Regulation of the Wip1 phosphatase and its effects on the stress response

Wip1 (PPM1D) is a stress responsive PP2C phosphatase that plays a key role in stress signaling. Although originally identified as a gene induced by p53 after genotoxic stress, we now know that Wip1 expression is additionally regulated by other mechanisms. Wip1 is not only a target of p53, but is also a target of other transcription factors, including Estrogen Receptor-alpha and NF-kappaB. Additionally, Wip1 expression is regulated by post-transcriptional mechanisms such as mRNA stabilization and alternative splicing. Upon induction, Wip1 dampens the stress response by dephosphorylating and inactivating proteins such as p53, p38 MAPK, and ATM, usually as part of a negative feedback loop. As a result, Wip1 functions to abrogate cell cycle checkpoints and inhibit senescence, apoptosis, DNA repair, and the production of inflammatory cytokines. Furthermore, Wip1 is overexpressed in several types of human cancers and has oncogenic functions. The regulation of Wip1, the role of Wip1 in stress signaling, and the cooperation of Wip1 with oncogenes in promoting tumorigenesis will be discussed in this review.