The phosphatase Wip1 is induced by a variety of types of stress, and, although several mechanisms regulating Wip1 expression have been described recently, it is likely that many aspects of the regulation of Wip1 remain to be discovered. Although Wip1 was originally described as a p53-induced protein, recent studies have shown that p53-independent regulation of Wip1 also plays a critical role in the cellular response to stress. p53-independent mechanisms for Wip1 regulation may be especially important in tumor cells. Many of the tumors that overexpress Wip1 also lack over-expressed (mutant) p53, suggesting that they possess wild-type but functionally inactive p53. This is not surprising given that inhibition of p53, through direct dephosphorylation and stabilization of its negative regulators Mdm2 and MdmX, is an important role for Wip1. As described in this review, the stabilization of Wip1 mRNA by BRCA1-IRIS and transcriptional upregulation by CREB and NF-kappaB provide examples of p53-independent mechanisms leading to increased Wip1 levels.
