Overexpression of human βTrCP1 deleted of its F box induces tumorigenesis in transgenic mice

Genetic alterations affecting β-catenin, adenomatous polyposis coli or axin proteins are associated with the pathogenesis of numerous human tumors. All these mutations result in the synthesis of unphosphorylated β-catenin that escapes recognition by the β transducin repeat protein (βTrCP1), the receptor of an ubiquitin. The stabilized β-catenin translocates to the nucleus and activates the transcription of genes crucial for tumorigenesis. Recent evidence implicates mutations and overexpresssion of βTrCP1 in human prostate and colon tumors, respectively, suggesting that deregulated βTrCP1 may be involved in tumorigenesis. To explore this possibility further, we generated transgenic mice that specifically express a dominant-negative mutant of βTrCP1 (ΔFβTrCP1) or full-length βTrCP1 in intestine, liver and kidney. We found that 46% (16/35) of the transgenic mice that overexpressed the transgenes developed either intestinal adenomas (10/35) or hepatic (4/35) or urothelial (2/35) tumors. Immunohistological analysis of the tumors revealed that upregulation of cyclin D1, glutamine synthetase and chemotaxin 2 was associated with nuclear accumulation of β-catenin. These results show that the overexpression of ΔFβTrCP1 or βTrCP1 in vivo induce tumors through β-catenin activation.