Induction of choline kinase alpha by carbon tetrachloride (CCl4) occurs via increased binding of c-jun to an AP-1 element.

The mechanism by which treatment of mice with CCl4 induces an increase in choline kinase alpha has been investigated. Nuclear run on assays demonstrated a major increase in the transcript for choline kinase alpha in livers from mice 3 h and 6 h after administration of CCl4 compared to vehicle (olive oil). 5'deletion analyses of choline kinase alpha promoter-luciferase constructs expressed in Hepa-1 cells identified a promoter element between -875 and -866 that was nearly identical to an AP-1 consensus site. Mutation of this AP-1 site caused a striking decrease in the expression of choline kinase alpha promoter-luciferase constructs. Electromobility shift assays with nuclear extracts from mouse liver demonstrated that c-Jun, but not c-fos, bound oligonucleotides with the AP-1 site. The amount of c-jun bound was greatly increased when hepatic nuclear extracts from mice treated with CCl4 were used. Chromatin immunoprecipitation assays confirmed that c-jun binds to the choline kinase alpha promoter. The results from these studies provide strong evidence that the choline kinase alpha promoter has a distal element (-875/-867) that binds c-jun and the binding of c-jun is enhanced by treatment with CCl4.