The roles of p16INK4a
/RB-pathway in senescence cell cycle arrest. In proliferating cells, the effects of mitogenic signals in ROS production are counterbalanced by E2F/DP activity. However, when E2F/DP activity is shut down by fully activated pRb, mitogenic signaling, in turn, increases the level of ROS and elicits a positive feedback activation of ROS/PKC-δ signaling pathway. Elevated levels of p16INK4a therefore establish an autonomous activation of ROS/PKC-δ signaling, leading to an irrevocable block to cytokinesis in human senescent cells.