PPM1D

Gene Summary

Gene:PPM1D; protein phosphatase, Mg2+/Mn2+ dependent 1D
Aliases: WIP1, PP2C-DELTA
Location:17q23.2
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]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein phosphatase 1D
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PPM1D (cancer-related)

Wang P, Ye JA, Hou CX, et al.
Combination of lentivirus-mediated silencing of PPM1D and temozolomide chemotherapy eradicates malignant glioma through cell apoptosis and cell cycle arrest.
Oncol Rep. 2016; 36(5):2544-2552 [PubMed] Free Access to Full Article Related Publications
Temozolomide (TMZ) is approved for use as first-line treatment for glioblastoma multiforme (GBM). However, GBM shows chemoresistance shortly after the initiation of treatment. In order to detect whether silencing of human protein phosphatase 1D magnesium dependent (PPM1D) gene could increase the effects of TMZ in glioma cells, glioma cells U87-MG were infected with lentiviral shRNA vector targeting PPM1D silencing. After PPM1D silencing was established, cells were treated with TMZ. The multiple functions of human glioma cells after PPM1D silencing and TMZ chemotherapy were detected by flow cytometry and MTT assay. Significantly differentially expressed genes were distinguished by microarray-based gene expression profiling and analyzed by gene pathway enrichment analysis and ontology assessment. Western blotting was used to establish the protein expression of the core genes. PPM1D gene silencing improves TMZ induced cell proliferation and induces cell apoptosis and cell cycle arrest. When PPM1D gene silencing combined with TMZ was performed in glioma cells, 367 genes were upregulated and 444 genes were downregulated compared with negative control. The most significant differential expression pathway was pathway in cancer and IGFR1R, PIK3R1, MAPK8 and EP300 are core genes in the network. Western blotting showed that MAPK8 and PIK3R1 protein expression levels were upregulated and RB1 protein expression was decreased. It was consistent with that detected in gene expression profiling. In conclusion, PPM1D gene silencing combined with TMZ eradicates glioma cells through cell apoptosis and cell cycle arrest. PIK3R1/AKT pathway plays a role in the multiple functions of glioma cells after PPM1D silencing and TMZ chemotherapy.

Canevari RA, Marchi FA, Domingues MA, et al.
Identification of novel biomarkers associated with poor patient outcomes in invasive breast carcinoma.
Tumour Biol. 2016; 37(10):13855-13870 [PubMed] Related Publications
Breast carcinoma (BC) corresponds to 23 % of all cancers in women, with 1.38 million new cases and 460,000 deaths worldwide annually. Despite the significant advances in the identification of molecular markers and different modalities of treatment for primary BC, the ability to predict its metastatic behavior is still limited. The purpose of this study was to identify novel molecular markers associated with distinct clinical outcomes in a Brazilian cohort of BC patients. We generated global gene expression profiles using tumor samples from 24 patients with invasive ductal BC who were followed for at least 5 years, including a group of 15 patients with favorable outcomes and another with nine patients who developed metastasis. We identified a set of 58 differentially expressed genes (p ≤ 0.01) between the two groups. The prognostic value of this metastasis signature was corroborated by its ability to stratify independent BC patient datasets according to disease-free survival and overall survival. The upregulation of B3GNT7, PPM1D, TNKS2, PHB, and GTSE1 in patients with poor outcomes was confirmed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in an independent sample of patients with BC (47 with good outcomes and eight that presented metastasis). The expression of BCL2-associated agonist of cell death (BAD) protein was determined in 1276 BC tissue samples by immunohistochemistry and was consistent with the reduced BAD mRNA expression levels in metastatic cases, as observed in the oligoarray data. These findings point to novel prognostic markers that can distinguish breast carcinomas with metastatic potential from those with favorable outcomes.

Nikbakht H, Panditharatna E, Mikael LG, et al.
Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma.
Nat Commun. 2016; 7:11185 [PubMed] Free Access to Full Article Related Publications
Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M--including H3.2K27M--mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships.

