Wip1 also inhibits E2F1-induced and UV radiation-induced apoptosis, presumably through p38 MAPK (32, 43). Hershko et al. showed that active E2F1 induces the phosphorylation and activation of p38 MAPK through apoptosis signal-regulating kinase 1 (ASK1), which promotes apoptosis (32). As discussed in Section 3, the authors also identified Wip1 as a target of E2F1. E2F1-induced Wip1 is required for p38 MAPK dephosphorylation, since depletion of Wip1 by siRNA lead to prolonged p38 MAPK phosphorylation. This Wip1-dependent suppression of activated p38 MAPK led to suppression of E2F1-induced apoptosis, as indicated by an increase in the percentage of apoptotic cells when Wip1 is knocked down by siRNA (32). Additionally, Chock et al. showed that BRCA1-IRIS-induced Wip1 inhibited UV radiation-induced apoptosis through inhibition of p38 MAPK/p53 signaling (43). Overexpression of BRCA1-IRIS attenuates p38 MAPK and p53 activation and suppressed cell death after UV radiation exposure, whereas BRCA1-IRIS knock down by siRNA enhances p38 MAPK and p53 activation. Since BRCA1-IRIS upregulates Wip1, the authors conclude that the mechanism by which BRCA1-IRIS inhibits UV radiation-induced apoptosis is through Wip1 inhibition of the p38 MAPK/p53 pathway (43).
