Although considerable evidence from chemical carcinogenesis experiments using mouse skin has established that the activation of the cellular Harvey ras (rasH) gene at codon 61 occurs frequently as an initiating event in this model, questions remain as to what additional events are required for subsequent stages that eventually lead to malignant conversion. Recent in vitro studies indicate that activated fos oncogenes can cooperate with the rasH oncogene in the malignant conversion of mouse epidermal cells. However, these in vitro systems cannot determine the influence of factors known to effect carcinogenesis in vivo such as blood supply, an intact immune system, humoral and cell-mediated growth controls, and physical barriers to cell growth. The ability to target the expression of genes with oncogenic potential to the epidermis of mice would allow the development of a genetically programmed in vivo model of skin carcinogenesis. Preliminary evidence is presented in this proposal documenting the feasibility of targeting gene expression to the epidermis of transgenic mice by the use of regulatory sequences of a keratin gene which are expressed exclusively in the epidermis at a late stage of development and in cells with proliferative potential. Through the use of this unique targeting ability, the oncogenic potential of expression of the v-rasH and v-fos oncogenes in the epidermis of mice as well as effects on the proliferation and differentiation states of epidermal cells will be determined. The availability of strains of mice expressing individual oncogenes will allow mating experiments that will determine if these genes act synergistically with each other during different stages of carcinogenesis or with other genes with oncogenic potential, which have previously been shown to transform epidermal cells in vitro. Due to the accessibility of the epidermis, it will also be possible to determine the potential role of chemical and physical carcinogens as well as tumor promoters in this process. Finally, differentiation-state specific promoters will be used to determine the effects of oncogenes on post- mitotic epidermal cells. The production of transgenic mice which exclusively express oncogenes in the skin could be useful for screening environmental agents to detect carcinogen or tumor promoters, for defining new compounds to act as cancer chemopreventive agents, and to develop insights into a variety of diseases of the skin which are associated with abnormal regulation of growth.
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