Fukami S, Riemenschneider MJ, Kohno M, Steiger HJ
Expression and gene doses changes of the p53-regulator PPM1D in meningiomas: a role in meningioma progression?
Brain Tumor Pathol. 2016; 33(3):191-9 [PubMed] Related Publications
The aim of our study was to clarify the expression and gene copy number levels of protein phosphatase 1D magnesium-dependent, delta isoform (PPM1D), which is thought to be a regulator of the p53 protein in meningiomas of all three different WHO grades. Genomic DNA and mRNA were extracted from frozen tissues of meningiomas (WHO grade I, 20 cases; grade II, 17 cases; grade III, 20 cases). For analysis of the mRNA expression and gene dosage level of PPM1D, semiquantitative duplex RT-PCR, real-time RT-PCR, and semiquantitative duplex PCR were performed. We also analyzed several genes which locate near PPM1D in the genomic locus 17q22-24 using semiquantitative duplex RT-PCR. We found that the mean mRNA expression of PPM1D is higher in WHO grade II and III meningiomas than in grade I tumors. This finding is accompanied by moderate gene dosage increases for PPM1D in meningiomas of higher grades. Other genes located in the vicinity of PPM1D also showed mRNA overexpression in single meningioma cases. For these genes, however, no significant expression differences between meningioma grades could be observed. Thus, PPM1D in the chromosomal location 17q22-24 might be the most relevant candidate gene with respect to a potential functional implication in meningioma progression.

Esfandiari A, Hawthorne TA, Nakjang S, Lunec J
Chemical Inhibition of Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) by GSK2830371 Potentiates the Sensitivity to MDM2 Inhibitors in a p53-Dependent Manner.
Mol Cancer Ther. 2016; 15(3):379-91 [PubMed] Free Access to Full Article Related Publications
Sensitivity to MDM2 inhibitors is widely different among responsive TP53 wild-type cell lines and tumors. Understanding the determinants of MDM2 inhibitor sensitivity is pertinent for their optimal clinical application. Wild-type p53-inducible phosphatase-1 (WIP1) encoded by PPM1D, is activated, gained/amplified in a range of TP53 wild-type malignancies, and is involved in p53 stress response homeostasis. We investigated cellular growth/proliferation of TP53 wild-type and matched mutant/null cell line pairs, differing in PPM1D genetic status, in response to Nutlin-3/RG7388 ± a highly selective WIP1 inhibitor, GSK2830371. We also assessed the effects of GSK2830371 on MDM2 inhibitor-induced p53(Ser15) phosphorylation, p53-mediated global transcriptional activity, and apoptosis. The investigated cell line pairs were relatively insensitive to single-agent GSK2830371. However, a non-growth-inhibitory dose of GSK2830371 markedly potentiated the response to MDM2 inhibitors in TP53 wild-type cell lines, most notably in those harboring PPM1D-activating mutations or copy number gain (up to 5.8-fold decrease in GI50). Potentiation also correlated with significant increase in MDM2 inhibitor-induced cell death endpoints that were preceded by a marked increase in a WIP1 negatively regulated substrate, phosphorylated p53(Ser15), known to increase p53 transcriptional activity. Microarray-based gene expression analysis showed that the combination treatment increases the subset of early RG7388-induced p53 transcriptional target genes. These findings demonstrate that potent and selective WIP1 inhibition potentiates the response to MDM2 inhibitors in TP53 wild-type cells, particularly those with PPM1D activation or gain, while highlighting the mechanistic importance of p53(Ser15) and its potential use as a biomarker for response to this combination regimen.

Pharoah PD, Song H, Dicks E, et al.
PPM1D Mosaic Truncating Variants in Ovarian Cancer Cases May Be Treatment-Related Somatic Mutations.
J Natl Cancer Inst. 2016; 108(3) [PubMed] Free Access to Full Article Related Publications
Mosaic truncating mutations in the protein phosphatase, Mg(2+)/Mn(2+)-dependent, 1D (PPM1D) gene have recently been reported with a statistically significantly greater frequency in lymphocyte DNA from ovarian cancer case patients compared with unaffected control patients. Using massively parallel sequencing (MPS) we identified truncating PPM1D mutations in 12 of 3236 epithelial ovarian cancer (EOC) case patients (0.37%) but in only one of 3431 unaffected control patients (0.03%) (P = .001). All statistical tests were two-sided. A combination of Sanger sequencing, pyrosequencing, and MPS data suggested that 12 of the 13 mutations were mosaic. All mutations were identified in post-chemotherapy treatment blood samples from case patients (n = 1827) (average 1234 days post-treatment in carriers) rather than from cases collected pretreatment (less than 14 days after diagnosis, n = 1384) (P = .002). These data suggest that PPM1D variants in EOC cases are primarily somatic mosaic mutations caused by treatment and are not associated with germline predisposition to EOC.

