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1.
Proc Natl Acad Sci U S A ; 111(42): E4513-22, 2014 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-25288773

RESUMEN

Deregulated transcription factor (TF) activities are commonly observed in hematopoietic malignancies. Understanding tumorigenesis therefore requires determining the function and hierarchical role of individual TFs. To identify TFs central to lymphomagenesis, we identified lymphoma type-specific accessible chromatin by global mapping of DNaseI hypersensitive sites and analyzed enriched TF-binding motifs in these regions. Applying this unbiased approach to classical Hodgkin lymphoma (HL), a common B-cell-derived lymphoma with a complex pattern of deregulated TFs, we discovered interferon regulatory factor (IRF) sites among the top enriched motifs. High-level expression of the proinflammatory TF IRF5 was specific to HL cells and crucial for their survival. Furthermore, IRF5 initiated a regulatory cascade in human non-Hodgkin B-cell lines and primary murine B cells by inducing the TF AP-1 and cooperating with NF-κB to activate essential characteristic features of HL. Our strategy efficiently identified a lymphoma type-specific key regulator and uncovered a tumor promoting role of IRF5.


Asunto(s)
Cromatina/metabolismo , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/metabolismo , Factores Reguladores del Interferón/metabolismo , Factor de Transcripción AP-1/metabolismo , Secuencias de Aminoácidos , Animales , Linfocitos B/citología , Línea Celular Tumoral , Linaje de la Célula , Quimiocinas/metabolismo , Quimiotaxis , Citocinas/metabolismo , Desoxirribonucleasa I/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inflamación , Leucocitos Mononucleares/citología , Linfoma/metabolismo , Linfoma no Hodgkin/metabolismo , Ratones , FN-kappa B/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Plásmidos/metabolismo , Bazo/citología
2.
PLoS One ; 8(1): e54935, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23383005

RESUMEN

The gene encoding the receptor for macrophage colony-stimulating factor (CSF-1R) is expressed exclusively in cells of the myeloid lineages as well as trophoblasts. A conserved element in the second intron, Fms-Intronic Regulatory Element (FIRE), is essential for macrophage-specific transcription of the gene. However, the molecular details of how FIRE activity is regulated and how it impacts the Csf1r promoter have not been characterised. Here we show that agents that down-modulate Csf1r mRNA transcription regulated promoter activity altered the occupancy of key FIRE cis-acting elements including RUNX1, AP1, and Sp1 binding sites. We demonstrate that FIRE acts as an anti-sense promoter in macrophages and reversal of FIRE orientation within its native context greatly reduced enhancer activity in macrophages. Mutation of transcription initiation sites within FIRE also reduced transcription. These results demonstrate that FIRE is an orientation-specific transcribed enhancer element.


Asunto(s)
Secuencia Conservada/genética , Sitios Genéticos/genética , Intrones/genética , Receptor de Factor Estimulante de Colonias de Macrófagos/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Animales , Secuencia de Bases , Sitios de Unión , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/genética , Sitios Genéticos/efectos de los fármacos , Humanos , Intrones/efectos de los fármacos , Lipopolisacáridos/farmacología , Factor Estimulante de Colonias de Macrófagos/farmacología , Macrófagos/metabolismo , Ratones , Datos de Secuencia Molecular , ARN Polimerasa II/genética , ARN sin Sentido/genética , ARN Mensajero/genética , Factor de Transcripción Sp1/metabolismo , Factores de Tiempo , Factor de Transcripción AP-1/metabolismo
3.
FASEB J ; 27(4): 1519-31, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23303209

RESUMEN

11ß-Hydroxysteroid dehydrogenase type-1 (11ß-HSD1) converts inert cortisone into active cortisol, amplifying intracellular glucocorticoid action. 11ß-HSD1 deficiency improves cardiovascular risk factors in obesity but exacerbates acute inflammation. To determine the effects of 11ß-HSD1 deficiency on atherosclerosis and its inflammation, atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice were treated with a selective 11ß-HSD1 inhibitor or crossed with 11ß-HSD1-KO mice to generate double knockouts (DKOs) and challenged with an atherogenic Western diet. 11ß-HSD1 inhibition or deficiency attenuated atherosclerosis (74-76%) without deleterious effects on plaque structure. This occurred without affecting plasma lipids or glucose, suggesting independence from classical metabolic risk factors. KO plaques were not more inflamed and indeed had 36% less T-cell infiltration, associated with 38% reduced circulating monocyte chemoattractant protein-1 (MCP-1) and 36% lower lesional vascular cell adhesion molecule-1 (VCAM-1). Bone marrow (BM) cells are key to the atheroprotection, since transplantation of DKO BM to irradiated ApoE-KO mice reduced atherosclerosis by 51%. 11ß-HSD1-null macrophages show 76% enhanced cholesterol ester export. Thus, 11ß-HSD1 deficiency reduces atherosclerosis without exaggerated lesional inflammation independent of metabolic risk factors. Selective 11ß-HSD1 inhibitors promise novel antiatherosclerosis effects over and above their benefits for metabolic risk factors via effects on BM cells, plausibly macrophages.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/deficiencia , Aterosclerosis/metabolismo , Médula Ósea/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Aterosclerosis/genética , Médula Ósea/efectos de los fármacos , Glucocorticoides/metabolismo , Ratones , Ratones Noqueados , Factores de Riesgo , Molécula 1 de Adhesión Celular Vascular/metabolismo
4.
Exp Hematol ; 39(7): 730-40.e1-2, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21549805

