| http://purl.uniprot.org/citations/12695546 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/12695546 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/12695546 | http://www.w3.org/2000/01/rdf-schema#comment | "Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of more than 50% of currently used therapeutic drugs, yet the mechanisms that control CYP3A4 basal expression in liver are poorly understood. Several putative binding sites for CCAAT/enhancer-binding protein (C/EBP) and hepatic nuclear factor 3 (HNF-3) were found by computer analysis in CYP3A4 promoter. The use of reporter gene assays, electrophoretic mobility shift assays, and site-directed mutagenesis revealed that one proximal and two distal C/EBP alpha binding sites are essential sites for the trans-activation of CYP3A4 promoter. No trans-activation was found in similar reporter gene experiments with a HNF-3 gamma expression vector. The relevance of these findings was further explored in the more complex DNA/chromatin structure within endogenous CYP3A4 gene. Using appropriate adenoviral expression vectors, we found that both hepatic and nonhepatic cells overexpressing C/EBP alpha had increased CYP3A4 mRNA levels, but no effect was observed when HNF-3 gamma was overexpressed. In contrast, overexpression of HNF-3 gamma simultaneously with C/EBP alpha resulted in a greater activation of the CYP3A4 gene. This cooperative effect was hepatic-specific and also occurred in CYP3A5 and CYP3A7 genes. To investigate the mechanism for HNF-3 gamma action, we studied its binding to CYP3A4 promoter and the effect of the deacetylase inhibitor trichostatin A. HNF-3 gamma was able to bind CYP3A4 promoter at a distal position, near the most distal C/EBP alpha binding site. Trichostatin A increased C/EBP alpha effect but abolished HNF-3 gamma cooperative action. These findings revealed that C/EBP alpha and HNF-3 gamma cooperatively regulate CYP3A4 expression in hepatic cells by a mechanism that probably involves chromatin remodeling."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.org/dc/terms/identifier | "doi:10.1124/mol.63.5.1180"xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.org/dc/terms/identifier | "doi:10.1124/mol.63.5.1180"xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/author | "Ingelman-Sundberg M."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/author | "Ingelman-Sundberg M."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/author | "Castell J.V."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/author | "Castell J.V."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/author | "Gomez-Lechon M.J."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/author | "Gomez-Lechon M.J."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/author | "Jover R."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/author | "Jover R."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/author | "Rodriguez-Antona C."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/author | "Rodriguez-Antona C."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/author | "Bort R."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/author | "Bort R."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/author | "Tindberg N."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/author | "Tindberg N."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/date | "2003"xsd:gYear |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/date | "2003"xsd:gYear |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/name | "Mol. Pharmacol."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/name | "Mol. Pharmacol."xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/pages | "1180-1189"xsd:string |
| http://purl.uniprot.org/citations/12695546 | http://purl.uniprot.org/core/pages | "1180-1189"xsd:string |