RESUMEN
There is a strong correlation between the acetylation status of nucleosomal histones and transcriptional activity. Here we show that the histone deacetylase inhibitor trichostatin A (TSA) activates reporter gene constructs driven by the human platelet-derived growth factor B (PDGF-B) gene promoter. This activation showed an inverse correlation with the cell type-specific transcriptional activities of the promoter. The TSA response was minimal in three tumor cell lines that exhibit high-level promoter activity. In JEG-3 choriocarcinoma cells, however, where the basal promoter activity is considerably lower, there was a strong response to TSA. This was in contrast to constructs that included a PDGF-B enhancer, which were refractory to TSA effects, indicating a possible function of the enhancer in modulating acetylation status. Analysis of PDGF-B promoter mutants with respect to TSA induction revealed no specific TSA-responsive element, but suggested that association of nonacetylated histones to the PDGF-B promoter may be a default process in the absence of enhancer activation. TSA treatment of JEG-3 cells, either alone or in combination with the demethylating agent 5-azacytidine, failed to activate the silenced endogenous PDGF-B transcript, however, which appears to be repressed by additional mechanisms.
Asunto(s)
Elementos de Facilitación Genéticos/fisiología , Inhibidores de Histona Desacetilasas , Regiones Promotoras Genéticas/fisiología , Proteínas Proto-Oncogénicas c-sis/genética , Adenocarcinoma , Neoplasias de la Mama , Carcinoma Hepatocelular , Coriocarcinoma , Cromosomas , Metilación de ADN , Inhibidores Enzimáticos/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/fisiología , Histona Desacetilasas/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Intrones , Neoplasias Hepáticas , Mutagénesis/fisiología , Rabdomiosarcoma , Transcripción Genética/efectos de los fármacos , Transcripción Genética/fisiología , Células Tumorales CultivadasRESUMEN
On Thursday 8 January 1998, a Czech Hip helicopter with 21 personnel on board crashed shortly after take off from Bos Krupa, northwest Bosnia. Seventeen casualties (including six with severe injuries) were airlifted from the scene for treatment at the British Hospital Squadron in Sipovo before aeromedical evacuation the next day to Prague, or discharge to their unit. This was the largest mass casualty incident dealt with by the British Defence Medical Services since British troops deployed to Bosnia in 1992.