MDMX, like Wip1, is a negative regulator of p53. Upregulation of MDMX leads to an autoregulatory negative feedback loop, since MDMX in complex with MDM2 enhances ubiquitination and degradation of the p53 protein (48, 49). Because of its negative regulation of p53, MDMX facilitates down-regulation of the DNA damage response after stress and is thought to promote tumorigenesis. The finding that Wip1 enhances the negative effects of MDMX on p53 signaling indicates that Wip1 and MDMX cooperate to reduce p53 activity and stability. Zhang et al. showed that Wip1 directly dephosphorylated MDMX on serine 403, a site that is phosphorylated by ATM after genotoxic stress (Table 1), and additionally inhibited phosphorylation of MDMX of S342 and S376 by an indirect mechanism (50). Overexpression of Wip1 reduced the levels of pS403-MDMX after NCS treatment, indicating that Wip1 inhibits MdmX phosphorylation. Co-immunoprecipitation 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
