A negative feedback signaling network underlies oncogene-induced senescence.
Oncogene-induced senescence functions to limit tumor development. However, a complete understanding of the signals that trigger this type of senescence is currently lacking. We found that mutations affecting NF1, Raf, and Ras induce a global negative feedback response that potently suppresses Ras and/or its effectors. Moreover, these signals promote senescence by inhibiting the Ras/PI3K pathway, which can impact the senescence machinery through HDM2 and FOXO. This negative feedback program is regulated in part by RasGEFs, Sprouty proteins, RasGAPs, and MKPs. Moreover, these signals function in vivo in benign human tumors. Thus, the ultimate response to the aberrant activation of the Ras pathway is a multifaceted negative feedback signaling network that terminates the oncogenic signal and participates in the senescence response.
Courtois-Cox
Stéphanie
S
Genetics Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 458c NRB, 77 Louis Pasteur Avenue, Boston, Massachusetts 02115, USA.
Genther Williams
Sybil M
SM
Reczek
Elizabeth E
EE
Johnson
Bryan W
BW
McGillicuddy
Lauren T
LT
Johannessen
Cory M
CM
Hollstein
Pablo E
PE
MacCollin
Mia
M
Cichowski
Karen
K
D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence; D005246:Feedback; D016514:Genes, Neurofibromatosis 1 / Q000502:physiology; D016161:Genes, Retinoblastoma / Q000502:physiology; D016158:Genes, p53 / Q000502:physiology; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000473:pathology; D048490:raf Kinases / Q000502:physiology
D019869:Phosphatidylinositol 3-Kinases; D048490:raf Kinases