Xu Z, Cao C, Xia H, et al.
Protein phosphatase magnesium-dependent 1δ is a novel tumor marker and target in hepatocellular carcinoma.
Front Med. 2016; 10(1):52-60 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a lethal liver malignancy worldwide. In this study, we reported that protein phosphatase magnesium-dependent 1δ (PPM1D) was highly expressed in the majority of HCC cases (approximately 59%) and significantly associated with high serum α-fetoprotein (AFP) level (P = 0.044). Kaplan- Meier and Cox regression data indicated that PPM1D overexpression was an independent predictor of HCCspecific overall survival (HR, 2.799; 95% CI, 1.346-5.818, P = 0.006). Overexpressing PPM1D promoted cell viability and invasion, whereas RNA interference-mediated knockdown of PPM1D inhibited proliferation, invasion, and migration of cultured HCC cells. In addition, PPM1D suppression by small interfering RNA decreased the tumorigenicity of HCC cells in vivo. Overall, results suggest that PPM1D is a potential prognostic marker and therapeutic target for HCC.

Dodgshun AJ, Sexton-Oates A, Saffery R, Sullivan MJ
Biallelic FANCD1/BRCA2 mutations predisposing to glioblastoma multiforme with multiple oncogenic amplifications.
Cancer Genet. 2016 Jan-Feb; 209(1-2):53-6 [PubMed] Related Publications
Fanconi anaemia (FA) caused by biallelic mutation in FANCD1/BRCA2 is rare but carries a high risk of early onset cancer. Medulloblastoma is well described in this cohort but reports of other brain tumours are uncommon. The molecular profile of tumours from FA patients is not well reported. A glioblastoma multiforme (GBM) from a 3-year-old patient with FA and confirmed biallelic BRCA2 mutations was submitted for methylation analysis. This revealed strong clustering with the K27 mutation subgroup and copy number analysis showed gains of chromosomes 1q, 4q, part of 7q, part of 8q and 17q with resultant amplifications of MDM4, CDK6, MET, MYC and PPM1D (WIP1). We also describe for the first time the germline mutation in BRCA2 c.8057T > C resulting in p.Leu2686Pro in our patient with confirmed FA. Biallelic BRCA2 mutations have predisposed to an aggressive and universally fatal subtype of childhood GBM in our patient. Copy number alterations and multiple oncogenic amplifications may be secondary to inherent chromosomal instability and this raises the question of what role BRCA2 may play in the development of GBM in children without FA.

Wang HY, Liu ZS, Qiu L, et al.
Knockdown of Wip1 Enhances Sensitivity to Radiation in HeLa Cells Through Activation of p38 MAPK.
Oncol Res. 2014; 22(4):225-33 [PubMed] Related Publications
The objectives of the study were to investigate the functional role and potential mechanism of wild-type p53-induced phosphatase (Wip1) in cervical cancer cell line HeLa cells, along with the effect of knockdown of Wip1 in combination with γ-irradiation on the HeLa cells. Expression of Wip1 was silenced or overexpressed. After transfection, cell viability was determined. Moreover, γ-irradiation and SB203580 were performed to explore the effect of colony formation and cell apoptosis. Likewise, protein expression levels of p38, p-p38, p53, and p-p53 were assessed in the presence or not of SB203580 and overexpression of Wip1. Both the mRNA and protein levels of Wip1 were significantly decreased by transfection with Wip1-specific small interfering RNA (siRNA) but were significantly increased by transfection with pcDNA3.1-Wip1. Knockdown of Wip1 significantly decreased cell growth and colony formation ability and increased apoptotic rate. Additionally, better results were obtained by knockdown of Wip1 in combination with γ-irradiation. The protein expression levels of p-p38 (p < 0.05), p53 (p < 0.01), and p-p53 (p < 0.05) were all significantly increased by knockdown of Wip1. However, application of SB203580 reversed the effects. Our study confirms the important roles of Wip1 in cervical cancer. Knockdown of Wip1 enhances sensitivity to radiation in HeLa cells by inhibiting cell proliferation and inducing apoptosis through activation of p38 MAPK.

