The predicted 605-amino acid PPM1D protein contains 2 putative nuclear localization signals and 3 regions conserved in serine/threonine PP2C phosphatases. In vitro, recombinant PPM1D showed phosphatase activity. It displayed characteristics of a type 2C phosphatase, including magnesium dependence and relative insensitivity to okadaic acid.
NCBI Summary:
The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell stress response pathways. The expression of this gene is induced in a p53-dependent manner in response to various environmental stresses. While being induced by tumor suppressor protein TP53/p53, this phosphatase negatively regulates the activity of p38 MAP kinase, MAPK/p38, through which it reduces the phosphorylation of p53, and in turn suppresses p53-mediated transcription and apoptosis. This phosphatase thus mediates a feedback regulation of p38-p53 signaling that contributes to growth inhibition and the suppression of stress induced apoptosis. This gene is located in a chromosomal region known to be amplified in breast cancer. The amplification of this gene has been detected in both breast cancer cell line and primary breast tumors, which suggests a role of this gene in cancer development. [provided by RefSeq, Jul 2008]
General function
Enzyme
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Cellular localization
Nuclear
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Ovarian function
Luteinization
Comment
WIP1 phosphatase suppresses the DNA damage response during G2/prophase arrest in mouse oocytes. Leem J et al. (2018) Maternal DNA damage during meiosis causes genetic abnormalities that can lead to infertility, birth defects, and abortion. While DNA damage can rapidly halt cell cycle progression and promote DNA repair in somatic cells, mammalian oocytes are unable to mount a robust G2/prophase arrest in response to DNA damage unless damage levels are severe. Here we show that inhibition of WIP1 phosphatase enhances the ability of oocytes to respond to DNA damage. We found that WIP1 was expressed constantly during meiotic maturation, and that inhibition of WIP1 activity did not impair meiotic maturation. However, oocytes in G2/prophase were sensitized to DNA damage following WIP1 inhibition, not only increasing γ-H2AX level and ATM phosphorylation, but also decreasing entry into meiosis. Moreover, WIP1 inhibition significantly promoted the repair of damaged DNA during G2/prophase arrest, suggesting that WIP1 suppresses DNA repair in oocytes. Therefore, our results suggest that WIP1 is a key suppressor of the DNA damage response during G2/prophase arrest in mouse oocytes.//////////////////
Expression regulated by
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Ovarian localization
Oocyte, Granulosa, Luteal cells
Comment
Chaffin CL, et al 2003 reported dynamics of Myc/Max/Mad Expression during Luteinization of Primate Granulosa Cells in Vitro: Association with Periovulatory Proliferation.
Granulosa cell luteinization involves the attenuation of gonadotropin-induced proliferation. Although recent evidence indicates that primate granulosa cells stop dividing within 12 h of an ovulatory stimulus, early events in cell cycle arrest remain unknown. In the current study an in vitro model of primate granulosa cell luteinization is established that allows assessment of early events in terminal differentiation. A luteinizing dose of human chorionic gonadotropin (hCG) results in a secondary rise in proliferation before cell cycle arrest that is paralleled by a transient increase in the expression of c-Myc. In contrast, the c-Myc antagonists Mad1, Mad4, and Mxi1 are transiently repressed by hCG. Max, the common dimerization partner for Myc and Mad, is similarly repressed by hCG, suggesting that changes in the expression of this gene may further regulate the activity of Myc and Mad. To determine whether other cell cycle regulatory families are involved in luteinization, the expression of p53 and the wild-type p53-inducible phosphatase (wip1) was examined. Similar to Mad and Max, p53 and wip1 are transiently repressed by hCG, suggesting that the p53 and Mad pathways have either parallel or cooperative roles in luteinization. Thus, luteinization of primate granulosa cells is preceded by a burst of proliferation that is regulated by changes in the relative levels of c-Myc, Max, and Mad as well as p53.