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Cellular transformation and malignancy induced by ras require c-jun
R Johnson1, B Spiegelman, D Hanahan
1Hormone Research Institute, University of California, San Francisco 94143, USA.
Abstract:
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.
Insights
Ras oncogene activation relies on the transcription factor AP-1, specifically c-Jun. Loss of c-Jun impairs Ras-driven cell transformation, but restoring c-Jun rescues these properties, confirming its critical role.
Area of Science:
- Oncogenes and cancer biology
- Molecular mechanisms of cell transformation
- Transcription factor regulation
Background:
- Ras is a key oncogene implicated in various cancers.
- Activated Ras proteins induce the AP-1 transcription factor, a complex of Fos and Jun proteins.
- Dysregulated AP-1 protein expression can lead to neoplastic transformation, suggesting AP-1 as a Ras effector.
Purpose of the Study:
- To investigate the role of AP-1 as a critical effector of Ras-induced transformation.
- To determine if c-Jun is essential for Ras-mediated cellular changes and tumorigenicity.
Main Methods:
- Analysis of Ras-induced transcriptional responses in c-jun null fibroblasts.
- Comparison of transformation characteristics (loss of contact inhibition, anchorage independence, tumorigenicity) between wild-type and c-jun null cells.
- Restoration of c-Jun expression in c-jun null cells to assess rescue of transformation phenotypes.
Main Results:
- Ras-induced transcriptional activation of AP-1-responsive genes was significantly impaired in c-jun null fibroblasts.
- c-jun null cells exhibited a lack of key Ras transformation hallmarks compared to wild-type cells.
- Forced expression of c-Jun restored contact inhibition, anchorage independence, and tumorigenicity in Ras-expressing c-jun null cells.
- Tumorigenic variants arising from Ras-expressing c-jun null cells consistently showed restored AP-1 activity.
Conclusions:
- c-Jun is a crucial effector for transformation induced by activated Ras proteins.
- Genetic evidence supports c-Jun's essential role in mediating Ras-driven oncogenesis.
- Targeting the Ras-c-Jun pathway may offer therapeutic strategies for Ras-driven cancers.