The mouse skin model of chemically induced malignant epithelial tumors has served as a paradigm for understanding the pathogenesis of squamous cancers in humans. The mouse skin model can be operationally subdivided into three stages. Chemical initiation of mouse skin involves mutational events and has been linked to activation of the Harvey-ras gene by point mutations. The second stage, tumor promotion, involves selective outgrowth of initiated cells under the influence of the hyperplastic tumor promoting agent to give rise to benign papillomas. The third stage involves the conversion of benign papillomas to malignant squamous carcinomas in part through alterations in expression of genes involved in tumor cell invasion. The focus of this grant proposal is on molecular mechanisms of tumor promotion by the non-phorbol ester tumor promoter, okadaic acid, and the induction and maintenance of malignant squamous carcinomas. Evidence has accumulated implicating the transcription factor complex, AP- 1, that transcriptionally regulates downstream effector genes, in mouse skin tumor promotion and in the maintenance of malignant squamous carcinomas. Therefore, the central hypotheses to be tested in this proposal are that okadaic acid induced skin tumor promotion is mediated through transient activation of AP-1 and constitutively elevated AP- 1 activity is functionally involved in the induction and maintenance of malignant epidermal carcinomas.
The specific aims to test these hypotheses are: 1) to determine whether a dominant negative c-Jun mutant protein when expressed in transgenic mice during tumor promotion by okadaic acid inhibits tumor promotion 2) to determine whether okadaic acid induction of increased AP- 1 expression in benign tumor cells is mediated by Ets protein(s) which transactivate the AP- 1 genes 3) to determine whether the JunB protein acts in a dominant negative fashion to inhibit AP-1 activity in benign tumor cells and can reduce constitutively elevated AP-l activity in a malignant variant cell line 4) to determine how the dominant negative c-Jun mutant protein, TAM-67, exerts its anti-oncogenic effects in a malignant variant cell line 5) to determine whether expression of TAM-67 in the epidermis of transgenic mice will inhibit the development of squamous carcinomas induced in a complete carcinogenesis protocol. A more complete understanding of specific gene alterations that occur during the development of experimental skin carcinomas will lead to better diagnosis of and intervention in human squamous carcinomas.
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