Evidence for enhanced expression of c-fos, c-jun, and the Ca(2+)-activated neutral protease in rat liver following carbon tetrachloride administration.

The effects of CCl4 on hepatic c-fos and c-jun gene expression were examined, and the correspondence between intermediate-early gene expression and the expression of the Ca(2+)-activated neutral proteinase (mu and mCANP) characterized. Administration of CCl4 to rats resulted in a pronounced dose- and time-dependent increase in c-jun and c-fos mRNA levels (approximately 8 to 17-fold) as detected by either Northern blot or RT-PCR analyses. The expression of mu and mCANP following CCl4 treatment was monitored by Northern blot analysis and mu and mCANP mRNA levels were found to be elevated approximately 5- to 15-fold over the time period of 18 to 24 h. Experiments were performed to determine whether the Fos-Jun heterodimeric AP-1 transcription factor complex bound the AP-1-like binding motif present in the mCANP gene. Gel retardation assays using hepatic nuclear extracts from CCl4-treated animals revealed binding of a protein to the AP-1-like motif present in the mCANP gene and competition and supershift assays confirmed the specificity of AP-1 transcription factor binding. These results show that CANP gene expression is enhanced in response to oxidative cellular damage and that the AP-1 complex may be involved in the regulation of CANP gene expression.