Revised model of oncogene-induced senescence
A: In cells that are insensitive to oncogene-induced senescence, activation of the Ras pathway leads to hyper-activation of well known effector pathways which function to promote tumorigenesis.
B: In sensitive cells the ultimate response to the aberrant activation of the Ras pathway is the initiation of a multi-faceted negative feedback signaling network designed to terminate the oncogenic signal. These signals are triggered by the Raf/MEK/ERK pathway and involve numerous transcriptional and post-translational events, including the suppression of Ras exchange factors, and the up-regulation of Sprouty proteins and RasGAPs, among others. These inhibitory signals, via the consequential suppression of PI3K, can activate Rb and p53 through multiple signals. Thus, we propose that oncogene-induced senescence is mediated by this negative feedback signaling program, that functions along with other known senescence regulators, such as p16 and ARF, to achieve a threshold senescence signal.