title: Phenotype of single hepatocytes expressing an activated version of β-catenin in liver of transgenic mice.
abstract: The gene CTNNB1 encoding β-catenin is mutated in about 30% of hepatocellular carcinoma, generally often combined with other genetic alterations. In transgenic mice, it has been shown that activation of β-catenin in more than 70% of all hepatocytes causes immediate proliferation leading to hepatomegaly. In this study we established a novel mouse model where β-catenin is activated only in individual, dispersed hepatocytes. Hepatocyte-specific expression of activated point-mutated β-catenin (human β-catenin(S33Y)) was established using the Cre/loxP system. Expression of several downstream targets of β-catenin signaling such as glutamine synthetase and several cytochrome P450 isoforms was confirmed by immunostaining. Only a minor portion of hepatocytes expressed the β-catenin(S33Y) transgene, which were mainly positioned as dispersed individual cells within the normal liver parenchyma. The hepatocytes with activated β-catenin did not show increased proliferation and the mice did not develop hepatomegaly. In conclusion, activated β-catenin in single hepatocytes induces a gene expression pattern in hepatocytes which is similar to that of Ctnnb1-mutated mouse liver tumors, but is apparently not sufficient to induce increased cell proliferation. Therefore, onset of proliferation seems to require concomitant activation of β-catenin in clusters of hepatocytes, suggesting a role of cell-cell communication in this process.
authors.affiliation: Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, Wilhelmstr. 56, 72074 Tübingen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schreiber
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rignall
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
authors.forename: Philip
authors.initials: P
authors.lastname: Marx-Stoelting
authors.forename: Thomas
authors.initials: T
authors.lastname: Ott
authors.forename: Albrecht
authors.initials: A
authors.lastname: Buchmann
authors.forename: Seddik
authors.initials: S
authors.lastname: Hammad
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
authors.forename: Christoph
authors.initials: C
authors.lastname: Köhle
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D012333:RNA, Messenger; D051176:beta Catenin