We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Conditional expression of mutated K-ras accelerates intestinal tumorigenesis in Msh2-deficient mice.
- Authors
Luo, F.; Brooks, D. G.; Ye, H.; Hamoudi, R.; Poulogiannis, G.; Patek, C. E.; Winton, D. J.; Arends, M. J.
- Abstract
K-ras mutation occurs in 40–50% of human colorectal adenomas and carcinomas, but its contribution to intestinal tumorigenesis in vivo is unclear. We developed K-rasV12 transgenic mice that were crossed with Ah-Cre mice to generate K-rasV12/Cre mice, which showed β-naphthoflavone-induction of Cre-mediated LoxP recombination that activated intestinal expression of K-rasV12 4A and 4B transcripts and proteins. Only very occasional intestinal adenomas were observed in β-naphthoflavone-treated K-rasV12/Cre mice aged up to 2 years, suggesting that mutated K-ras expression alone does not significantly initiate intestinal tumourigenesis. To investigate the effects of mutated K-ras on DNA mismatch repair (MMR)-deficient intestinal tumour formation, these mice were crossed with Msh2−/− mice to generate K-rasV12/Cre/Msh2−/− offspring. After β-naphthoflavone treatment, K-rasV12/Cre/Msh2−/− mice showed reduced average lifespan of 17.3±5.0 weeks from 26.9±6.8 (control Msh2−/− mice) (P<0.01). They demonstrated increased adenomas in the small intestine from 1.41 (Msh2−/− controls) to 7.75 per mouse (increased fivefold, P<0.01). In the large intestine, very few adenomas were found in Msh2−/− mice (0.13 per mouse) whereas K-rasV12/Cre/Msh2−/− mice produced 2.70 adenomas per mouse (increased 20-fold, P<0.01). Over 80% adenomas from K-rasV12/Cre/Msh2−/− mice showed transgene recombination with expression of K-rasV12 4A and 4B transcripts and proteins. Sequencing of endogenous murine K-ras showed mutations in two out of 10 tumours examined from Msh2−/− mice, but no mutations in 17 tumours from K-rasV12/Cre/Msh2−/− mice. Expression of K-rasV12 in tumours caused activation of the mitogen-activated protein kinase and Akt/protein kinase B signaling pathways, demonstrated by phosphorylation of p44MAPK, Akt and GSK3β, as well as transcriptional upregulation of Pem, Tcl-1 and Trap1a genes (known targets of K-rasV12 expression in stem cells). Thus, mutated K-ras cooperates synergistically with MMR deficiency to accelerate intestinal tumorigenesis, particularly in the large intestine.Oncogene (2007) 26, 4415–4427; doi:10.1038/sj.onc.1210231; published online 5 February 2007
- Subjects
RAS oncogenes; CANCER genes; INTESTINAL cancer; DNA damage; CARCINOGENESIS; TUMORS; TRANSGENIC mice; MSH2 gene
- Publication
Oncogene, 2007, Vol 26, Issue 30, p4415
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1210231