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 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.
Gebelein
B
B
Department of Molecular Neuroscience, Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota 55905, USA.
Fernandez-Zapico
M
M
Imoto
M
M
Urrutia
R
R
D016475:3T3 Cells / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000737:chemistry; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D015723:Gene Library; D005796:Genes; D016147:Genes, Tumor Suppressor; D016162:Genes, Wilms Tumor; D011905:Genes, ras; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D010179:Pancreas / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000473:pathology; D011487:Protein Conformation; D051381:Rats; D012097:Repressor Proteins / Q000502:physiology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers / Q000235:genetics*
D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C116326:ZNF382 protein, human; C115768:ZNF85 protein, human; C485494:Zfp382 protein, rat; D004815:Epidermal Growth Factor