RESUMEN
The transcriptional co-activator BOB.1/OBF.1 is crucial for Octamer-driven transcription in B cells. BOB.1/OBF.1-deficiency leads to tremendous defects in B-cell development and function. Therefore, in the past research focused on the identification of BOB.1/OBF.1 target genes. However, the regulation of BOB.1/OBF.1 expression itself is poorly understood. Here we show that in B cells NF-κB as well as to some extent NFAT proteins are involved in the activation of basal as well as inducible BOB.1/OBF.1 expression by direct binding to the BOB.1/OBF.1 promoter. Moreover, the analysis of different inducers of NF-κB, like several TLR ligands, TNF-α, BAFF, or LTα1ß2, revealed that both the canonical and noncanonical NF-κB pathways are involved in the induction of BOB.1/OBF.1 gene. The identification of so far unknown inducers that regulate BOB.1/OBF.1 expression in B cells provides novel insights in the potential function of BOB.1/OBF.1 during different aspects of B-cell development and function.
Asunto(s)
Linfocitos B/metabolismo , FN-kappa B/fisiología , Proteínas de Transporte de Catión Orgánico/genética , Transducción de Señal/fisiología , Transactivadores/genética , Animales , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/metabolismo , Transportador 2 de Cátion Orgánico , Regiones Promotoras GenéticasRESUMEN
The transcriptional co-activator BOB.1/OBF.1 was originally identified in B cells and is constitutively expressed throughout B cell development. BOB.1/OBF.1 associates with the transcription factors Oct1 and Oct2, thereby enhancing octamer-dependent transcription. In contrast, in T cells, BOB.1/OBF.1 expression is inducible by treatment of cells with PMA/Ionomycin or by antigen receptor engagement, indicating a marked difference in the regulation of BOB.1/OBF.1 expression in B versus T cells. The molecular mechanisms underlying the differential expression of BOB.1/OBF.1 in T and B cells remain largely unknown. Therefore, the present study focuses on mechanisms controlling the transcriptional regulation of BOB.1/OBF.1 and Oct2 in T cells. We show that both calcineurin- and NF-κB-inhibitors efficiently attenuate the expression of BOB.1/OBF.1 and Oct2 in T cells. In silico analyses of the BOB.1/OBF.1 promoter revealed the presence of previously unappreciated combined NFAT/NF-κB sites. An array of genetic and biochemical analyses illustrates the involvement of the Ca(2+)/calmodulin-dependent phosphatase calcineurin as well as NFAT and NF-κB transcription factors in the transcriptional regulation of octamer-dependent transcription in T cells. Conclusively, impaired expression of BOB.1/OBF.1 and Oct2 and therefore a hampered octamer-dependent transcription may participate in T cell-mediated immunodeficiency caused by the deletion of NFAT or NF-κB transcription factors.
Asunto(s)
FN-kappa B/metabolismo , Factores de Transcripción NFATC/metabolismo , Factor 2 de Transcripción de Unión a Octámeros/genética , Linfocitos T/metabolismo , Transactivadores/genética , Animales , Sitios de Unión , Células Cultivadas , Humanos , Células Jurkat , Ratones , Ratones Endogámicos C57BL , FN-kappa B/antagonistas & inhibidores , Factores de Transcripción NFATC/antagonistas & inhibidores , Factor 2 de Transcripción de Unión a Octámeros/biosíntesis , Regiones Promotoras Genéticas , Transactivadores/biosíntesis , Transcripción GenéticaRESUMEN
How lymphoma cells (LCs) invade the brain during the development of central nervous system lymphoma (CNSL) is unclear. We found that NF-κB-induced gliosis promotes CNSL in immunocompetent mice. Gliosis elevated cell-adhesion molecules, which increased LCs in the brain but was insufficient to induce CNSL. Astrocyte-derived CCL19 was required for gliosis-induced CNSL. Deleting CCL19 in mice or CCR7 from LCs abrogated CNSL development. Two-photon microscopy revealed LCs transiently entering normal brain parenchyma. Astrocytic CCL19 enhanced parenchymal CNS retention of LCs, thereby promoting CNSL formation. Aged, gliotic wild-type mice were more susceptible to forming CNSL than young wild-type mice, and astrocytic CCL19 was observed in both human gliosis and CNSL. Therefore, CCL19-CCR7 interactions may underlie an increased age-related risk for CNSL.
Asunto(s)
Envejecimiento/patología , Neoplasias del Sistema Nervioso Central/patología , Quimiocina CCL19/metabolismo , Gliosis/patología , Linfoma/patología , Adolescente , Adulto , Anciano , Animales , Astrocitos/metabolismo , Astrocitos/patología , Barrera Hematoencefálica/citología , Barrera Hematoencefálica/diagnóstico por imagen , Barrera Hematoencefálica/patología , Línea Celular Tumoral/trasplante , Neoplasias del Sistema Nervioso Central/diagnóstico por imagen , Neoplasias del Sistema Nervioso Central/cirugía , Quimiocina CCL19/genética , Quimiocina CXCL12 , Modelos Animales de Enfermedad , Femenino , Gliosis/diagnóstico por imagen , Humanos , Microscopía Intravital , Linfoma/diagnóstico por imagen , Linfoma/cirugía , Masculino , Ratones , Ratones Transgénicos , Microscopía de Fluorescencia por Excitación Multifotónica , Persona de Mediana Edad , FN-kappa B/metabolismo , Receptores CCR7/genética , Receptores CCR7/metabolismo , Imagen de Lapso de Tiempo , Adulto JovenRESUMEN
We present the STM investigation of four different oligopyridines at the liquid/highly oriented pyrolytic graphite interface. The heteroaromatic compounds are constitutional isomers showing the same overall shape regardless of their actual conformation. On the basis of weak intermolecular C-H...N hydrogen-bonding interactions, different nanopatterns are formed following a simple general concept for the two dimensional self-assembly. The molecules arrange either in linear or in cyclic structures. Though the oligopyridines are achiral, the formation of prochiral trimeric superstructures leads to chiral phases due to the immobilization on the surface. Some of the molecules show polymorphic structures depending on the solvent. The large variety of the presented structures formed by self-assembly of the different oligopyridines which retain the same functional heteroaromatic backbone shall open the possibility of exploiting these patterns as templates for the nanostructuring of surfaces with guests such as small molecules or metal ions for intriguing applications in, for example, catalysis.