Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Más filtros

Banco de datos
Tipo de estudio
Tipo del documento
País de afiliación
Intervalo de año de publicación
1.
Mol Cell Biol ; 27(15): 5275-85, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17526724

RESUMEN

The BAZF (BCL-6b) protein is highly similar to the BCL-6 transcriptional repressor. While BCL-6 has been characterized extensively, relatively little is known about the normal function of BAZF. In order to understand the physiological role of BAZF, we created BAZF-deficient mice. Unlike BCL-6-deficient mice, BAZF-deficient mice are healthy and normal in size. However, BAZF-deficient mice have a hematopoietic progenitor phenotype that is almost identical to that of BCL-6-deficient mice. Compared to wild-type mice, both BAZF-deficient and BCL-6-deficient mice have greatly reduced numbers of cycling hematopoietic progenitor cells (HPC) in the BM and greatly increased numbers of cycling HPC in the spleen. In contrast to HPC from wild-type mice, HPC from BAZF-deficient and BCL-6-deficient mice are resistant to chemokine-induced myelosuppression and do not show a synergistic growth response to granulocyte-macrophage colony-stimulating factor plus stem cell factor. Depletion of CD8 T cells in BAZF-deficient mice reverses several of the hematopoietic defects in these mice. Since both BAZF- and BCL-6-deficient mice have defects in CD8 T-cell differentiation, we hypothesize that both BCL-6 and BAZF regulate HPC homeostasis by an indirect pathway involving CD8 T cells.


Asunto(s)
Linfocitos T CD8-positivos/fisiología , Hematopoyesis , Proteínas Represoras/metabolismo , Animales , Recuento de Células Sanguíneas , Linfocitos T CD8-positivos/efectos de los fármacos , Quimiocinas/farmacología , Proteínas de Unión al ADN/deficiencia , Hematopoyesis/efectos de los fármacos , Hematopoyesis Extramedular/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Heterocigoto , Ratones , Ratones Endogámicos C57BL , Mutación/genética , Células Mieloides/efectos de los fármacos , Fenotipo , Proteínas Proto-Oncogénicas c-bcl-6 , Factor de Células Madre/metabolismo
2.
Crit Rev Oncol Hematol ; 41(1): 1-9, 2002 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-11796228

RESUMEN

The proto-oncogene BCL-6 encodes a transcriptional repressor protein that is expressed at high levels in germinal center B cells and lymphomas with a germinal center B cell phenotype. The BCL-6 gene is a frequent target of chromosomal translocations, micro-deletions, and point mutations in non-Hodgkin's lymphoma. Studies of BCL-6-deficient mice have revealed that BCL-6 is critical for normal lymphocyte differentiation and also that BCL-6 is a negative regulator of inflammation. Recent studies have shed light on how BCL-6 controls these processes by showing that BCL-6 regulates a broad spectrum of target genes. BCL-6 represses transcription of genes involved in lymphocyte activation, differentiation, proliferation, and migration. Although much progress has been made in understanding gene regulation by BCL-6, many important questions are unresolved.


Asunto(s)
Proteínas de Unión al ADN/fisiología , Regulación de la Expresión Génica/fisiología , Proteínas Proto-Oncogénicas/fisiología , Factores de Transcripción/fisiología , Animales , Humanos , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-bcl-6
3.
J Immunol ; 174(4): 2098-105, 2005 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-15699140

RESUMEN

IL-10 is a key regulatory cytokine produced by T lymphocytes. Although Th2 cells are a major source of IL-10, little is known about IL-10 gene regulation in Th2 cells. High levels of IL-10 mRNA transcription are induced in the Th2 clone D10 after PMA plus ionomycin (P/I) stimulation; however we found that the IL-10 promoter was not inducible by P/I in D10 cells. We therefore sought regulatory regions in the IL-10 gene that could promote P/I-activated transcription in Th2 cells. Two strong DNase I-hypersensitive sites (DHSSs) were identified in the IL-10 gene in mouse T cells, and conserved noncoding sequences (CNSs) between the mouse and human IL-10 genes were also identified. One IL-10 DHSS maps within or next to a highly conserved CNS region, CNS-3. The CNS-3 region contains an AP-1 site that binds JunB and c-Jun proteins specifically in Th2 cells and not in Th1 cells. The CNS-3 element activates transcription from the IL-10 promoter after P/I stimulation and is responsive to c-Jun and JunB. Retroviral mediated-expression of either c-Jun or JunB in primary T cells led to a large increase in IL-10 expression, and inhibition of AP-1 activity by a dominant negative form of c-Jun in primary T cells strongly repressed IL-10 expression. IFN-gamma was relatively unaffected by modulations in AP-1 activity. These data indicate that we have identified a novel regulatory element that can specifically activate transcription of the IL-10 gene in Th2 cells via the AP-1/Jun pathway.


