytes. Induction of BLIMP-1 mRNA during macrophage differentiation of U937 and HL-60 shows a biphasic pattern. Overexpression of BLIMP-1 is sufficient to initiate macrophage differentiation of U937 cells whereas blocking endogenous BLIMP-1 inhibits differentiation. One target of BLIMP-1-dependent transcriptional repression in U937 cells is c-myc, providing an explanation for cessation of cell division. Thus BLIMP-1 is a key regulator of terminal differentiation in two separate hematopoietic lineages: myeloid cells and B lymphocytes.
Asunto(s)
Diferenciación Celular , Proteínas Represoras , Factores de Transcripción/metabolismo , Dedos de Zinc , Linaje de la Célula , Expresión Génica , Células HL-60 , Humanos , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas Proto-Oncogénicas c-myc/genética , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Células U937RESUMEN
Abelson murine leukemia virus (A-MuLV) is an acute transforming retrovirus that preferentially transforms early B-lineage cells both in vivo and in vitro. Its transforming protein, v-Abl, is a tyrosine kinase related to v-Src but containing an extended C-terminal domain. Many mutations affecting the C-terminal portion of the molecule block the pre-B-transforming activity of v-Abl without affecting the fibroblast-transforming ability. In this study we have determined the abilities of both wild-type and C-terminally truncated (p90) forms of v-Abl to transform cells from p53(-/-) mice. Lack of p53 increases the susceptibility of bone marrow cells to transformation by v-Abl by a factor of more than 7 but does not alter v-Abl's preference for B220(+) IgM(-) pre-B cells. p53-deficient mice have earlier tumor onset, more rapid tumor progression, and decreased survival time following A-MuLV infection, but all of the tumors are pre-B lymphomas. Thus, p53-dependent pathways inhibit v-Abl transformation but play no role in conferring preferential transformation of pre-B cells. Surprisingly, the C-terminally truncated form of v-Abl (p90) transforms pre-B cells very efficiently in mice lacking p53, thus demonstrating that the C terminus of v-Abl does not determine preB tropism but is necessary to overcome p53-dependent inhibition of transformation.
Asunto(s)
Linfocitos B/patología , Transformación Celular Neoplásica/patología , Eliminación de Gen , Linfoma/patología , Proteínas Oncogénicas v-abl/metabolismo , Proteína p53 Supresora de Tumor/fisiología , Animales , Linfocitos B/metabolismo , Linfocitos B/virología , Linaje de la Célula , Transformación Celular Neoplásica/genética , Transformación Celular Viral , Células Cultivadas , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Células Madre Hematopoyéticas/virología , Virus de la Leucemia Murina/enzimología , Virus de la Leucemia Murina/genética , Virus de la Leucemia Murina/patogenicidad , Linfoma/genética , Linfoma/mortalidad , Linfoma/virología , Masculino , Ratones , Ratones Noqueados , Proteínas Oncogénicas v-abl/química , Proteínas Oncogénicas v-abl/genética , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Ensayo de Tumor de Célula Madre , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Tumorigenesis is a multistep process that involves the activation of oncogenes and the inactivation of tumor suppressor genes. The transforming activity of the v-Abl oncogene of Abelson murine leukemia virus (A-MuLV) in immortal cell lines has been well studied, while the effects of v-Abl in primary fibroblasts are less clear. Here we show that v-Abl causes cell cycle arrest in primary mouse embryonic fibroblasts (MEFs) and elevated levels of both p53 and the cyclin-dependent kinase inhibitor p21Cip. p53-/- or p19ARF-/- MEFs were resistant to v-Abl-induced cell cycle arrest. Although wild-type MEFs were resistant to v-Abl transforming activity, p53-/- or p19ARF-/- MEFs were susceptible. The results indicate that loss of p19ARF and p53 function plays an important role during the transformation of primary cells by v-Abl. We suggest that although v-Abl is a potent oncogene, its full potential transforming activity cannot be realized until the ARF-, and p53-dependent growth inhibitory pathway is disabled. We also show that p53 is not the mediator of v-Abl toxicity in immortal fibroblasts and does not determine the susceptibility of immortal fibroblasts to v-Abl transformation.
