Gebelein B, Fernandez-Zapico M, Imoto M, Urrutia R
Department of Molecular Neuroscience, Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota 55905, USA.
J Clin Invest. 1998 Dec 1;102(11):1911-9. doi: 10.1172/JCI1919.
The study of zinc finger proteins has revealed their potential to act as oncogenes or tumor suppressors. Here we report the molecular, biochemical, and 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 motif, and an ID sequence that has been shown previously to participate in growth factor-regulated gene expression. Northern blot analysis using pancreatic 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 transcriptional repressor domains, R1 and R2. R1 corresponds to the KRAB-A motif, whereas R2 represents a novel sequence. Transformation assays using NIH3T3 cells demonstrate that KS1 suppresses transformation by the potent oncogenes Ha-ras, Galpha12, and Galpha13. Deletion of the R1/ KRAB-A domain does not modify the transformation suppressive activity of KS1, whereas deletion of R2 abolishes this function. Thus, KS1 is a novel growth factor-inducible zinc finger transcriptional repressor protein with the potential to protect against neoplastic transformation induced by several oncogenes.
对锌指蛋白的研究揭示了它们作为癌基因或肿瘤抑制因子发挥作用的潜力。在此，我们报告了KS1（KRAB/锌指抑制蛋白1）的分子、生化及功能特性，KS1是一个新的、广泛表达的锌指基因，最初从大鼠胰腺文库中分离得到。KS1含有10个C2H2锌指、一个KRAB - A/B基序以及一个先前已证明参与生长因子调控基因表达的ID序列。使用胰腺细胞系进行的Northern印迹分析表明，KS1 mRNA可被血清和表皮生长因子诱导，提示该基因在细胞生长调控中发挥作用。生化分析显示，KS1是一种核蛋白，含有两个转录抑制结构域R1和R2。R1对应于KRAB - A基序，而R2代表一个新序列。使用NIH3T3细胞进行的转化试验表明，KS1可抑制强效癌基因Ha - ras、Galpha12和Galpha13诱导的转化。R1/KRAB - A结构域的缺失不会改变KS1的转化抑制活性，而R2的缺失则会消除该功能。因此，KS1是一种新的生长因子诱导型锌指转录抑制蛋白，具有预防多种癌基因诱导的肿瘤转化的潜力。
