Figure 9.
Cross talk between the p53 and p16 pathways through DDR. Although oncogenic Ras signaling has a potential to activate p16Ink4a gene expression, this effect is initially counteracted by an elevation of DNMT1 level and thereby causes a strong proliferative burst, resulting in the accumulation of DNA damage. The accumulation of DNA damage activates ROS production, which in turn blocks DNMT1 gene expression, thereby causing epigenetic derepression of p16Ink4a gene expression and thus senescence cell cycle arrest. This pathway is counterbalanced by the p53 pathway because p53 is immediately activated by DNA damage and blocks proliferation of damaged cells that cause further accumulation of DNA damage. Thus, the DDR pathway activating p16Ink4a expression is accelerated in the event of p53 inactivation.