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Activating Met mutations produce unique tumor profiles in mice with selective duplication of the mutant allele

Official URL:https://doi.org/10.1073/pnas.0407651101
PubMed:View item in PubMed
Creators Name:Graveel, C. and Su, Y. and Koeman, J. and Wang, L.M. and Tessarollo, L. and Fiscella, M. and Birchmeier, C. and Swiatek, P. and Bronson, R. and Vande Woude, G.F.
Journal Title:Proceedings of the National Academy of Sciences of the United States of America
Journal Abbreviation:Proc Natl Acad Sci U S A
Volume:101
Number:49
Page Range:17198-17203
Date:7 December 2004
Keywords:Alleles, Chromosomal Instability, Disease Progression, Gene Amplification, Mutant Strains Mice, Mutation, Missense Mutation, Neoplasms, Proto-Oncogene Proteins C-Met, Survival Analysis, Trisomy, Animals, Mice
Abstract:Tyrosine kinase-activating mutations in Met have been observed in hereditary papillary renal carcinomas as well as in other cancers. These mutations have been examined in several in vitro systems, where they cause constitutive Met activation, focus formation, and cell motility, and are tumorigenic in xenografts. To study the influence of these mutations on tumorigenesis in vivo, we generated mice with targeted mutations in the murine met locus. The following five mouse lines with mutant Met were created: WT, D1226N, Y1228C, M1248T, and M1248T/L1193V. We observed that mice harboring D1226N, Y1228C, and M1248T/L1193V mutations developed a high frequency of sarcomas and some lymphomas, whereas the M1248T mice developed carcinomas and lymphomas. Of considerable interest, we observed trisomy of chromosome 6 and duplication of the mutant met allele in a majority of the tumors, similar to what has been reported in patients with hereditary renal papillary carcinomas. These results demonstrate that activating Met mutations and met amplification play key roles in promoting tumorigenesis in vivo. Moreover, our findings show that different mutations in the Met kinase domain can influence the types of cancers that develop.
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Item Type:Article

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