Asunto(s)
Transformación Celular Neoplásica , Genes abl , Genes p53 , Proteínas Oncogénicas v-abl/metabolismo , Proteínas/genética , Proteínas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Virus de la Leucemia Murina de Abelson/genética , Animales , Células Cultivadas , Embrión de Mamíferos , Fibroblastos/citología , Fibroblastos/patología , Regulación Neoplásica de la Expresión Génica , Ratones , Ratones Noqueados , Transcripción Genética , Proteína p14ARF Supresora de Tumor , Proteína p53 Supresora de Tumor/deficienciaAsunto(s)
Linfocitos B/citología , Linfocitos B/metabolismo , Proteínas Represoras , Factores de Transcripción/metabolismo , Animales , Diferenciación Celular , Genes myc , Histona Desacetilasas/metabolismo , Humanos , Macrófagos/citología , Macrófagos/metabolismo , Ratones , Células Plasmáticas/citología , Células Plasmáticas/metabolismo , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Regiones Promotoras Genéticas , Factores de Transcripción/química , Factores de Transcripción/genéticaRESUMEN
The importance of V(D)J recombination for generating diversity in the immune system is well established, but the mechanisms which regulate V(D)J recombination are still poorly understood. Although transcription of unrearranged (germ line) immunoglobulin and T-cell receptor gene segments often precedes V(D)J recombination and has been implicated in its control, the actual role of germ line transcripts in V(D)J recombination is not known. We used a sensitive reverse transcription-PCR assay to study immunoglobulin VH germ line transcripts in proB lines from RAG-deficient mice. All 10 VH families analyzed were germ line transcribed, and germ line transcription was found in all of the cell lines examined, indicating that active chromatin was present in the VH region. However, not all VH families were germ line transcribed in every cell line, and there was a surprising lack of uniformity in the number and family distribution of germ line VH transcripts in individual lines. When V(D)J recombination was activated by restoration of RAG activity, recombinational activity of endogenous VH genes for which germ line transcription was observed could be compared with those of genes for which it was not observed. This analysis revealed multiple examples of endogenous VH gene segments which were rearranged in cells where their germ line transcription was not detectable prior to RAG expression. Thus, our data provide strong support for the idea that V-(D)J recombination does not require germ line transcription of the recombining variable gene segment.
Asunto(s)
Genes de Inmunoglobulinas/genética , Células Germinativas/fisiología , Región Variable de Inmunoglobulina/genética , Recombinación Genética/genética , Animales , Linfocitos B/metabolismo , Secuencia de Bases , Línea Celular , Proteínas de Unión al ADN/genética , Regulación del Desarrollo de la Expresión Génica/genética , Genes RAG-1/genética , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , ADN Polimerasa Dirigida por ARN/metabolismo , Análisis de Secuencia de ADN , Transcripción Genética/genética , Transfección/genéticaRESUMEN
NF-IL6 is an important transcriptional regulator of genes induced in activated monocytes/macrophages, and NF-IL6 is the only CCAAT/enhancer-binding protein (C/EBP) family member whose steady-state mRNA levels increase upon activation of monocytes (1). We show that increased transcription of the NF-IL6 gene is responsible, at least in part, for induction of NF-IL6 mRNA following activation of U937 promonocytic cells. We have identified a 104-bp minimal promoter region of the NF-IL6 gene that is sufficient for basal and activation-dependent induction of transcription in U937 cells. This region contains binding sites for the cAMP response element-binding protein/activation transcription factor (CREB/ATF) and Sp1 families of transcription factors. Each site is functionally important and contributes independently to transcription of the NF-IL6 gene in U937 cells.
