The inhibition of apoptosis by Wip1 also reflects its negative feedback on the p38 MAPK/p53 pathway. Takekawa et al. showed that Wip1-overexpressing A549 cells (p53-proficient) exhibited a significant decrease in apoptosis after UV radiation compared to control cells, and this decrease was dependent on Wip1 phosphatase activity, since over-expression of a Wip1 phosphatase dead mutant had no effect (4). Furthermore, Schito et al. illustrated that the DP thymocyte population (double-positive for CD4 and CD8) and not the DN population (double-negative for CD4 and CD8) from Wip1−/− mice exhibited a higher rate of apoptosis (68). The relevance to Wip1 negative feedback on the p38 MAPK/p53 pathway resides in the fact that active p38 MAPK facilitates early thymocyte differentiation, but its inactivation (and consequent inactivation of p53) is necessary for thymocyte differentiation from DN to DP. Hence, persistent activation of p38 MAPK in mice deficient in Wip1 led to both defective T-cell maturation to the DP state and increased apoptosis in the DP population due to higher levels of p53 activation (68).
