The type 2C phosphatase Wip1: An oncogenic regulator of tumor suppressor and DNA damage response pathways

Background: Wip1 is a phosphatase involved in DNA-damage response. Results: Wip1 expression is down-regulated in premature senescent cancer cells. Failure to down-regulate Wip1 expression results in cell death and polyploidy. Conclusion: Wip1 down-regulation is important for maintenance of permanent cell cycle arrest in premature senescent tumor cells. Significance: These findings improve our understanding of the mechanism by which Wip1 promotes tumor progression.

Section: Effects Of Wip1 Overexpression In Premature Senescentmentioning

confidence: 99%

Down-regulation of Wild-type p53-induced Phosphatase 1 (Wip1) Plays a Critical Role in Regulating Several p53-dependent Functions in Premature Senescent Tumor Cells

Crescenzi

Raia

Pacifico

et al. 2013

“…One such DDR-inactivating phosphatase may be the wildtype p53-induced phosphatase 1 (WIP1, or PPM1D; protein phosphatase 1D Mg 2ϩ -dependent, delta isoform), a serine/ threonine phosphatase and a member of the type 2C protein phosphatase family (PP2C) (5,6). Like other PP2C members, WIP1 depends on divalent cations (mainly Mg 2ϩ or Mn 2ϩ ) for its activity.…”

mentioning

confidence: 99%

“…For most of these targets, dephosphorylation by WIP1 is accompanied by reduced function relative to the phosphorylated form. Thus, we have proposed that the primary role of WIP1 may be the dephosphorylation and deactivation of DDR-activated proteins (6,14).…”

mentioning

confidence: 99%

Wild-type p53-induced Phosphatase 1 Dephosphorylates Histone Variant γ-H2AX and Suppresses DNA Double Strand Break Repair

Moon

Lin

Zhang

et al. 2010

Self Cite

In response to DNA double strand breaks, the histone variant H2AX at the break site is phosphorylated at serine 139 by DNA damage sensor kinases such as ataxia telangiectasia-mutated, forming ␥-H2AX. This phosphorylation event is critical for sustained recruitment of other proteins to repair the break. After repair, restoration of the cell to a prestress state is associated with ␥-H2AX dephosphorylation and dissolution of ␥-H2AX-associated damage foci. The phosphatases PP2A and PP4 have previously been shown to dephosphorylate ␥-H2AX. Here, we demonstrate that the wild-type p53-induced phosphatase 1 (WIP1) also dephosphorylates ␥-H2AX at serine 139 in vitro and in vivo. Overexpression of WIP1 reduces formation of ␥-H2AX foci in response to ionizing and ultraviolet radiation and blocks recruitment of MDC1 (mediator of DNA damage checkpoint 1) and 53BP1 (p53 binding protein 1) to DNA damage foci. Finally, these inhibitory effects of WIP1 on ␥-H2AX are accompanied by WIP1 suppression of DNA double strand break repair. Thus, WIP1 has a homeostatic role in reversing the effects of ataxia telangiectasia-mutated phosphorylation of H2AX.

“…The wild-type p53-induced phosphatase Wip1 (PP2C␦ or PPM1D), as the best studied example of a DNA damage response phosphatase, has been shown to bind and dephosphorylate a number of key DNA damage response factors, including ATM, ␥-H2AX, Chk1, Chk2, and p53. Wip1 expression is up-regulated after DNA damage in a p53-dependent manner and is required for efficient checkpoint inactivation and recovery (5). In addition to protein dephosphorylation, ubiquitin and proteasome-mediated degradation of key checkpoint activators has also been linked to checkpoint recovery.…”

mentioning

confidence: 99%

Greatwall and Polo-like Kinase 1 Coordinate to Promote Checkpoint Recovery

Peng

Fisher

2011

Checkpoint recovery upon completion of DNA repair allows the cell to return to normal cell cycle progression and is thus a crucial process that determines cell fate after DNA damage. We previously studied this process in Xenopus egg extracts and established Greatwall (Gwl) as an important regulator. Here we show that preactivated Gwl kinase can promote checkpoint recovery independently of cyclin-dependent kinase 1 (Cdk1) or Plx1 (Xenopus polo-like kinase 1), whereas depletion of Gwl from extracts exhibits no synergy with that of Plx1 in delaying checkpoint recovery, suggesting a distinct but related relationship between Gwl and Plx1. In further revealing their functional relationship, we found mutual dependence for activation of Gwl and Plx1 during checkpoint recovery, as well as their direct association. We characterized the protein association in detail and recapitulated it in vitro with purified proteins, which suggests direct interaction. Interestingly, Gwl interaction with Plx1 and its phosphorylation by Plx1 both increase at the stage of checkpoint recovery. More importantly, Plx1-mediated phosphorylation renders Gwl more efficient in promoting checkpoint recovery, suggesting a functional involvement of such regulation in the recovery process. Finally, we report an indirect regulatory mechanism involving Aurora A that may account for Gwl-dependent regulation of Plx1 during checkpoint recovery. Our results thus reveal novel mechanisms underlying the involvement of Gwl in checkpoint recovery, in particular, its functional relationship with Plx1, a well characterized regulator of checkpoint recovery. Coordinated interplays between Plx1 and Gwl are required for reactivation of these kinases from the G 2 /M DNA damage checkpoint and efficient checkpoint recovery.Various types of DNA damage are frequently induced by both endogenous and exogenous agents, posing enormous threats to the cell and its genomic integrity. The cell responds to the occurrence of DNA damage by engaging DNA repair machineries to restore normal DNA structure and by activating the checkpoint mechanism through complex networks of signal transduction to halt cell cycle progression (1). Eventually, if the cell successfully repairs its damaged DNA, checkpoints are to be turned off to allow resumption of cell cycle progression. This process, termed "checkpoint recovery," is contrasted by permanent checkpoint arrest or programmed cell death (senescence or apoptosis, respectively), both of which are believed to result from unrepaired DNA damage and sustained DNA damage signaling (2, 3).The turn-off mechanism of the DNA damage checkpoint during recovery is poorly understood. Existing studies suggest that protein dephosphorylation and proteolysis are effective ways to deactivate checkpoint signaling. The involvement of numerous serine/threonine phosphatases in checkpoint recovery is not surprising given the crucial role of protein phosphorylation and kinase cascades in checkpoint activation (4). The wild-type p53-induced phosphatase Wip1 (PP2C␦ or PP...