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A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence
13:59

A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence

Published on: August 12, 2018

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
PubMed

Insights

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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