Cited by 40Wnt/β-catenin signaling in development and cancerLiver physiology and pathologyDrug-Induced Hepatotoxicity and Protection

Gender-Specific Interplay of Signaling through β-Catenin and CAR in the Regulation of Xenobiotic-Induced Hepatocyte Proliferation

Braeuning, Albert, Heubach, Yvonne, Knorpp, Thomas, Kowalik, Marta Anna, Templin, Markus, Columbano, Amedeo, Schwarz, Michael·2011·Toxicological Sciences

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.

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Crossref · 10.1093/toxsci/kfr166

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  • CAR's pro-proliferative role in liver is mediated through induction of c-Myc, Foxm1, and cyclin D1, and modulation of β-catenin and YAP signaling pathways.

    “Prior studies have focused primarily on the pro-proliferative role of CAR in the liver, mediated through the induction of factors such as cellular-myelocytomatosis oncogene (c-Myc),15 forkhead box m1 (Foxm1),15 and cyclin D1 (Ccnd1),16 as well as modulation of β-catenin17,18 and Yes-associated protein19, 20, 21, 22 signaling pathways.”

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Authors
Braeuning, A., Heubach, Y., Knorpp, T., Kowalik, M. A., Templin, M., Columbano, A., & Schwarz, M.
Affiliations
  • University of Tübingen (DE)
  • Natural and Medical Sciences Institute (DE)
  • University of Cagliari (IT)
Venue
Toxicological Sciences
Published
2011-06-24
Volume
123
Issue
1
Pages
113-122
ISSN
  • 1096-0929 (ISSN-L)
  • 1096-6080
OpenAlex
W2127625114
Cited by
40
References
45
Citations by year
2026: 1 · 2025: 3 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 5 · 2019: 2 · 2018: 5 · 2017: 2 · 2016: 3 · 2015: 3 · 2014: 6 · 2013: 4 · 2012: 1
FWCI
1.43
Type
journal article
Language
en
Open access
closed
Locations
  • Toxicological Sciences (publishedVersion)
  • PubMed (publishedVersion)
  • UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
β-catenin signaling, Wnt/β-catenin signaling, constitutive androstane receptor, hepatocyte proliferation, hepatocarcinogenesis, sex differences, estrogen signaling, FOXM1, TCPOBOP, phenobarbital
MeSH terms
Forkhead Box Protein M1, Animals, Female, Gene Expression Regulation, Male, Phenobarbital, Pyridines, Sex Factors, Protein Serine-Threonine Kinases, Mice, Knockout, Hepatocytes, Ribosomal Protein S6 Kinases, 90-kDa, Protein Array Analysis, Cell Proliferation, beta Catenin, Mice, Recoverin, Forkhead Transcription Factors, Wnt Signaling Pathway, 3-Phosphoinositide-Dependent Protein Kinases

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