Although it is generally believed that cancer results from a series of acquired somatic mutations, precise molecular mechanisms explaining how mutations in cellular genes contribute to carcinogenesis are not available. v-fos represents an important model for studies of viral carcinogenesis because its cellular homologue (c-fos) has defined cellular and molecular functions which v-fos lacks. The ultimate goal of this application is to establish how an acquired mutation in a cellular gene contributes to carcinogenesis. This broad question will be investigated by studying an ideal model system: FBR v-fos transformation. Proposed studies will test the hypothesis that Tumorigenesis may result from disruption of the AP-1 (c-fos/c-jun) transcriptional program.
The Specific Aims are: 1. Determine how v-fos inhibits c-fos DNA binding in vitro; 2. Delineate the role of v-fos inhibition in fibroblast transformation; 3. Determine whether v-fos has an altered DNA-binding sequence specificity; 4. Determine whether AP-1 transcription is altered in v-fos induced mouse tumors; 5. Determine the frequency of alterations in the AP-1 transcriptional program in human bone tumors. These studies are focused on whether mutations which alter AP-1 transcription in vitro represent models of human or animal tumorigenesis. Mouse bone tumors induced by the FBR and FBJ murine sarcoma viruses (v-fos) will be analyzed to determine the effect of v-fos expression of FOS/JUN/AP- 1 DNA interactions. These studies will employ molecular methods including gel mobility shift assays, DNA affinity chromatography, and immunoprecipitations with specific antibodies. These in vivo results will be compared to results employing in vitro translated proteins. The results of studies of v-fos induced bone tumors will be employed as a model system for studies which will evaluate whether human bone tumors have frequent alterations in the AP-1 transcriptional program. These human tumor studies will employ PCR amplification to sequence c-fos and c-jun genes within bone tumors to determine whether disruption of the AP-1 transcriptional program is an important mechanism during human tumorigenesis.
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