The SKVs are avian retroviruses that encode the nuclear oncogene, v-ski. These viruses, and retroviruses that express c-ski proto- oncogene cDNAs, transform cells in culture and induce the terminal differentiation of muscle in quail cells that are otherwise incapable of myogenesis. Because mutational analysis failed to separate ski's ability to transform cells from its ability to induce differentiation it is felt that the two activities are mechanistically related, so that analysis of one will provide insights into the other. The present studies will employ constructed avian and murine retroviruses expressing various normal and mutated ski genes to analyze the activity of ski in promoting cellular transformation and differentiation. Studies will include assays for the activation of muscle-specific mRNA transcription and mapping of regulatory regions that respond to ski's activation. Other studies will involve an assessment of ski's indirect action on myogenesis by inducing the developmental commitment of cells to the myogenic lineage by sensitizing them to stimulatory factors or by activating other genes involved in this process. Experiments will also be performed to analyze the expression of individual c- ski mRNAs and their encoded proteins in relationship to cellular proliferation. Monoclonal antibodies generated for this purpose will be used to examine intracellular location and modification of ski proteins in order to correlate these variables with activities of the proteins in promoting in vitro transformation or differentiation and with the induction of tumors in animals. An initial study of ski's possible involvement in human cancer will be made by analyzing the expression and structure of human c-ski in selected tumors with cytogenetic abnormalities at the ski locus and in human squamous carcinoma cell lines.
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