Asunto(s)
Proteínas Sanguíneas/fisiología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/fisiología , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica/inmunología , Monocitos/metabolismo , Proteínas Nucleares/genética , Regiones Promotoras Genéticas/inmunología , Factor de Transcripción Sp1/fisiología , Factores de Transcripción/fisiología , Transcripción Genética/inmunología , Factores de Transcripción Activadores , Secuencia de Bases , Sitios de Unión/genética , Sitios de Unión/inmunología , Proteínas Sanguíneas/metabolismo , Proteínas Potenciadoras de Unión a CCAAT , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Humanos , Lipopolisacáridos/farmacología , Activación de Macrófagos/efectos de los fármacos , Activación de Macrófagos/genética , Datos de Secuencia Molecular , Monocitos/inmunología , Factor de Transcripción Sp1/metabolismo , Células Madre/inmunología , Células Madre/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
Information is increasingly available concerning the molecular events that occur during primary and antigen-dependent stages of B cell development. In this review the roles of transcription factors and coactivators are discussed with respect to changes in expression patterns of various genes during B cell development. Transcriptional regulation is also discussed in the context of developmentally regulated immunoglobulin gene V(D)J recombination, somatic hypermutation, and isotype switch recombination.
Asunto(s)
Linfocitos B/fisiología , Transcripción Genética/fisiología , Animales , HumanosRESUMEN
The importance of CCAAT/enhancer binding proteins (C/EBPs) and binding sites for HIV-1 replication in primary macrophages, T cell lines and primary CD4(+) T cells was examined. When lines overexpressing the C/EBP dominant-negative protein LIP were infected with HIV-1, replication occurred in Jurkat T cells but not in U937 promonocytes, demonstrating a requirement for C/EBP activators by HIV-1 only in promonocytes. Primary macrophages did not support the replication of HIV-1 harboring mutant C/EBP binding sites in the long terminal repeat but Jurkat, H9 and primary CD4(+) T cells supported replication of wild-type and mutant HIV-1 equally well. Thus the requirement for C/EBP sites is also confined to monocyte/macrophages. The requirement for C/EBP proteins and sites identifies the first uniquely macrophage-specific regulatory mechanism for HIV-1 replication.
Asunto(s)
Linfocitos T CD4-Positivos/virología , Proteínas de Unión al ADN/fisiología , VIH-1/fisiología , Macrófagos/virología , Proteínas Nucleares/fisiología , Replicación Viral , Sitios de Unión/inmunología , Proteínas Potenciadoras de Unión a CCAAT , Antígenos CD4 , Linfocitos T CD4-Positivos/inmunología , Humanos , Células Jurkat , Macrófagos/inmunología , Especificidad de ÓrganosRESUMEN
TFE3 is a ubiquitously expressed member of the TFE3/mi family of basic helix loop helix zipper transcription factors. TFE3 binds to muE3 sites located in the immunoglobulin heavy-chain (IgH) intronic enhancer, heavy-chain variable region promoters, the Ig kappa intronic enhancer, and regulatory sites in other genes. To understand the role of TFE3 in Ig expression and lymphoid development, we used embryonic stem (ES) cell-mediated gene targeting and RAG2-/- blastocyst complementation to generate mice which lack TFE3 in their B and T lymphocytes. TFE3- ES cells fully reconstitute the B- and T-cell compartments, giving rise to normal patterns of IgM+ B220+ B cells and CD4+ and CD8+ T cells. However, TFE3- B cells show several defects consistent with poor B-cell activation. Serum IgM levels are reduced twofold and IgG and IgA isotypes are reduced three- to sixfold in the TFE3- chimeras even though in vitro, the TFE3- splenocytes secrete normal levels of all isotypes in response to lipopolysaccharide activation. Peripheral TFE3- B cells also show reduced surface expression of CD23 and CD24 (heat-stable antigen).