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Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis
Abstract:
Cellular proto-oncogenes can be activated by both point mutations and chromosomal translocations, suggesting that there may be a direct link between exposure to agents which damage DNA and genetic change leading to malignancy. Several groups have therefore analysed mutations found in cellular oncogenes of tumours induced by particular physical or chemical carcinogens. Here, we have analysed the molecular changes at different stages of carcinogenesis in mouse skin tumours induced by initiating and promoting agents. Over 90% of tumours, including premalignant papillomas, initiated with dimethylbenzanthracene (DMBA) have a specific A----T transversion at the second nucleotide of codon 61 of the Harvey-ras (Ha-ras) gene. The frequency of this mutation was dependent on the initiating agent used, but not on the promoter, suggesting that the mutation occurs at the time of initiation. The mutation was heterozygous in most papillomas tested, but was homozygous or amplified in some carcinomas. The development of further chromosomal changes at the c-Ha-ras gene locus is therefore a common feature of tumour progression.
Insights
Exposure to carcinogens like dimethylbenzanthracene (DMBA) frequently causes a specific mutation in the Harvey-ras (Ha-ras) gene, initiating skin tumor development. This genetic change is crucial for early carcinogenesis and can progress in later stages.
Area of Science:
- Oncology
- Molecular Biology
- Carcinogenesis
Background:
- Cellular proto-oncogenes are critical in cancer development.
- DNA-damaging agents can lead to genetic mutations and malignancy.
- Understanding oncogene mutations in chemically induced tumors is vital.
Purpose of the Study:
- To analyze molecular changes during mouse skin carcinogenesis.
- To investigate the role of specific mutations in tumor initiation and progression.
- To determine the link between carcinogen exposure and oncogene mutation.
Main Methods:
- Induction of mouse skin tumors using initiating and promoting agents.
- Analysis of mutations in cellular oncogenes, specifically the Harvey-ras (Ha-ras) gene.
- Genotyping of tumors at different stages (papillomas, carcinomas) to identify mutations.
Main Results:
- Over 90% of dimethylbenzanthracene (DMBA)-initiated tumors showed an A-T transversion in codon 61 of the Ha-ras gene.
- The specific Ha-ras mutation frequency correlated with the initiating agent, not the promoter.
- The mutation was typically heterozygous in papillomas and became homozygous or amplified in carcinomas.
Conclusions:
- The specific Ha-ras codon 61 mutation is a key event during initiation of DMBA-induced skin carcinogenesis.
- Tumor progression involves further genetic alterations, including changes at the c-Ha-ras gene locus.
- This study highlights a direct link between DNA-damaging agents and oncogene mutations in cancer development.