Fbw7 and p53 Cooperatively Suppress Advanced and Chromosomally Unstable Intestinal Cancer
| Autor: | Jeffrey J. Delrow, Jherek Swanger, William M. Grady, Keiichi I. Nakayama, Tom Small, Jessica Hespelt, Amanda Hagar, Katherine A. Guthrie, Bruce E. Clurman, Jonathan E. Grim, Sue E. Knoblaugh |
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| Rok vydání: | 2012 |
| Předmět: |
F-Box-WD Repeat-Containing Protein 7
Cyclin E Colorectal cancer Ubiquitin-Protein Ligases Cell Cycle Proteins Adenocarcinoma Biology medicine.disease_cause Metastasis Mice Cell Movement Chromosomal Instability Chromosome instability medicine Animals Humans Molecular Biology F-Box Proteins Cell Differentiation Articles Cell Biology medicine.disease Phenotype digestive system diseases Ubiquitin ligase Gene Expression Regulation Neoplastic Disease Models Animal Cell Transformation Neoplastic biology.protein Cancer research Tumor Suppressor Protein p53 Colorectal Neoplasms Carcinogenesis Gene Deletion |
| Zdroj: | Molecular and Cellular Biology. 32:2160-2167 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.00305-12 |
| Popis: | Colorectal cancer (CRC) remains a major cause of cancer mortality worldwide. Murine models have yielded critical insights into CRC pathogenesis, but they often fail to recapitulate advanced-disease phenotypes, notably metastasis and chromosomal instability (CIN). New models are thus needed to understand disease progression and to develop therapies. We sought to model advanced CRC by inactivating two tumor suppressors that are mutated in human CRCs, the Fbw7 ubiquitin ligase and p53. Here we report that Fbw7 deletion alters differentiation and proliferation in the gut epithelium and stabilizes oncogenic Fbw7 substrates, such as cyclin E and Myc. However, Fbw7 deletion does not cause tumorigenesis in the gut. In contrast, codeletion of both Fbw7 and p53 causes highly penetrant, aggressive, and metastatic adenocarcinomas, and allografts derived from these tumors form highly malignant adenocarcinomas. In vitro evidence indicates that Fbw7 ablation promotes genetic instability that is suppressed by p53, and we show that most Fbw7−/−; p53−/− carcinomas exhibit a CIN+ phenotype. We conclude that Fbw7 and p53 synergistically suppress adenocarcinomas that mimic advanced human CRC with respect to histopathology, metastasis, and CIN. This model thus represents a novel tool for studies of advanced CRC as well as carcinogenesis associated with ubiquitin pathway mutations. |
| Databáze: | OpenAIRE |
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