Role of hepatocyte nuclear factor 3 gamma in the expression of human CYP2C genes.
Hepatocyte nuclear factor 3 gamma (HNF-3 gamma) is an important transcription factor for the maintenance of specific liver functions. However, its relevance in the expression of human cytochrome P450 (CYP) genes has not yet been explored. Several HNF3 putative binding sites can be identified in human CYP2C 5'-flanking regions. Gene reporter experiments with proximal promoters revealed that HNF-3 gamma transactivated CYP2C8, CYP2C9, and CYP2C19 (25-, 4-, and 4-fold, respectively), but it did not transactivate CYP2C18. However, overexpression of HNF-3 gamma in hepatoma cells by means of a recombinant adenovirus induced CYP2C9, CYP2C18, and CYP2C19 mRNA (4.5-, 20-, and 50-fold, respectively) but did not activate endogenous CYP2C8. The lack of effect of HNF-3 gamma on endogenous CYP2C8 could be reversed by treating cells with the deacetylase inhibitor, trichostatin A, suggesting the existence of chromatin condensation around functional HNF3 elements in this gene. We conclude that HNF3 gamma is an important transcription factor for the hepatic-specific expression of human CYP2C genes. Our results also evidence that efficient transfection tools, such as adenoviral vectors, may be decisive for assessing the role of transcription factor on chromatin organized genes.
Bort
Roque
R
Unidad de Hepatología Experimental, Centro de Investigación, Hospital Universitario La Fe. Avda. Campanar 21, E-46009, Valencia, Spain.
Gómez-Lechón
M José
MJ
Castell
José V
JV
Jover
Ramiro
R
D000256:Adenoviridae / Q000235:genetics; D001665:Binding Sites; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D005822:Genetic Vectors; D006367:HeLa Cells; D051543:Hepatocyte Nuclear Factor 3-gamma; D022781:Hepatocytes / Q000201:enzymology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D024363:Transcription Initiation Site; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014162:Transfection
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C496505:FOXA3 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C400322:cytochrome P-450 CYP2C subfamily; D051543:Hepatocyte Nuclear Factor 3-gamma; C012589:trichostatin A; D003577:Cytochrome P-450 Enzyme System; D008156:Luciferases