p53-dependent apoptosis is well characterized and involves numerous signaling proteins to induce the caspase-dependent and mitochondrial apoptotic pathways (reviewed in (64)). Since p53 is a central regulator of apoptosis, Wip1 inhibition of p53 by direct dephosphorylation and through the inactivation of upstream proteins promotes cell survival by suppressing apoptosis (Figure 4). For example, Wip1 suppresses myc-induced apoptosis through inhibition of the ATM-p53 apoptotic pathway and thereby promotes tumorigenesis. Myc-induced lymphoma tumors from Wip1−/− mice exhibited elevated levels of apoptosis compared to control mice, and the additional deletion of ATM or p53 lowered the level of apoptosis to values similar to those seen in tumors from ATM−/− or p53−/− mice (9). Thus, Wip1 inactivates ATM signaling to p53 and promotes cell survival when myc expression levels are high. Additionally, intestinal stem cells from Wip1−/− mice exhibited higher levels of apoptosis that correlated with higher levels of activated p53, thus demonstrating that Wip1 inhibits intestinal stem cell apoptosis through inhibition of p53 (65). Furthermore, Kong et al. showed that depletion of Wip1 in MCF-7 breast cancer cells lead to higher levels of
