Gender-specific interplay of signaling through β-catenin and CAR in the regulation of xenobiotic-induced hepatocyte proliferation.

Abstract

Aberrant signaling through the Wnt/β-catenin pathway is a critical determinant in human and rodent liver carcinogenesis and generally accepted to be a potent driver of proliferation. Xenobiotic agonists of the constitutive androstane receptor (CAR) induce massive acute hyperplasia of mouse liver and facilitate the outgrowth of hepatocellular carcinomas with activated β-catenin. In the present study, the interplay of β-catenin-dependent and CAR-dependent signaling in the liver and its effect on hepatocyte proliferation were analyzed in transgenic mice with hepatocyte-specific knockout of Ctnnb1 (encoding β-catenin) following treatment with two CAR agonists, 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP) and phenobarbital. Hepatocyte-specific knockout of β-catenin inhibited CAR agonists-induced hepatocyte proliferation in male mice. By contrast, the proliferative effect of CAR agonists was strongly augmented in female β-catenin knockout animals. This was due to prolonged proliferation of the knockout hepatocytes. CAR-mediated hepatocyte proliferation was, at least in part, dependent on estrogen signaling and was associated with enhanced expression of FoxM1 and elevated activity of the PDK1/p90RSK pathway. In conclusion, our study shows that gender-specific factors determine whether β-catenin signaling plays a pro- or an antiproliferative role in the regulation of mouse hepatocyte proliferation induced by CAR agonists.

• Authors: Albert Braeuning, Yvonne Heubach, Thomas Knorpp, Marta Anna Kowalik, Markus Templin, Amedeo Columbano, Michael Schwarz
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 123 Issue 1 Pg. 113-22 (Sep 2011) ISSN: 1096-0929 [Electronic] United States
• PMID: 21705713 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Forkhead Box Protein M1
• Forkhead Transcription Factors
• Foxm1 protein, mouse
• Pyridines
• Rcvrn protein, mouse
• beta Catenin
• Recoverin
• 1,4-bis(2-(3,5-dichloropyridyloxy))benzene
• 3-Phosphoinositide-Dependent Protein Kinases
• PDPK1 protein, human
• Pdpk1 protein, mouse
• Protein Serine-Threonine Kinases
• Ribosomal Protein S6 Kinases, 90-kDa
• Phenobarbital

Topics

• 3-Phosphoinositide-Dependent Protein Kinases
• Animals
• Cell Proliferation (drug effects)
• Female
• Forkhead Box Protein M1
• Forkhead Transcription Factors (genetics, metabolism)
• Gene Expression Regulation (drug effects)
• Hepatocytes (drug effects, metabolism)
• Male
• Mice
• Mice, Knockout
• Phenobarbital (toxicity)
• Protein Array Analysis
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Pyridines (toxicity)
• Recoverin (agonists, genetics, metabolism)
• Ribosomal Protein S6 Kinases, 90-kDa (genetics, metabolism)
• Sex Factors
• Wnt Signaling Pathway (drug effects)
• beta Catenin (genetics, metabolism)