KRAB-independent suppression of neoplastic cell growth by the novel zinc finger transcription factor KS1

The study of zinc finger proteins has revealed their potential to act as on cogenes or tumor suppressors. Here we report the molecular, biochemical, an d functional characterization of KS1 (KRAB/zinc finger suppressor protein 1 ), a novel, ubiquitously expressed zinc finger gene initially isolated from a rat pancreas library. KS1 contains 10 C2H2 zinc fingers, a KRAB-A/B moti f, and an ID sequence that has been shown previously to participate in grow th factor-regulated gene expression. Northern blot analysis using pancreati c cell lines demonstrates that KS1 mRNA is inducible by serum and epidermal growth factor, suggesting a role for this gene in cell growth regulation. Biochemical analysis reveals that KS1 is a nuclear protein containing two t ranscriptional repressor domains, R1 and R2. R1 corresponds to the KRAB-A m otif, whereas R2 represents a novel sequence. Transformation assays using N IH3T3 cells demonstrate that KS1 suppresses transformation by the potent on cogenes Ha-ras, G alpha 12, and G alpha 13. Deletion of the R1/KRAB-A domai n does not modify the transformation suppressive activity of KS1, whereas d eletion of R2 abolishes this function. Thus, KS1 is a novel growth factor-i nducible zinc finger transcriptional repressor protein with the potential t o protect against neoplastic transformation induced by several oncogenes.