Horwacik I, Durbas M, Boratyn E, et al.
Analysis of genes involved in response to doxorubicin and a GD2 ganglioside-specific 14G2a monoclonal antibody in IMR-32 human neuroblastoma cells.
Acta Biochim Pol. 2015; 62(3):423-33 [PubMed] Related Publications
Neuroblastoma is the most common extra-cranial solid tumor of childhood and it is characterized by the presence of a glycosphingolipid, GD2 ganglioside. Monoclonal antibodies targeting the antigen are currently tested in clinical trials. Additionally, several research groups reported results revealing that ganglioside-specific antibodies can affect cellular signaling and cause direct cytotoxicity against tumor cells. To shed more light on gene expression signatures of tumor cells, we used microarrays to analyze changes of transcriptome in IMR-32 human neuroblastoma cell cultures treated with doxorubicin (DOX) or a mouse monoclonal antibody binding to GD2 ganglioside 14G2a (mAb) for 24 h. The obtained results highlight that disparate cellular pathways are regulated by doxorubicin and 14G2a. Next, we used RT-PCR to verify mRNA levels of selected DOX-responsive genes such as RPS27L, PPM1D, SESN1, CDKN1A, TNFSF10B, and 14G2a-responsive genes such as SVIL, JUN, RASSF6, TLX2, ID1. Then, we applied western blot and analyzed levels of RPS27L, PPM1D, sestrin 1 proteins after DOX-treatment. Additionally, we aimed to measure effects of doxorubicin and topotecan (TPT) and 14G2a on expression of a novel human NDUFAF2 gene encoding for mimitin protein (MYC-induced mitochondrial protein) and correlate it with expression of the MYCN gene. We showed that expression of both genes was concomitantly decreased in the 14G2a-treated IMR-32 cells after 24 h and 48 h. Our results extend knowledge on gene expression profiles after application of DOX and 14G2a in our model and reveal promising candidates for further research aimed at finding novel anti-neuroblastoma targets.

Bakhshaiesh TO, Armat M, Shanehbandi D, et al.
Arsenic Trioxide Promotes Paclitaxel Cytotoxicity in Resistant Breast Cancer Cells.
Asian Pac J Cancer Prev. 2015; 16(13):5191-7 [PubMed] Related Publications
A partial response or resistance to chemotherapeutic agents is considered as a main obstacle in treatment of patients with cancer, including breast cancer. Refining taxane-based treatment procedures using adjuvant or combination treatment is a novel strategy to increase the efficiency of chemotherapy. PPM1D is a molecule activated by reactive oxygen species. whose expression is reported to modulate the recruitment of DNA repair molecules. In this study we examined the impact of arsenic trioxide on efficacy of paclitaxel-induced apoptosis in paclitaxel-resistant MCF-7 cells. We also investigated the expression of PPM1D and TP53 genes in response to this combination treatment. Resistant cells were developed from the parent MCF-7 cell line by applying increasing concentrations of paclitaxel. MTT assays were applied to determine the rate of cell survival. DAPI staining using fluorescent microscopy was employed to study apoptotic bodies. Real-time RT-PCR analysis was also applied to determine PPM1D mRNA levels. Our results revealed that combination of arsenic trioxide and paclitaxel elevates the efficacy of the latter in induction of apoptosis in MCF-7/PAC resistant cells. Applying arsenic trioxide also caused significant decreases in PPM1D mRNA levels (p<0.05). Our findings suggest that arsenic trioxide increases paclitaxel-induced apoptosis by down regulation of PPM1D expression. PPM1D dependent signaling can be considered as a novel target to improve the efficacy of chemotherapeutic agents in resistant breast cancer cells.

Mirzayans R, Andrais B, Scott A, et al.
Spontaneous γH2AX Foci in Human Solid Tumor-Derived Cell Lines in Relation to p21WAF1 and WIP1 Expression.
Int J Mol Sci. 2015; 16(5):11609-28 [PubMed] Free Access to Full Article Related Publications
Phosphorylation of H2AX on Ser139 (γH2AX) after exposure to ionizing radiation produces nuclear foci that are detectable by immunofluorescence microscopy. These so-called γH2AX foci have been adopted as quantitative markers for DNA double-strand breaks. High numbers of spontaneous γH2AX foci have also been reported for some human solid tumor-derived cell lines, but the molecular mechanism(s) for this response remains elusive. Here we show that cancer cells (e.g., HCT116; MCF7) that constitutively express detectable levels of p21WAF1 (p21) exhibit low numbers of γH2AX foci (<3/nucleus), whereas p21 knockout cells (HCT116p21-/-) and constitutively low p21-expressing cells (e.g., MDA-MB-231) exhibit high numbers of foci (e.g., >50/nucleus), and that these foci are not associated with apoptosis. The majority (>95%) of cells within HCT116p21-/- and MDA-MB-231 cultures contain high levels of phosphorylated p53, which is localized in the nucleus. We further show an inverse relationship between γH2AX foci and nuclear accumulation of WIP1, an oncogenic phosphatase. Our studies suggest that: (i) p21 deficiency might provide a selective pressure for the emergence of apoptosis-resistant progeny exhibiting genomic instability, manifested as spontaneous γH2AX foci coupled with phosphorylation and nuclear accumulation of p53; and (ii) p21 might contribute to positive regulation of WIP1, resulting in dephosphorylation of γH2AX.

