Role of the transcription factor c-Jun/AP–1 in response to β-Catenin signaling in the liver

Abstract

Background & Aims: The Wnt/β-Catenin signaling pathway is important in liver physiology and frequently deregulated in hepatocellular carcinoma. Analysis of the immediate hepatic phenotypes and molecular events following β-Catenin activation e.g. by deletion of the tumor suppressor APC may therefore identify novel candidates for targeted therapies. The AP–1 transcription factor c-Jun is considered as a β-Catenin target gene. In the liver, c-Jun strongly promotes hepatocyte proliferation, survival and hepatocarcinogenesis, raising the question whether c-Jun is involved in the signaling network following β-Catenin activation. Methods: To address this issue, inducible mutant mice lacking c-Jun as well as APC were generated and analyzed by histology. Expression analysis was performed by quantitative PCR and immunoblotting. Results: Inducible deletion of APC resulted in a rapid increase in nuclear (i.e. active) β-Catenin and c-Jun expression. Moreover, loss of APC resulted in increased hepatocyte proliferation, hepatomegaly and premature death. Interestingly, additional deletion of c-Jun did not affect hepatocyte proliferation but resulted in increased hepatocyte damage and mortality. On the molecular level, c-Jun was not required for the expression of many canonical β-Catenin target genes. However, expression of insulin receptor and related genes such as IGF–1, C/EBPα and C/EBPβ as well as many lipogenic genes was more deregulated in double mutant livers. Conclusions: These data indicate that c-Jun is not required for β-Catenin-dependent hepatocyte proliferation upon loss of APC, but rather promotes hepatocyte survival, likely by affecting metabolic functions. Ongoing experiments will determine whether these functions also promote β-Catenin-dependent hepatocarcinogenesis.