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Association of Specific DNA Binding and Transcriptional Repression with the Transforming and Myogenic Activities of c-Ski¹

Department of Biochemistry, Case Western Reserve University, Cleveland Ohio 44106 [R. N., G. Z., E. S.]; Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267 [R. N.]; National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702 [P. S.]; and Department of Animal Science, University of Minnesota, St Paul, Minnesota 55108 [D. N. F.]

The ski oncogene encodes a transcription factor that induces both transformation and muscle differentiation in avian fibroblasts. The first 304 amino acids of chicken Ski, the transformation domain, are both necessary and sufficient to mediate these biological activities. Ski’s biological duality is mirrored by its transcriptional activities: it coactivates or corepresses transcription depending on its interactions with other transcription factors. Ski represses transcription through specific binding to GTCTAGAC (GTCT element) but it possesses a transferable repression activity that can function independently of this DNA element. In this study, we locate this repression domain to the NH₂-terminal two-thirds and the GTCT binding region to the COOH-terminal one-third of Ski’s transformation domain. Mutations in the transformation domain of c-Ski reveal a strong correlation between GTCT-mediated transcriptional repression and the biological activities of transformation and myogenesis. We also show that a dimerization domain located at the COOH terminal end of the Ski protein increases its transforming activity and its binding to GTCTAGAC.

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