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Most tumors in transgenic mice with human c-Ha-ras gene contained somatically activated transgenes
A Saitoh1, M Kimura, R Takahashi
1Department of DNA Biology, School of Medicine, Tokai University, Kanagawa, Japan.
Abstract:
Two independent transgenic mouse lines carrying human hybrid c-Ha-ras genes with their own promoter region encoding prototype products, were established. In these lines, about 50% of transgenic offspring had tumors within 18 months. The tumors developed in restricted tissues and about 60% of affected mice had angiosarcomas. The transgenes were expressed both in the tumors and in all normal tissues. However, somatic mutational activation was detected only in the transgenes of the tumors. The point mutation at the 61st codon, from CAG(Gln) to CTG(Leu), was detected in all angiosarcomas (22/22), some lung adenocarcinomas (3/11) and Harderian gland adenocarcinomas (4/7) in both lines. The other point mutation at the 12th codon from GGC(Gly) to GTC(Val) was detected in two of the four skin papillomas. No mutations on these codons were detected in normal tissues of transgenic mice. Nontransgenic littermates had no tumors at all. From these results, it was strongly suggested that the mouse tumors do not develop only by the expression of the transgenes, and that definite somatic point mutation of the human c-Ha-ras transgenes in certain cell types may be a causative event in tumorigenesis in these transgenic mice.
Insights
Transgenic mice expressing human c-Ha-ras developed tumors, primarily angiosarcomas. Somatic mutations in the c-Ha-ras transgene, not just expression, were critical for tumor development in these mice.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Transgenic mouse models are crucial for studying oncogene roles in tumorigenesis.
- The human c-Ha-ras gene is frequently implicated in various cancers.
Purpose of the Study:
- To investigate the role of human c-Ha-ras transgene expression and somatic mutation in tumor development.
- To identify specific mutations and their correlation with tumor types in transgenic mice.
Main Methods:
- Generation of two independent transgenic mouse lines harboring the human c-Ha-ras gene.
- Monitoring tumor incidence and types in transgenic offspring over 18 months.
- Analysis of transgene expression and somatic mutations in tumor and normal tissues.
Main Results:
- Approximately 50% of transgenic mice developed tumors, with angiosarcomas being the most common type.
- Transgenes were expressed in both tumors and normal tissues, but somatic mutations were exclusively found in tumors.
- Specific point mutations at codons 61 and 12 of the c-Ha-ras transgene were identified in various tumor types.
Conclusions:
- Tumorigenesis in these transgenic mice requires not only c-Ha-ras transgene expression but also specific somatic point mutations.
- Somatic mutational activation of the human c-Ha-ras transgene is a key event in the development of specific tumors.