Zhang M, Xu E, Zhang J, Chen X
PPM1D phosphatase, a target of p53 and RBM38 RNA-binding protein, inhibits p53 mRNA translation via dephosphorylation of RBM38.
Oncogene. 2015; 34(48):5900-11 [PubMed] Free Access to Full Article Related Publications
PPM1D phosphatase, also called wild-type p53-induced phosphatase 1, promotes tumor development by inactivating the p53 tumor suppressor pathway. RBM38 RNA-binding protein, also called RNPC1 and a target of p53, inhibits p53 messenger RNA (mRNA) translation, which can be reversed by GSK3 protein kinase via phosphorylation of RBM38 at serine 195. Here we showed that ectopic expression of RBM38 increases, whereas knockdown of RBM38 inhibits, PPM1D mRNA translation. Consistent with this, we found that RBM38 directly binds to PPM1D 3'-untranslated region (3'-UTR) and promotes expression of a heterologous reporter gene that carries PPM1D 3'-UTR in a dose-dependent manner. Interestingly, we showed that PPM1D directly interacts with and dephosphorylates RBM38 at serine 195. Furthermore, we showed that PPM1D modulates p53 mRNA translation and p53-dependent growth suppression through dephosphorylation of RBM38. These findings provide evidence that the crosstalk between PPM1D and RBM38, both of which are targets and modulators of p53, has a critical role in p53 expression and activity.

Tang YL, Liu X, Gao SY, et al.
WIP1 stimulates migration and invasion of salivary adenoid cystic carcinoma by inducing MMP-9 and VEGF-C.
Oncotarget. 2015; 6(11):9031-44 [PubMed] Free Access to Full Article Related Publications
The wild-type p53 induced phosphatase 1 (WIP1) is an oncogene overexpressed in a variety of human cancers. Here, we demonstrated that WIP1 silencing reduced MMP-9 and VEGF-C expression as well as migration and invasion of salivary adenoid cystic carcinoma (ACC) cells. Overexpression of MMP-9 or VEGF-C restored migration and invasion in WIP1 knockdown cells, indicating that MMP-9 and VEGF-C are downstream targets of WIP1 signaling. Levels of cyclin D1 and c-Myc, targets of Wnt/β-catenin pathway, were significantly decreased by WIP1 silencing. In addition, WIP1 expression was positively associated with metastasis and prognosis of ACC patients as well as with MMP-9 or VEGF-C in ACC tissues.

Zajkowicz A, Butkiewicz D, Drosik A, et al.
Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients.
Br J Cancer. 2015; 112(6):1114-20 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: PPM1D (WIP1) negatively regulates by dephosphorylation many proteins including p53 tumour suppressor. The truncating mutations (nonsense and frameshift) in exon 6 of PPM1D were found recently in blood cells of patients with breast, ovarian or colorectal cancer. These mutants code for gain-of-function PPM1D with retained phosphatase activity. Their significance in carcinogenesis is unknown.
METHODS: The exon 6 of PPM1D was sequenced in blood DNA of 543 non-small-cell lung cancer patients (NSCLC). The functional significance of selected PPM1D alterations (Arg458X, Lys469Glu) was compared with the wild-type gene and examined by recombinant DNA techniques, immunoblotting and luciferase reporter assays.
RESULTS: The frameshift mutations were found in five NSCLC patients (5/543; 0.92%), all of them had squamous cell carcinomas (5/328; 1.5%). All patients with the mutations were exposed, before the blood collection, to the DNA damaging agents as a part of chemotherapeutic regimen. Functional tests demonstrated that truncating mutation Arg458X causes enhancement of dephosphorylation activity of PPM1D toward serine 15 of p53, whereas Lys469Glu version is equivalent to the wild-type. Neither version of PPM1D (wild-type, Arg458X, Lys469Glu) significantly modulated the ability of p53 to transactivate promoters of the examined p53-target genes (BAX and MDM2).
CONCLUSIONS: The truncating mutations of PPM1D are present in blood DNA of NSCLC patients at frequency similar to percentage determined for ovarian cancer patients. Our findings raise a question if the detected lesions are a result of chemotherapy.

