Overexpression of human beta TrCP1 deleted of its F box induces tumorigenesis in transgenic mice.
Genetic alterations affecting beta-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 beta-catenin that escapes recognition by the beta transducin repeat protein (beta TrCP1), the receptor of an ubiquitin. The stabilized beta-catenin translocates to the nucleus and activates the transcription of genes crucial for tumorigenesis. Recent evidence implicates mutations and overexpresssion of beta TrCP1 in human prostate and colon tumors, respectively, suggesting that deregulated beta TrCP1 may be involved in tumorigenesis. To explore this possibility further, we generated transgenic mice that specifically express a dominant-negative mutant of beta TrCP1 (Delta F beta TrCP1) or full-length beta TrCP1 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 beta-catenin. These results show that the overexpression of Delta F beta TrCP1 or beta TrCP1 in vivo induce tumors through beta-catenin activation.
Belaïdouni
Nadia
N
Department of Infectious Diseases, Department of INSERM U567, Institut Cochin, CNRS UMR8104, Université R Descartes Paris V, 27 rue du Faubourg Saint Jacques, 75014 Paris, France.
Peuchmaur
Michel
M
Perret
Christine
C
Florentin
Agnes
A
Benarous
Richard
R
Besnard-Guérin
Corinne
C
D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics*; D017384:Sequence Deletion; D015534:Trans-Activators / Q000235:genetics; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics*
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins