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Background  The Wnt/β-Catenin signaling pathway is central for liver functions and frequently deregulated in hepatocellular carcinoma (HCC). Analysis of the early phenotypes and molecular events following β-Catenin activation is therefore essential for better understanding HCC pathogenesis. The AP-1 transcription factor c-Jun is a putative β-Catenin target gene and promotes hepatocyte survival, proliferation, and liver tumorigenesis, suggesting that c-Jun may be a key target of β-Catenin signaling in the liver.    Methodology/Principal Findings  To address this issue, the immediate hepatic phenotypes following deletion of the tumor suppressor  Apc  and subsequent β-Catenin activation were analyzed in mice. The contribution of c-Jun to these phenotypes was dissected in double mutant animals lacking both,  Apc  and  c-Jun . β-Catenin was rapidly activated in virtually all  Apc  mutant hepatocytes while c-Jun was induced only after several days, suggesting that its expression was rather a secondary event following  Apc  deletion in the liver. Loss of  Apc  resulted in increased hepatocyte proliferation, hepatomegaly, deregulated protein metabolism, and premature death. Interestingly, additional deletion of  c-Jun  did not affect hepatocyte proliferation but resulted in increased liver damage and mortality. This phenotype correlated with impaired expression of hepatoprotective genes such as Birc5, Egfr Igf1 and subsequently deregulated Akt signaling.    Conclusions/Significance  These data indicate that c-Jun is not a primary target of β-Catenin signaling in the liver, but rather protects against liver damage, which in turn may promote liver tumorigenesis.

The Transcription Factor c-Jun Protects against Liver Damage following Activated β-Catenin Signaling