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Novel role of Wip1 in p53-mediated cell homeostasis under non-stress conditions

The wild-type p53-induced phosphatase 1 (Wip1, also-called PPM1D) is a type 2C protein phosphatase (PP2C™) that requires Mg2+ or Mn2+ for catalytic efficacy and is insensitive to phosphatase inhibitor okadaic acid. Wip1 was originally identified as a p53-induced gene in response to ionizing radiation.1 Subsequent studies indicated that Wip1 acts as a homeostatic regulator of the DNA damage response, facilitating the return of cells to a normal pre-stress state following repair of damaged DNA.2,3 In addition, Wip1 inhibits several tumor suppressor pathways, including ATM-CHK2-p53 and p38MAPK-p53.2 Furthermore, Wip1 is found to be aberrantly expressed in several types of human cancers, and Wip1-null mice are resistant to cancer.4,5 These unique features make Wip1 an oncogenic phosphatase and a promising drug target for cancer therapy. 
 
The p53 tumor suppressor plays a pivotal role in preserving the integrity of the genome and in preventing cancer development. The importance of p53 in this process is demonstrated by the fact that inactivation of p53 occurs in over 50% of human cancers, and loss of p53 function is known to be essential for carcinogenesis.6 In response to various cellular stresses, p53 is activated and functions as a sequence-specific DNA binding transcriptional factor to induce its downstream targets, which mediate cell cycle arrest, DNA repair, and apoptosis.7 Consistently, numerous studies have shown that p53 exerts pivotal roles in guarding genomic stability under stress conditions.6 
 
Most studies on Wip1 have been focused on how Wip1 facilitates the return of cells to homeostasis after DNA damage. The study by Park et al. convincingly showed that under non-stress conditions, Wip1 plays a critical role in p53-mediated cell homeostasis. Specifically, they showed that Wip1 is able to induce G2/M arrest in cells with wild-type p53 but not the ones with mutant p53. In addition, Wip1-mediated G2/M arrest is able to decrease cell death in mouse embryonic fibroblasts. To uncover the underlying mechanism, they showed that Wip1 is able to decrease Cdc2 kinase activity by increasing phosphorylation of the inhibitory tyrosine-15 of Cdc2. Together, the current studies suggest that, under non-stress conditions, Wip1 collaborates with p53 to induce G2/M arrest, which enables normal cells to be ready for mitosis and avoid mitotic catastrophe. Similarly, this regulation favors cancer cells with wild-type p53 to escape from the mitotic checkpoint and, thus, promotes tumor formation. Therefore, targeting Wip1 in cancer cells with wild-type p53 may lead to a shorter G2 preparation and render cell death via mitotic catastrophe. In support of this notion, Wip1 inhibition has been shown to decrease cancer cell proliferation in a p53-dependent manner.8,9 
 
At this point, it still remains unclear how Wip1 induces G2/M arrest in cells with wild-type p53. It will be interesting to address how Wip1 increases the phosphorylation of the inhibitory tyrosine-15 of Cdc2. Additionally, is there any other mechanism by which Wip1 inhibits Cdc2 kinase activity? Finally, it will also be interesting to address how p53 modulates Wip1-induced G2/M arrest under non-stress conditions, which will advance our understanding of how p53 makes cell fate decisions. Although much work remains to be explored, these findings clearly highlight a novel role of Wip1 in p53 guarding homeostasis under non-stress conditions. The work also shed a light on a novel mechanism by which Wip1, in addition to its ability to inhibit p53, promotes tumorigenesis by helping cancer cells escape from the mitotic checkpoint.