The Apc 1322T mouse develops severe polyposis associated with submaximal nuclear beta-catenin expression
| Autor: | Kimberley Howarth, Annabelle Lewis, Lisa Willis, Andrew Silver, Bradley Spencer–Dene, Richard Poulsom, Philip East, Matthew E. Cockman, Robert A. Goodlad, Gordon Stamp, Nicholas A. Wright, N Mandir, Andrew Rowan, Emma Nye, Maesha Deheragoda, Patrick J. Pollard, Ian Tomlinson, Stefania Segditsas, Amy McCart |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Paneth Cells
Beta-catenin Genes APC Adenomatous polyposis coli Blotting Western Loss of Heterozygosity medicine.disease_cause Familial adenomatous polyposis Loss of heterozygosity Mice Species Specificity Mutant protein medicine Animals Genetic Predisposition to Disease Alleles beta Catenin Hepatology biology Models Genetic Gastroenterology Wnt signaling pathway medicine.disease Gene Expression Regulation Neoplastic Mice Inbred C57BL Disease Models Animal Cell Transformation Neoplastic Adenomatous Polyposis Coli Mice Inbred DBA Catenin Immunology Mutation Cancer research biology.protein Carcinogenesis Colorectal Neoplasms Signal Transduction |
| Zdroj: | Gastroenterology. 136(7) |
| ISSN: | 1528-0012 |
| Popis: | BACKGROUND and AIMS: We previously demonstrated that the 2 APC mutations in human colorectal tumors are coselected, because tumorigenesis requires an optimal level of Wnt signaling. We and others subsequently showed that the truncated APC proteins in colorectal tumors usually retain a total of 1-2 beta-catenin binding/degradation repeats (20AARs); very few intestinal tumors have proteins with no 20AARs. The coselection of the "2 hits" at APC makes it difficult to undertake further mechanistic studies in this area in humans. In mice, however, second hits appear to vary with the strain or genetic background used. This suggested the possibility of creating suboptimal Apc genotypes in the mouse. METHODS: We have constructed a mouse, Apc(1322T), with a mutant protein retaining one 20AAR. After repeated backcrossing to the C57BL/6J background, we compared the 1322T animals with the widely used Min mouse in which the mutant Apc protein has zero 20AARs. RESULTS: In both mice, intestinal adenomas showed copy-neutral loss of heterozygosity, making them homozygous for the mutant Apc allele. 1322T animals had markedly more severe polyposis, with earlier-onset, larger, more numerous, and more severely dysplastic adenomas. 1322T tumors also had more marked Paneth cell differentiation and higher frequencies of crypt fission. Somewhat surprisingly, nuclear beta-catenin expression was lower in 1322T than Min tumors. CONCLUSIONS: We propose that the Apc(1322T) mutation produces submaximal beta-catenin levels that promote early tumor growth more effectively than the Apc(Min) mutation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|