Disease relevance of PPM1D

• PPM1D is a potential target for 17q gain in neuroblastoma [1].
• Immunohistochemistry revealed strong expression of PPM1D in 148 (88%) of 168 and CDK6 in 50 (30%) of 169 medulloblastomas [2].
• Male PPM1D null mice show a modest reduction in longevity, reduced serum insulin-like growth factor 1 (IGF-1) levels, and reduced body weight compared to WT mice [3].
• Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23 [4].
• Among the 135 primary breast carcinomas further examined, a significant association was found between the Wip1 overexpression and negative staining for p53 (P value = 0.057), indicating that the tumors are wild-type for p53 [5].

High impact information on PPM1D

• Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity [6].
• The gene encoding PPM1D (PPM1D, at 17q22/q23) is amplified in human breast-tumor cell lines and in approximately 11% of primary breast tumors, most of which harbor wildtype p53 [6].
• Retrovirus-mediated overexpression of PPM1D reduced p53 phosphorylation at these sites, abrogated Ras-induced apoptosis and partially rescued cells from cell-cycle arrest [6].
• Inactivation of p38 MAPK (the product of Mapk14) in vivo by gene targeting or by PPM1D overexpression expedited tumor formation after injection of mouse embryo fibroblasts (MEFs) expressing E1A+Ras into nude mice [6].
• Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair [7].

Chemical compound and disease context of PPM1D

• We found that PPM1D, encoding a serine/threonine protein phosphatase, lies within an epicenter of the region at 17q23 that is amplified in breast cancer [4].
• Thus, we speculate that PPM1D promotes breast tumor growth both by inhibiting p53 activity and by enhancing steroid hormone receptor action [8].
• Consistent with this, the transcriptional activity of endogenous PR in MCF-7 breast cancer cells was preferentially inhibited by small interfering RNA for PPM1D; SB202190 failed to reverse the inhibition [8].
• In vitro, inactivation of Wip1 reduces the proliferation rate of breast cancer cell lines and enhances growth inhibition caused by doxorubicin [9].

Biological context of PPM1D

• PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation [7].
• PPM1D is an oncogene in transformation assays and is amplified or overexpressed in several human tumor types [10].
• Thus, PPM1D may inhibit BER by dephosphorylating UNG2 to facilitate its inactivation after completion of DNA repair [10].
• Point mutations that inactivate PPM1D phosphatase activity abrogate BER suppression, indicating that dephosphorylation by PPM1D is important for BER inhibition [10].
• Moreover, down-regulation of PPM1D by transfection of an antisense oligonucleotide suppressed the growth of NB cell lines to a remarkable degree, at least partly by participating in a process leading to apoptotic cell death [1].

Anatomical context of PPM1D

• In turn, deletion of the inhibitory ATM phosphatase, Wip1, results in ATM up-regulation and suppression of Emu-myc-induced B cell lymphomas [11].
• Reduced expression of Wip1 and BRCA-2 region transcription unit CG005 was significantly correlated with poorer differentiation of HCCs, and mRNA expression of these genes was significantly reduced in HCCs associated with portal vein involvement compared with HCCs without such involvement [12].

Associations of PPM1D with chemical compounds

• PPM1D dephosphorylation of UNG2 at phosphothreonine 6 is associated with reduced UNG2 activity [10].
• Wip1 selectively inactivates p38 by specific dephosphorylation of its conserved threonine residue [13].
• We found that Wip1 is also inducible by other environmental stresses, such as anisomycin, H(2)O(2) and methyl methane sulfonate [13].
• Development of a Substrate-Based Cyclic Phosphopeptide Inhibitor of Protein Phosphatase 2Cdelta, Wip1 [14].

Physical interactions of PPM1D

• The p53-induced oncogenic phosphatase PPM1D interacts with uracil DNA glycosylase and suppresses base excision repair [10].

Enzymatic interactions of PPM1D

• PPM1D also dephosphorylates p53 at phospho-Ser 15 [7].

Regulatory relationships of PPM1D

• Wip1 expression also suppresses both p53-mediated transcription and apoptosis in response to UV radiation [13].
• Dual roles for the phosphatase PPM1D in regulating progesterone receptor function [8].

Other interactions of PPM1D

• Here, we demonstrate that PPM1D interacts with the nuclear isoform of uracil DNA glycosylase, UNG2, and suppresses base excision repair (BER) [10].
• In this review we summarize the structural studies of the amplicon that have been carried out, we outline the evidence implicating the RPS6KB1, TBX2, and PPM1D genes as oncogenes, and we describe some of the other candidate oncogenes from the region [15].
• Overexpression of Wip1 was inversely correlated with that of active (phosphor-) p38 MAPK (P = 0.007) [5].
• Interestingly, PPM1D amplification was associated with ERBB2 expression (p=0.0001) thus implying that PPM1D aberrations occurs in tumours with poor prognosis [16].
• In turn, overexpression of Wip1 was sufficient to reduce activation of the ATM-dependent signaling cascade after DNA damage [17].

Analytical, diagnostic and therapeutic context of PPM1D

• Among 15 candidate genes within the 17q21-q24 region, we found significantly elevated expression of PPM1D and APPBP2, and their heightened expression correlated negatively with disease-free survival (P = 0.0090, log-rank test adjusted for multiple comparisons) [18].
• PPM1D copy number analysis showed amplification in 11% (13/117) of the tumours and quantitative real-time RT-PCR revealed a significant correlation (p=0.0148) between PPM1D amplification and increased expression [16].
• Three-dimension homology models of Wip1 with bound substrate peptides were constructed, and site-directed mutagenesis was performed to confirm the importance of specific residues for substrate recognition [19].

References