Related Experiment Videos
Oncogenic Ras inhibits Fas ligand-mediated apoptosis by downregulating the expression of Fas
1Swiss Cancer Research Institute (ISREC), BIL Biomedical Research Center, Chemin des Boveresses 155, Switzerland.
Abstract:
Tumor growth is the result of deregulated tissue homeostasis which is maintained through the delicate balance of cell growth and apoptosis. One of the most efficient inducers of apoptosis is the death receptor Fas. We report here that oncogenic Ras (H-Ras) downregulates Fas expression and renders cells of fibroblastic and epitheloid origin resistant to Fas ligand-induced apoptosis. In Ras-transformed cells, Fas mRNA is absent. Inhibition of DNA methylation restores Fas expression. H-Ras signals via the PI 3-kinase pathway to downregulate Fas, suggesting that the known anti-apoptotic effect of the downstream PKB/Akt kinase may be mediated, at least in part, by the repression of Fas expression. Thus, the oncogenic potential of H-ras may reside on its capacity not only to promote cellular proliferation, but also to simultaneously inhibit Fas-triggered apoptosis.
Insights
Oncogenic Ras inhibits Fas expression, preventing apoptosis and promoting tumor growth. DNA methylation inhibition and PI 3-kinase signaling are involved in this process, highlighting Ras
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Research
Background:
- Tumor growth arises from disrupted tissue homeostasis, a balance between cell growth and apoptosis.
- The Fas death receptor is a key inducer of apoptosis.
- Oncogenic Ras proteins are frequently implicated in cancer development.
Purpose of the Study:
- To investigate the effect of oncogenic Ras (H-Ras) on Fas expression and apoptosis.
- To elucidate the molecular mechanisms by which H-Ras influences Fas-mediated apoptosis.
- To explore the role of DNA methylation and the PI 3-kinase pathway in H-Ras-induced apoptosis resistance.
Main Methods:
- Analysis of Fas expression in Ras-transformed cells.
- Investigation of Fas mRNA levels.
- Assessment of apoptosis induction by Fas ligand.
- Studies on the impact of DNA methylation inhibition.
- Examination of the PI 3-kinase/PKB/Akt pathway signaling.
Main Results:
- Oncogenic H-Ras downregulates Fas expression in fibroblastic and epitheloid cells.
- Ras-transformed cells exhibit resistance to Fas ligand-induced apoptosis.
- Fas mRNA is absent in Ras-transformed cells.
- Inhibition of DNA methylation restores Fas expression.
- H-Ras signaling through the PI 3-kinase pathway downregulates Fas.
Conclusions:
- Oncogenic H-Ras inhibits Fas expression, contributing to apoptosis resistance and potentially promoting tumor growth.
- The PI 3-kinase/PKB/Akt pathway may mediate H-Ras's anti-apoptotic effects, at least partly, through Fas repression.
- H-Ras's oncogenic potential may stem from its ability to simultaneously promote proliferation and inhibit Fas-triggered apoptosis.