Asunto(s)
Regulación de la Expresión Génica/inmunología , Interleucina-10/biosíntesis , Interleucina-10/genética , Proteínas Proto-Oncogénicas c-jun/fisiología , Células Th2/inmunología , Células Th2/metabolismo , Animales , Secuencia de Bases , Línea Celular , Línea Celular Tumoral , Células Cultivadas , Cromatina/genética , Cromatina/metabolismo , Células Clonales , Secuencia Conservada , Desoxirribonucleasa I/genética , Humanos , Interleucina-10/metabolismo , Ratones , Datos de Secuencia Molecular , Células 3T3 NIH , Unión Proteica , Proteínas Proto-Oncogénicas c-jun/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos , Factor de Transcripción AP-1/metabolismo , Factor de Transcripción AP-1/fisiología
4.
J Immunol ; 170(5): 2435-41, 2003 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-12594267

RESUMEN

The B cell lymphoma (BCL)-6 transcriptional repressor protein is an important regulator of Th2 responses. Mice deficient in BCL-6 develop severe Th2-type inflammation that can develop even in the absence of IL-4 signaling. We have investigated the mechanism for how BCL-6 regulates Th2 cell differentiation and have found that IL-6 signaling can promote dramatically increased levels of Th2 differentiation in BCL-6(-/-) CD4 T cells compared with wild-type CD4 T cells. IL-6 can induce a low level of Th2 cytokine expression in BCL-6(-/-)STAT6(-/-) cells but not in STAT6(-/-) cells. Since the promoters for Th2 cytokines such as IL-4, IL-5, IL-10, and IL-13 do not contain consensus BCL-6 DNA binding sites, we investigated whether BCL-6 might regulate the GATA-3 transcription factor that activates the expression of multiple Th2 cytokines. Consistent with the idea that BCL-6 represses GATA-3 expression, we found that GATA-3 levels are up-regulated in BCL-6(-/-)STAT6(-/-) CD4 T cells compared with STAT6(-/-) CD4 T cells. Retrovirus-mediated expression of BCL-6 in BCL-6(-/-)STAT6(-/-) T cells as well as developing wild-type Th2 cells leads to a potent repression of IL-4 and IL-10 secretion. Retrovirus-mediated expression of BCL-6 in both BCL-6(-/-)STAT6(-/-) and wild-type T cells also leads to a significant decrease in GATA-3 protein levels. Surprisingly, BCL-6 does not appear to regulate GATA-3 mRNA levels and thus BCL-6 appears to regulate GATA-3 expression at a posttranscriptional level. Regulation of GATA-3 protein levels is likely a key mechanism for how BCL-6 regulates Th2 cytokine expression and Th2 differentiation independently of STAT6. These data also point to a novel regulatory mechanism for BCL-6 separate from transcriptional repression.


Asunto(s)
Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/fisiología , Inhibidores de Crecimiento/fisiología , Proteínas Proto-Oncogénicas/fisiología , Células Th2/citología , Células Th2/metabolismo , Transactivadores/antagonistas & inhibidores , Transactivadores/biosíntesis , Factores de Transcripción/fisiología , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Citocinas/antagonistas & inhibidores , Citocinas/biosíntesis , Citocinas/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Factor de Transcripción GATA3 , Inhibidores de Crecimiento/deficiencia , Inhibidores de Crecimiento/genética , Interleucina-6/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcl-6 , Procesamiento Postranscripcional del ARN/inmunología , Factor de Transcripción STAT6 , Transducción de Señal/genética , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células Th2/inmunología , Transactivadores/deficiencia , Transactivadores/genética , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología
5.
J Immunol ; 169(4): 1922-9, 2002 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-12165517

RESUMEN

The B cell lymphoma-6 (BCL-6) transcriptional repressor protein is an important regulator of B cell differentiation and is strongly implicated in the development of B cell lymphoma. Expression of the Blimp-1 transcription factor, which is critical for promoting B cell differentiation into plasma cells, is repressed by BCL-6. We have investigated the mechanism for how BCL-6 represses Blimp-1 transcription, and have found that BCL-6 regulates the Blimp-1 promoter through a novel mechanism involving AP-1 elements. Specifically, BCL-6 is a potent repressor of transcriptional activity mediated by AP-1 factors. We found that the zinc-finger region of BCL-6 interacts with c-Jun, JunB, and JunD proteins but does not bind c-Fos or Fra-2 proteins. An estrogen receptor ligand binding domain fusion with the BCL-6 zinc finger domain can act as a estrogen-inducible dominant negative protein and increase AP-1 activity in BCL-6(+) cells but not in BCL-6(-) cells, indicating that endogenous BCL-6 represses AP-1 activity. Additionally, we have confirmed a specific interaction between c-Jun and the zinc finger domain of BCL-6 in vivo using a mammalian two-hybrid assay. Repression of AP-1 function by BCL-6 may be a key mechanism for how BCL-6 regulates gene expression to control inflammation, lymphocyte differentiation, and lymphomagenesis.


Asunto(s)
Linfocitos B/citología , Proteínas de Unión al ADN/genética , Proteínas Proto-Oncogénicas/genética , Proto-Oncogenes , Proteínas Represoras/genética , Factor de Transcripción AP-1/metabolismo , Factores de Transcripción/genética , Linfocitos B/inmunología , Linfocitos B/metabolismo , Secuencia de Bases , Diferenciación Celular , Línea Celular , Transformación Celular Neoplásica , ADN/genética , Humanos , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas Proto-Oncogénicas c-bcl-6 , Proteínas Proto-Oncogénicas c-jun/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Activación Transcripcional , Técnicas del Sistema de Dos Híbridos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA