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A mouse model of activating Met mutations

Carrie R Graveel1, Cheryl A London, George F Vande Woude

  • 1Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.

Cell Cycle (Georgetown, Tex.)
|March 2, 2005
PubMed

Insights

Activating mutations in the Met gene drive unique tumor development in mice. These Met mutations also caused selective gene duplication, mirroring findings in human hereditary papillary renal carcinomas (HPRC).

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Activating mutations in tyrosine kinase Met are implicated in hereditary papillary renal carcinomas (HPRC).
  • The transforming potential of these Met mutations has been previously studied in vitro and in tumor xenografts.

Purpose of the Study:

  • To investigate the in vivo effects of specific Met-activating mutations in the mouse germline.
  • To establish a mouse model for studying Met-driven tumorigenesis and evaluating Met inhibitors.

Main Methods:

  • Generated five mouse lines with targeted mutations in the murine met locus: wild-type (WT), D1226N, Y1228C, M1248T, and M1248T/L1193V.
  • Analyzed tumor profiles and genetic alterations, including allele duplication, in the generated mouse lines.

Main Results:

  • Different mutant Met mouse lines exhibited distinct tumor profiles, including carcinomas, sarcomas, and lymphomas.
  • Observed non-random duplication of the mutant met allele in a majority of tumors from mutant mouse lines, a phenomenon also seen in HPRC patients.
  • Mutations within the kinase domain distinctly affect downstream signaling pathways.

Conclusions:

  • Activating Met mutations are crucial drivers of tumorigenesis with distinct downstream signaling effects.
  • The generated Met mutant mice serve as a valuable model for understanding Met-mediated tumorigenesis and for preclinical testing of Met inhibitors against human cancers with activating Met mutations.

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