Mutagenesis of the Ha-ras oncogene in mouse skin tumors induced by polycyclic aromatic hydrocarbons.

Abstract

The importance of mutational activation of the Ha-ras protooncogene in polycyclic aromatic hydrocarboninduced mouse skin tumors was investigated in a complete carcinogenesis model using repetitive applications of 7,12-dimethylbenz [a]anthracene (DMBA), or in an initiation-promotion model using a single application of dibenz [c,h] an early event in skin carcinogenesis. Thus, mutation of the 61st codon of the Ha-ras-1 gene appears to be a critical step in the formation of mouse skin tumors induced in both of the two models tested. Our analyses also delineate two other classes of hydrocarbon-induced carcinomas-namely, tumors whose DNAs efficiently transform 3T3 cells but do not contain mutated ras genes and tumors whose DNAs do not transform 3T3 cells. treatment with the noncarcinogenic phorbol ester tumor promoter phorbol 12-myristate 13-acetate. In both models, tumor development can be easily visualized, tissue is readily accessible, and development of carcinomas is preceded by the appearance of benign papillomas. In the latter model, the initiation and promotion steps are distinct stages in the carcinogenic process and the ratio of papillomas to carcinomas is much higher than in the complete carcinogenesis model. The papillomas and carcinomas produced in both models appear similar by standard pathological criteria.The presence of a transforming Ha-ras oncogene in mouse skin papillomas and carcinomas induced by a single treatment with the polycyclic hydrocarbon DMBA and repetitive treatments with phorbol 12-myristate 13-acetate has been reported by Balmain and coworkers (6,7). However, the mechanism of activation was not determined. The critical change may not involve overexpression of the cellular protooncogene since Toftgard et al. (8) found no increase in RNA levels of Ha-ras or seven other protooncogenes in polycyclic hydrocarbon-induced skin tumors. Our initial studies, which included both RNA analysis and protein analysis using monoclonal antibodies to detect the ras gene product (to be published elsewhere), are consistent with these findings. Thus, we looked for qualitative rather than quantitative changes in ras and used the NIH 3T3 transfection system to facilitate these analyses.

Deregulated expression of cell-cycle proteins during premalignant progression in SENCAR mouse skin

“…It has been postulated that the malignant conversion of the benign papillomas occurs as a result of somatic mutations in the expanded population of initiated cells (Moolgavkar and Knudson, 1981;Potter, 1981). Initiation of tumorigenesis by the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) induces a speci®c point mutation at codon 61 of the Ha-ras-1 gene (Balmain and Pragnell, 1983;Bizub et al, 1986;Roop et al, 1986). Histopathological and cytogenetic studies demonstrated that relevant changes occur during papilloma progression.…”

Development of Keratoacanthomas and Squamous Cell Carcinomas in Transgenic Rabbits with Targeted Expression of EJras. Oncogene in Epidermis

“…24 In correlation with this, a relatively high incidence of the mutated Ha-ras oncogene has been found in keratoacanthomas from both human and experimental models, 5,10 and in human and animal cutaneous SCC. 16,[25][26][27] These findings further suggest that ras oncogenes play important roles in all steps of tumor initiation, regression, and progression, and that additional cellular factors appear to be involved in the malignant progression. However, the mechanisms of the rasrelated regression of keratoacanthoma and progression of SCC are still not well understood.…”

Genetic events and the role of TGFβ in epithelial tumour progression

“…This leads to a specific activating A<T mutation at codon 61 of the H-ras gene in virtually all DMBAinitiated tumours. 15,16 However, the same target gene is mutated, albeit by a different mechanism, when alternative mutagens are used for chemical initiation of mouse skin. Both methyl-nitrosourea (MNU) 17 and alkylating agents 18 result in activating G<A transitions at codon 12 of H-ras.…”