Wild-type p53-induced phosphatase 1 (Wip1), which is a member of the PP2C (the type 2C family of protein phosphatases) family of phosphatases, is emerging as a direct p53 target in response to stresses (1). Based on the critical role of p53 in regulating tumor development, previous studies mainly focused on the role of Wip1 in controlling tumor transformation (2) and found that Wip1 can regulate tumorigenesis through attenuating several stress-induced kinases activities (3). With newly emerging functions of Wip1 identified, more and more recent studies also suggested the critical role of Wip1 in a wide range of conditions such as aging (4) and adult neurogenesis (2). Since Wip1-deficient mice presented abnormal lymphoid tissue structure and increased susceptibility to pathogens (5), the role of Wip1 in regulating immunity has also been investigated. In this review, we will give a brief introduction of Wip1 in regulating several signaling pathway networks in the context of immunity to deepen our knowledge on this important phosphatase.

Wip1 was discovered in 1997 by Fiscella and is a direct p53 target, which is rapidly induced by ionizing radiation in p53-positive cells (1). Primary studies focused on the role of Wip1 in DNA damage repair and suggested that Wip1 serves as a negative feedback regulator for DNA damage checkpoints (6–8). Several key molecules within the DNA-damage response network have been shown to be direct targets of Wip1 including p38 mitogen-activated protein kinase (MAPK) (7), ataxia-telangiectasia mutated (ATM) (8, 9), and cell cycle checkpoint kinase 2 (10). It is also suggested that Wip1 is required for controlling H2A histone family in several cell lines after DNA damage in vitro (11–13). Since the function of DNA damage checkpoints is to preserve the genomic fidelity of proliferating cells and to prevent cellular transformation (6), the possible role of Wip1 in tumorigenesis is further studied. Wip1 deficiency can lead to the activation of p53, which plays a critical role in tumor suppression and the enhanced ATM/p53-mediated apoptosis (14), thereby resulting in significantly attenuated tumorigenesis in two tumor models including c-myc-induced lymphoma (14, 15) and adenomatosis polyposis coli (Min) intestinal tumorigenesis (3). The deletion of Wip1 can also protect mice from mammary tumorigenesis in MMTV-Erbb2 and MMTV-HRAS1 mice in a p38 MAPK-dependent manner (16, 17). Moreover, other types of oncogenes such as products of Cdkn2a gene, p16^lnk4a, and p19^arf are also elevated in the absence of Wip1 and promote tumor suppression in mammary gland tumors. Consistent with these results, overexpression of Wip1 was reported in many human cancers (2). All these results further support the role of Wip1 in regulating tumorigenesis. Interestingly, Wip1 overexpression in mice does not lead to spontaneous tumor appearance (18), and Wip1 overexpression in the mammary gland epithelium is also not sufficient to induce cancer (2, 19). Therefore, Wip1 may actually not act as a cancer-initiating oncogene on its own but provides advantages for tumor development through its function on multiple target molecules. Despite substantial evidence over the last decade that defines Wip1 as an onco-protein, recent studies have also shed lights on the role of Wip1 in regulating other normal and/or pathophysiological process due to its wide range of substrates, such as autophagy (20), aging (21), adult neurogenesis (4), and liver regeneration (22).

Primary evidence for the involvement of Wip1 in inflammation comes from the study, which showed that Wip1-deficient mice presented abnormal lymphoid structure, with increased susceptibility to ulcerated skin lesions and pathogens (5). We further demonstrated that Wip1 can modulate neutrophil function to regulate intestinal ischemia/reperfusion injury (26, 37) and inflammatory bowel diseases in a p38 MAPK-dependent manner (25). Moreover, Wip1 can also participate in neuro-inflammation through controlling tumor necrosis factor (TNF)-α synthesis (38) or NF-κB function (39). Further studies identified the interplay between Wip1 and NF-κB which plays an important role in cellular inflammatory response. NF-κB can activate WIP1 gene expression. The WIP1 gene has a conserved κB-binding site and the upregulation and inhibition of NF-κB function leads to increased and decreased Wipl expression, respectively. It was confirmed that the p65 subunit of NF-κB could directly bind to the upstream promoter of WIP1 gene to regulate its biological activity. On the other hand, Wipl can negatively regulate the expression of NF-κB. The inhibition of Wip1 can lead to the enhanced activation of NF-κB. The mRNA expression of NF-κB target molecules such as TNF-α in Wip1-deficient HeLa cells was increased, and the levels of NF-κB-dependent pro-inflammatory cytokines were also increased in Wip1-deficient splenic cells. Moreover, splenocytes in Wip1-deficient mice presented a pro-inflammatory phenotype with increased ratio of cells expression CD80, MHC II, and CD40. On the contrary, HeLa cells with overexpression of Wip1 expressed much more decreased level of NF-κB-dependent cytokines. Detailed mechanism studies further showed that Wipl can inhibit the recruitment of NF-κB to co-transcription factor p300 by dephosphorylating P65 (Ser536) of NF-κB, leading to the inability of NF-κB to effectively activate the downstream pathway. In addition, Wipl can also inhibit the function of NF-κB by negative regulation of p38, resulting in reduced expression of NF-κB-dependent inflammatory factors such as IL-1, 6, and 8. Therefore, mechanism for Wip1 in regulating inflammation can be described as follows: the activation of NF-κB by inflammatory signals can increase the expression of Wip1, which acts as a negative feedback regulator to inhibit NF-κB signaling and maintain the cell homeostasis through turning off the inflammatory process (Figure 2).

Wip1 has long been recognized as an oncotarget, and therapeutic strategies to modulate its activity such as the use of Wip1 inhibitor have also been suggested to be a promising treatment for patients with tumors. Despite the intrinsic interplay between Wip1 and other signaling pathways in tumor cells, substantial experimental evidence has identified the critical role of Wip1 in regulating immunity through mastering immune cell development and function through numerous signaling pathways including p38 MAPK, STAT1, NF-κB, and ATM/p53. Although there is no direct evidence for Wip1 in controlling immune system to promote tumor development, it is possible that Wip1 can modulate tumor transformation through regulating immune system because of the tight relationship between inflammation and tumorigenesis.

Despite in regulating in immune system and tumorigenesis, Wip1 also displays a broader function in aging, liver regeneration, and adult neurogenesis. All these facts raise the concern that although Wip1 can regulate numerous molecular networks, its function largely depends on cell type, the condition, and the age of organism. Moreover, due to its potent anti-inflammatory and anti-aging function, strategies to increase Wip1 expression to control inflammation and aging should also take into account possible pro-tumorigenic effect of Wip1 activation. Therefore, future studies on understanding the crosstalk between Wip1 and multiple signaling pathways in different cells, as well as in whole organism level (i.e., immune system and secretion), may help to better develop potential therapeutic strategies based on phosphatase Wip1.

J-FD and W-XG suggested this topic; YZ and J-PJ retrieved the relevant literature; J-FD and X-FS wrote the paper.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.