Most types of DNA damage lead to activation of p53 and subsequent induction of Wip1, but the signaling pathways leading to p53 activation may differ, depending on the nature of the damage. A good example of this is the difference in signaling to p53 after UV radiation and IR exposure. Following exposure to IR, the PI3K-like kinase ATM becomes activated through autophosphorylation and subsequently phosphorylates p53 on Ser15, leading to its activation (20). This differs from p53 activation after UV radiation exposure, which involves phosphorylation of p53 on Ser33 and Ser46 by p38 MAPK (21). Wip1 expression is induced by UV radiation exposure (17), and not surprisingly, p38 is required for induction of Wip1 post-UV radiation (and not IR) exposure. This was shown by the fact that an inhibitor of p38 MAPK reduced Wip1 induction in a dose-dependent manner in UV radiation-exposed (and not IR-exposed) A549 cells (Figure 2) (4). Therefore, p53 transcriptionally activates PPM1D after genotoxic stress, and the upstream mechanism depends on the type of genotoxic stress.