Richter M, Dayaram T, Gilmartin AG, et al.
WIP1 phosphatase as a potential therapeutic target in neuroblastoma.
PLoS One. 2015; 10(2):e0115635 [PubMed] Free Access to Full Article Related Publications
The wild-type p53-induced phosphatase 1 (WIP1) is a serine/threonine phosphatase that negatively regulates multiple proteins involved in DNA damage response including p53, CHK2, Histone H2AX, and ATM, and it has been shown to be overexpressed or amplified in human cancers including breast and ovarian cancers. We examined WIP1 mRNA levels across multiple tumor types and found the highest levels in breast cancer, leukemia, medulloblastoma and neuroblastoma. Neuroblastoma is an exclusively TP53 wild type tumor at diagnosis and inhibition of p53 is required for tumorigenesis. Neuroblastomas in particular have previously been shown to have 17q amplification, harboring the WIP1 (PPM1D) gene and associated with poor clinical outcome. We therefore sought to determine whether inhibiting WIP1 with a selective antagonist, GSK2830371, can attenuate neuroblastoma cell growth through reactivation of p53 mediated tumor suppression. Neuroblastoma cell lines with wild-type TP53 alleles were highly sensitive to GSK2830371 treatment, while cell lines with mutant TP53 were resistant to GSK2830371. The majority of tested neuroblastoma cell lines with copy number gains of the PPM1D locus were also TP53 wild-type and sensitive to GSK2830371A; in contrast cell lines with no copy gain of PPM1D were mixed in their sensitivity to WIP1 inhibition, with the primary determinant being TP53 mutational status. Since WIP1 is involved in the cellular response to DNA damage and drugs used in neuroblastoma treatment induce apoptosis through DNA damage, we sought to determine whether GSK2830371 could act synergistically with standard of care chemotherapeutics. Treatment of wild-type TP53 neuroblastoma cell lines with both GSK2830371 and either doxorubicin or carboplatin resulted in enhanced cell death, mediated through caspase 3/7 induction, as compared to either agent alone. Our data suggests that WIP1 inhibition represents a novel therapeutic approach to neuroblastoma that could be integrated with current chemotherapeutic approaches.

Kozakai Y, Kamada R, Kiyota Y, et al.
Inhibition of C-terminal truncated PPM1D enhances the effect of doxorubicin on cell viability in human colorectal carcinoma cell line.
Bioorg Med Chem Lett. 2014; 24(24):5593-6 [PubMed] Related Publications
PPM1D is a p53-inducible Ser/Thr phosphatase. One of the main functions of PPM1D in normal cells is to act as a negative regulator of the p53 tumor suppressor by dephosphorylating p53 and several kinases. PPM1D is considered an oncoprotein owing to both its functions and the fact that gene amplification and overexpression of PPM1D are reported in several tumors. Recently, PPM1D mutations resulting in C-terminal truncated alterations were found in brainstem gliomas and colorectal cancers, and these mutations enhanced the activity of PPM1D. Therefore, C-terminal truncated PPM1D should be also considered as a potential candidate target of anticancer drugs. Here we showed that combination treatment with PPM1D-specific inhibitor SPI-001 and doxorubicin suppressed cell viability of HCT-116 cells overexpressing C-terminal truncated PPM1D through p53 activation compared with doxorubicin alone. Our results suggest that combination treatment with PPM1D inhibitor and doxorubicin may be a potential anti-cancer treatment in PPM1D-mutated cancer cells.

Dogra S, Bandi S, Viswanathan P, Gupta S
Arsenic trioxide amplifies cisplatin toxicity in human tubular cells transformed by HPV-16 E6/E7 for further therapeutic directions in renal cell carcinoma.
Cancer Lett. 2015; 356(2 Pt B):953-61 [PubMed] Free Access to Full Article Related Publications
Human papillomavirus (HPV) DNA integrations may affect therapeutic responses in cancers through ATM network-related DNA damage response (DDR). We studied whether cisplatin-induced DDR was altered in human HK-2 renal tubular cells immortalized by HPV16 E6/E7 genes. Cytotoxicity assays utilized thiazolyl blue dye and DDR was identified by gene expression differences, double-strand DNA breaks, ATM promoter activity, and analysis of cell cycling and side population cells. After cisplatin, HK-2 cells showed greater ATM promoter activity indicating activation of this network, but DDR was muted, since little γH2AX was expressed, DNA strand breaks were absent and cells continued cycling. When HK-2 cells were treated with the MDM2 antagonist inducing p53, nutlin-3, or p53 transcriptional activator, tenovin-1, cell growth decreased but cisplatin toxicity was unaffected. By contrast, arsenic trioxide, which by inhibiting wild-type p53-induced phosphatase-1 that serves responses downstream of p53, and by depolymerizing tubulin, synergistically enhanced cisplatin cytotoxicity including loss of SP cells. Our findings demonstrated that HPV16 E6/E7 altered DDR through p53-mediated cell growth controls, which may be overcome by targeting of WIP1 and other processes, and thus should be relevant for treating renal cell carcinoma.


Integrated genomic characterization of papillary thyroid carcinoma.
Cell. 2014; 159(3):676-90 [PubMed] Free Access to Full Article Related Publications
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.

