Figure 1 - Senescence requires a mitogenic signal under conditions of cellular stress.

During low-stress conditions, mitogens inactivate Rb and therefore activate E2F to induce proliferation. The authors suggest that as part of its S-phase promoting activity, E2F activation decreases ROS levels by regulating genes involved in ROS production and metabolism. Therefore, under these settings, mitogenic signals are matched by low levels of ROS and proliferation ensues. In conditions of high cellular stress, however, tumour suppressor genes such as p53 and p16^INK4a are activated, leading to inhibition of E2F, through Rb. In this setting, mitogenic stimulation is not accompanied by E2F activation and ROS levels accumulate to senescence-promoting levels. The authors suggest that high levels of ROS also induce a PKC-mediated block of cytokinesis as part of the senescence programme.