experiments showed that Wip1 and MdmX physically interact, and recombinant Wip1 was able to dephosphorylate a phosphopeptide corresponding to MdmX (pS403). Furthermore, Wip1−/− mouse embryonic fibroblasts (MEFs) treated with NCS had reduced levels of MdmX compared to Wip1+/+ MEFs (which was dependent on ATM), and overexpression of Wip1 inhibited MdmX degradation after NCS. Additionally, Wip1 inhibits p53 through MdmX and enhances the interaction of MdmX with ubiquitin-specific peptidase 7 (USP7), which deubiquitinates and stabilizes MdmX (50). Therefore, Wip1 dephosphorylation of MdmX and enhancement of MdmX-dependent p53 degradation provides an additional mechanism by which Wip1 returns the cell to homeostasis after stress and promotes tumorigenesis (Figure 4).
