A negative feedback signaling network underlies oncogene-induced senescence
Stéphanie Courtois-Cox1, Sybil M Genther Williams, Elizabeth E Reczek
1Genetics Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 458c NRB, 77 Louis Pasteur Avenue, Boston, Massachusetts 02115, USA.
Cancer Cell
|December 13, 2006
Summary
Mutations in NF1, Raf, and Ras trigger a negative feedback response that suppresses the Ras pathway and promotes oncogene-induced senescence. This pathway involves Ras/PI3K, HDM2, and FOXO, functioning in human tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Biology
Background:
- Oncogene-induced senescence is a critical tumor suppression mechanism.
- The precise signals initiating this senescence are not fully understood.
Purpose of the Study:
- To elucidate the signaling pathways that trigger oncogene-induced senescence.
- To investigate the role of negative feedback in Ras-driven tumor suppression.
Main Methods:
- Analysis of mutations in NF1, Raf, and Ras.
- Investigation of the Ras/PI3K pathway and its effectors (HDM2, FOXO).
- In vivo studies in benign human tumors.
Main Results:
- Mutations in NF1, Raf, and Ras induce a global negative feedback response.
- This feedback suppresses Ras signaling and promotes senescence by inhibiting the Ras/PI3K pathway.
- Negative feedback is regulated by RasGEFs, Sprouty proteins, RasGAPs, and MKPs.
- These findings were validated in benign human tumors.
Conclusions:
- Aberrant Ras pathway activation elicits a complex negative feedback network.
- This network terminates oncogenic signals and contributes to senescence.
- Understanding this feedback loop is crucial for cancer therapy development.
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