title: A negative feedback signaling network underlies oncogene-induced senescence.
abstract: 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.
authors.affiliation: Genetics Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 458c NRB, 77 Louis Pasteur Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Courtois-Cox
authors.forename: Sybil M
authors.initials: SM
authors.lastname: Genther Williams
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Reczek
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Johnson
authors.forename: Lauren T
authors.initials: LT
authors.lastname: McGillicuddy
authors.forename: Cory M
authors.initials: CM
authors.lastname: Johannessen
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Hollstein
authors.forename: Mia
authors.initials: M
authors.lastname: MacCollin
authors.forename: Karen
authors.initials: K
authors.lastname: Cichowski
mesh_terms: 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
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D048490:raf Kinases