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Mechanism of H-ras oncogene activation in mouse squamous carcinoma induced by an alkylating agent
A E Hochwalt1, J J Solomon, S J Garte
1New York University Medical Center, Institute of Environmental Medicine, New York 10016.
Abstract:
A mouse skin squamous cell carcinoma induced by topical application of the direct-acting alkylating agent beta-propiolactone contains an activated H-ras oncogene with an A----T transversion at the second nucleotide of codon 61. The mutation was detected in NIH3T3 transfectant and original tumor DNA by an XbaI restriction enzyme polymorphism and confirmed by oligonucleotide "mismatch" hybridization. The mutation was not seen in the liver of the same animal. The activated oncogene also exhibited several restriction enzyme polymorphisms in transfectant DNA due to a reciprocal translocation 3' to the coding region of the gene, which occurred during transfection. The activating mutation was found in only 1 of 6 beta-propiolactone induced mouse skin tumors examined, the only tumor with a transforming H-ras oncogene. This is a much lower frequency of activation than that previously reported for the same tumor type induced by polycyclic aromatic hydrocarbons. The A----T transversion mutation is consistent with a potentially direct mutagenic effect of a specific beta-propiolactone-DNA adduct.
Insights
Beta-propiolactone induced skin tumors in mice can activate the H-ras oncogene via an A-T mutation. This specific mutation, linked to beta-propiolactone DNA adducts, occurred infrequently in the studied tumors.
Area of Science:
- Oncology
- Molecular Biology
- Toxicology
Background:
- Squamous cell carcinoma is a common skin cancer.
- Oncogene activation plays a critical role in carcinogenesis.
- Beta-propiolactone is a direct-acting alkylating agent with mutagenic potential.
Purpose of the Study:
- To investigate the role of the H-ras oncogene in beta-propiolactone-induced mouse skin tumors.
- To identify specific mutations in the H-ras oncogene and their frequency.
- To explore the potential mutagenic mechanisms of beta-propiolactone.
Main Methods:
- Induction of skin tumors in mice using topical beta-propiolactone.
- Detection of H-ras oncogene mutations using NIH3T3 transfection assays.
- Confirmation of mutations via XbaI restriction enzyme polymorphism and oligonucleotide mismatch hybridization.
Main Results:
- An activating A-T transversion mutation at codon 61 of the H-ras oncogene was identified in one tumor.
- This mutation was specific to the tumor and not found in the animal's liver.
- The activating mutation occurred at a lower frequency compared to tumors induced by polycyclic aromatic hydrocarbons.
Conclusions:
- The A-T transversion mutation in H-ras is consistent with a direct mutagenic effect of beta-propiolactone.
- Beta-propiolactone induces skin tumors with a lower frequency of H-ras activation than other carcinogens.
- Further research is needed to fully elucidate the oncogenic pathways involved.