Wang W, Zhu H, Zhang H, et al.
Targeting PPM1D by lentivirus-mediated RNA interference inhibits the tumorigenicity of bladder cancer cells.
Braz J Med Biol Res. 2014; 47(12):1044-9 [PubMed] Free Access to Full Article Related Publications
Protein phosphatase magnesium/manganese-dependent 1D (PPM1D) is a p53-induced phosphatase that functions as a negative regulator of stress response pathways and has oncogenic properties. However, the functional role of PPM1D in bladder cancer (BC) remains largely unknown. In the present study, lentivirus vectors carrying small hairpin RNA (shRNA) targeting PPM1D were used to explore the effects of PPM1D knockdown on BC cell proliferation and tumorigenesis. shRNA-mediated knockdown of PPM1D significantly inhibited cell growth and colony forming ability in the BC cell lines 5637 and T24. Flow cytometric analysis showed that PPM1D silencing increased the proportion of cells in the G0/G1 phase. Downregulation of PPM1D also inhibited 5637 cell tumorigenicity in nude mice. The results of the present study suggest that PPM1D plays a potentially important role in BC tumorigenicity, and lentivirus-mediated delivery of shRNA against PPM1D might be a promising therapeutic strategy for the treatment of BC.

Emelyanov A, Bulavin DV
Wip1 phosphatase in breast cancer.
Oncogene. 2015; 34(34):4429-38 [PubMed] Related Publications
Understanding the factors contributing to tumor initiation, progression and evolution is of paramount significance. Among them, wild-type p53-induced phosphatase 1 (Wip1) is emerging as an important oncogene by virtue of its negative control on several key tumor suppressor pathways. Originally discovered as a p53-regulated gene, Wip1 has been subsequently found amplified and more recently mutated in a significant fraction of human cancers including breast tumors. Recent development in the field further uncovered the utility of anti-Wip1-directed therapies in delaying tumor onset or in reducing the tumor burden. Furthermore, Wip1 could be an important factor that contributes to tumor heterogeneity, suggesting that its inhibition may decrease the rate of cancer evolution. These effects depend on several signaling pathways modulated by Wip1 phosphatase in a spatial and temporal manner. In this review we discuss the recent development in understanding how Wip1 contributes to tumorigenesis with its relevance to breast cancer.

Hirata Y, Murai N, Yanaihara N, et al.
MicroRNA-21 is a candidate driver gene for 17q23-25 amplification in ovarian clear cell carcinoma.
BMC Cancer. 2014; 14:799 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Epithelial ovarian cancer (EOC) is the most common cause of gynecological malignancy-related mortality. Ovarian clear cell carcinoma (CCC) has unique clinical characteristics and behaviors that differ from other histological types of EOC, including a frequent association with endometriosis and a highly chemoresistant nature, resulting in poor prognosis. However, factors underlying its malignant behavior are still poorly understood. Aberrant expression of microRNAs has been shown to be involved in oncogenesis, and microRNA-21 (miR-21) is frequently overexpressed in many types of cancers. The aim of this study was to investigate the role of miR-21 in 17q23-25 amplification associated with CCC oncogenesis.
METHODS: We identified 17q23-25 copy number aberrations among 28 primary CCC tumors by using a comparative genomic hybridization method. Next, we measured expression levels of the candidate target genes, miR-21 and PPM1D, for 17q23-25 amplification by real-time RT-PCR analysis and compared those data with copy number status and clinicopathological features. In addition, immunohistochemical analysis of PTEN (a potential target of miR-21) was performed using the same primary CCC cases. We investigated the biological significance of miR-21 overexpression in CCC using a loss-of-function antisense approach.
RESULTS: 17q23-25 amplification with both miR-21 overexpression and PTEN protein loss was detected in 4/28 CCC cases (14.2%). The patients with 17q23-25 amplification had significantly shorter progression-free and overall survival than those without 17q23-25 amplification (log-rank test: p = 0.0496; p = 0.0469, respectively). A significant correlation was observed between miR-21 overexpression and endometriosis. Both PTEN mRNA and PTEN protein expression were increased by miR-21 knockdown in CCC cells. We also confirmed that miR-21 directly bound to the 3'-untranslated region of PTEN mRNA using a dual-luciferase reporter assay.
CONCLUSIONS: MiR-21 is a possible driver gene other than PPM1D for 17q23-25 amplification in CCC. Aberrant expression of miR-21 by chromosomal amplification might play an important role in CCC carcinogenesis through the regulation of the PTEN tumor suppressor gene.

