Inhibition of jun transformation by a mutated fos gene: design of an anti-oncogene.
The protein products of the fos and jun oncogenes (Fos and Jun) function as transcriptional regulators in the form of homo- or heterodimeric complexes that bind to DNA. Dimerization is mediated by a leucine zipper structure that serves to juxtapose alpha-helical regions of each protein, rich in basic amino acids, that form a bipartite DNA-binding domain. Although Fos participates exclusively in heterodimeric complexes, Jun can function either as a homodimer that has a low apparent affinity for DNA or as a more stable heterodimer with Fos that has a higher apparent affinity for DNA. We have used these properties of Fos and Jun to design a mutated fos gene, lacking a functional DNA-binding domain (supfos1), that suppresses the transforming activity of jun in trans. Here we show that chicken embryo fibroblasts transformed by jun revert to a normal phenotype after infection by a retroviral vector encoding supFos1. Furthermore, infection of normal cells with the supfos1 vector renders them resistant to subsequent transformation by jun. Inhibition of jun transformation was associated with the appearance of supFos1-Jun heterodimers and a reduction in the AP-1 DNA-binding activity contributed by Jun homodimers. These findings demonstrate that the function of leucine zipper-containing transcription factors can be investigated by the procedure of intracellular immunization.
Department of Tumor Virus Research, University of Tokyo, Japan.
H
H
Okuno
T
T
Suzuki
T
T
Yoshida
Y
Y
Hashimoto
T
T
Curran
H
H
Iba
D000818:Animals; D002455:Cell Division; D002467:Cell Nucleus / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D016762:Genes, fos; D016758:Genes, jun; D016350:Leucine Zippers / Q000235:genetics; D016296:Mutagenesis; D014176:Protein Biosynthesis; D012190:Retroviridae / Q000235:genetics; D013489:Suppression, Genetic; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins