Cellular transformation and malignancy induced by ras require c-jun.
ras is an important oncogene in experimental animals and humans. In addition, activated ras proteins are potent inducers of the transcription factor AP-1, which is composed of heterodimeric complexes of Fos and Jun proteins. Together with the fact that deregulated expression of some AP-1 proteins can cause neoplastic transformation, this finding suggests that AP-1 may function as a critical ras effector. We have tested this hypothesis directly by analyzing the response to activated ras in cells that harbor a null mutation in the c-jun gene. The transcriptional response of AP-1-responsive genes to activated ras is severely impaired in c-jun null fibroblasts. Compared with wild-type cells, the c-jun null cells lack many characteristics of ras transformation, including loss of contact inhibition, anchorage independence, and tumorigenicity in nude mice; these properties are restored by forced expression of c-jun. Rare tumorigenic variants of ras-expressing c-jun null fibroblasts do arise. Analysis of these variants reveals a consistent restoration of AP-1 activity. The results provide genetic evidence that c-jun is a crucial effector for transformation by activated ras proteins.
Johnson
R
R
Hormone Research Institute, University of California, San Francisco 94143, USA.
Spiegelman
B
B
Hanahan
D
D
Wisdom
R
R
D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016758:Genes, jun; D011905:Genes, ras; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*
D009838:Oligodeoxyribonucleotides; D016755:Proto-Oncogene Proteins c-jun; D016283:Proto-Oncogene Proteins p21(ras)