p53 represses CAAT enhancer-binding protein (C/EBP)-dependent transcription of the albumin gene - A molecular mechanism involved in viral liver infection with implications for hepatocarcinogenesis

p53 is a transcription factor that is activated by genotoxic stress and med iates cell cycle arrest and apoptosis. Here we demonstrate that infection o f mouse liver with recombinant E1/E3-deleted adenovirus leads to p53 activa tion and simultaneously to the down-regulation of albumin gene expression. In vitro transcription assays indicate that transcriptional mechanisms medi ated through the albumin promoter are responsible for reduced albumin mRNA levels during viral infection. Albumin expression is maintained in the live r by a combination of liver-enriched transcription factors such as CAAT enh ancer binding protein (C/EBP)alpha and C/EBP beta, We show that p53 wild ty pe and tumor-derived p53 mutations repress C/EBP-mediated transactivation o f the albumin promoter. The binding of C/EBP alpha or -beta to its cognate sequence in the albumin promoter is not inhibited by p53 expression, Deleti on analysis and domain swapping experiments show that repression of C/EBP b eta-mediated transactivation is dependent on the N-terminal domain of p53 a nd the transactivation domain, leucine zipper domain, and the inhibitory do main II (amino acids 163-191) of C/EBP beta, Our results provide a molecula r explanation for the p53-mediated down-regulation of liver-specific gene e xpression after viral infection. Additionally, as overexpression of p53 mut ants is frequently found in undifferentiated hepatocellular carcinomas, the same mechanisms may contribute to the lack of liver-specific gene transcri ption in these tumors.