title: 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.affiliation: Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, 72074 Tübingen, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Heubach
authors.forename: Thomas
authors.initials: T
authors.lastname: Knorpp
authors.forename: Marta Anna
authors.initials: MA
authors.lastname: Kowalik
authors.forename: Markus
authors.initials: M
authors.lastname: Templin
authors.forename: Amedeo
authors.initials: A
authors.lastname: Columbano
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010634:Phenobarbital / Q000633:toxicity*; D040081:Protein Array Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000633:toxicity*; D051603:Recoverin / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D011725:Pyridines; C496732:Rcvrn protein, mouse; D051176:beta Catenin; D051603:Recoverin; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D010634:Phenobarbital