RESUMEN

OBJECTIVE: The transcription factor PAX5 is essential for the activation of B-cell-specific genes and for the silencing of myeloid-specific genes. We previously determined the molecular mechanism by which PAX5 silences the myeloid-specific colony-stimulating-factor-receptor (Csf1R) gene and showed that PAX5 directly binds to the Csf1r promoter as well as to an intronic enhancer that generates an antisense transcript in B cells. Here we examine the role of PAX5 in the regulation of sense and antisense transcription in B cells. MATERIALS AND METHODS: We performed PAX5-specific chromatin immunoprecipitation analyses across the Csfr1 locus. We investigated the role of PAX5 in regulating Csf1r sense and antisense promoter activity by transient transfections and by employing a Pax5(-/-) pro-B-cell line expressing an inducible PAX5 protein. PAX5 interacting factors were identified by pull-down experiments. The role of the transcription factor Sp3 in driving antisense promoter expression was examined in B cells from Sp3 knockout mice. RESULTS: PAX5 differentially regulates the Csf1r promoter and the promoter of the antisense transcript. PAX5 interferes with PU.1 transactivation at the sense promoter by binding to a PAX5 consensus sequence. At the antisense promoter, PAX5 does not specifically recognize DNA, but interacts with Sp3 to upregulate antisense promoter activity. Antisense promoter activation by PAX5 is dependent on the presence of its partial homeo-domain. CONCLUSIONS: We demonstrate that PAX5 regulates Csf1r in B cells by reducing the frequency of binding of the basal transcription machinery to the promoter and by activating antisense RNA expression.


Asunto(s)
Linfocitos B/metabolismo , Regulación de la Expresión Génica , Factor de Transcripción PAX5/genética , Regiones Promotoras Genéticas/genética , Receptor de Factor Estimulante de Colonias de Macrófagos/genética , Animales , Secuencia de Bases , Sitios de Unión/genética , Línea Celular , Línea Celular Tumoral , Células Cultivadas , Inmunoprecipitación de Cromatina , ADN sin Sentido/genética , Ratones , Ratones Noqueados , Mutación , Factor de Transcripción PAX5/metabolismo , Unión Proteica , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Factor de Transcripción Sp3/genética , Factor de Transcripción Sp3/metabolismo , Transactivadores/genética , Transactivadores/metabolismo
5.
Cell Metab ; 6(2): 137-43, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17681149

RESUMEN

Th1 cytokines promote monocyte differentiation into proatherogenic M1 macrophages, while Th2 cytokines lead to an "alternative" anti-inflammatory M2 macrophage phenotype. Here we show that in human atherosclerotic lesions, the expression of M2 markers and PPARgamma, a nuclear receptor controlling macrophage inflammation, correlate positively. Moreover, PPARgamma activation primes primary human monocytes into M2 differentiation, resulting in a more pronounced anti-inflammatory activity in M1 macrophages. However, PPARgamma activation does not influence M2 marker expression in resting or M1 macrophages, nor does PPARgamma agonist treatment influence the expression of M2 markers in atherosclerotic lesions, indicating that only native monocytes can be primed by PPARgamma activation to an enhanced M2 phenotype. Furthermore, PPARgamma activation significantly increases expression of the M2 marker MR in circulating peripheral blood mononuclear cells. These data demonstrate that PPARgamma activation skews human monocytes toward an anti-inflammatory M2 phenotype.


Asunto(s)
Inflamación/metabolismo , Inflamación/patología , Macrófagos/citología , Macrófagos/metabolismo , Monocitos/citología , PPAR gamma/metabolismo , Benzofenonas/farmacología , Biomarcadores , Células Sanguíneas/efectos de los fármacos , Enfermedades de las Arterias Carótidas/patología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Células Espumosas/efectos de los fármacos , Células Espumosas/patología , Humanos , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Monocitos/metabolismo , PPAR gamma/agonistas , Comunicación Paracrina/efectos de los fármacos , Fenotipo , Células Madre/efectos de los fármacos , Tirosina/análogos & derivados , Tirosina/farmacología
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