Liu S, Qi L, Han W, et al.
Overexpression of wip1 is associated with biologic behavior in human clear cell renal cell carcinoma.
PLoS One. 2014; 9(10):e110218 [PubMed] Free Access to Full Article Related Publications
Wild-type p53-induced phosphatase (Wip1 or PPM1D) has been reported to be aberrantly expressed in various cancers and correlated with the malignant behavior of cancer cells. However, the function of Wip1 in RCC remains unclear. The present study investigated its abnormal expression and dysfunctions in clear cell renal cell carcinoma (ccRCC) in vitro. With the combination of immunohistochemistry, western blotting, immunofluorescence, qRT-PCR, and cell proliferation, migration and invasion assays, we found that levels of Wip1 mRNA and protein were dramatically increased in human ccRCC tissues (P<0.001 for both), and upregulation of Wip1 was significantly associated with depth of invasion (P<0.001), Distant metastasis (P = 0.001), lymph node status (P<0.001) and Fuhrman grade (P<0.001). Wip1 knockdown inhibited the proliferation, migration and invasion of 786-O and RLC-310 cells, whereas Wip1 overexpression promoted the growth and aggressive phenotype of 786-O and RLC-310 cells in vitro. The uni- and multivariate analyses indicated that expression of Wip1 was an independent predictor for survival of ccRCC patients (P = 0.003, P = 0.027 respectively). Wip1- negative patients had a higher tumor-free/overall survival rate than patients with high Wip1 expression (P = 0.001, P = 0.002 respectively). Overexpression of Wip1 is useful in the prediction of survival in ccRCC patients.

Xie M, Lu C, Wang J, et al.
Age-related mutations associated with clonal hematopoietic expansion and malignancies.
Nat Med. 2014; 20(12):1472-8 [PubMed] Free Access to Full Article Related Publications
Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia and/or lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5-6% of people older than 70 years) contain mutations that may represent premalignant events that cause clonal hematopoietic expansion.

Zhang C, Chen Y, Wang M, et al.
PPM1D silencing by RNA interference inhibits the proliferation of lung cancer cells.
World J Surg Oncol. 2014; 12:258 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: PPM1D (protein phosphatase, Mg2+/Mn2+ dependent, 1D) has been reported to be involved in multiple human tumors. This study was designed to investigate the functional role of PPM1D in lung cancer cells.
METHODS: Expression levels of PPM1D were analyzed in A549 and H1299 cells by real-time PCR and Western blotting. Lentivirus-mediated short hairpin RNA (shRNA) was used to knock down PPM1D expression in both cell lines. The effects of PPM1D on lung cancer cell growth were investigated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), colony formation and flow cytometry assays.
RESULTS: Knockdown of PPM1D in lung cancer cells resulted in decreased cell proliferation and impaired colony formation ability. Moreover, flow cytometry analysis showed that knockdown of PPM1D arrested cell cycle at the G0/G1 phase. Furthermore, PPM1D silencing downregulated the expression of cyclin B1 in H1299 cells. Therefore, it is reasonable to speculate that the mechanisms by which PPM1D knockdown alleviates cell growth may be partly via the induction of cell cycle arrest due to the suppression of cyclin B1.
CONCLUSIONS: These results suggest that PPM1D silencing by RNA interference (RNAi) may be a potential therapeutic approach for the treatment of lung cancer.

Sun GG, Zhang J, Ma XB, et al.
Overexpression of Wild-Type p53-Induced Phosphatase 1 Confers Poor Prognosis of Patients with Nasopharyngeal Carcinoma.
Pathol Oncol Res. 2015; 21(2):283-91 [PubMed] Related Publications
This study aimed to analyze the expression, clinical significance of proto-oncogene in nasopharyngeal carcinoma and the biological effect in its cell line by siRNA targeting wild-type p53-induced phosphatase 1 (Wip1). Immunohistochemistry and western blot were respectively used to analyze Wip1 protein expression in 85 cases of nasopharyngeal cancer and normal tissues to study the relationship between Wip1 expression and clinical factors. Wip1 siRNA was transiently transfected into papillary nasopharyngeal carcinoma cell by liposome-mediated method and was detected by Quantitative real-time RT-PCR (qRT-PCR) and western blot. MTT assay, cell apoptosis, migration and invasion were also conducted as to the influence of the down-regulated expression of Wip1 that might be found on CNE2 cells biological effect. The level of Wip1 protein expression was found to be significantly higher in nasopharyngeal cancer tissue than normal tissues (P <0.05). There were significant differences between Wip1 expression and T stages, lymph node metastasis, clinical stages, tumor differentiation and radiotherapy response (P < 0.05), regardless of age, gender (P > 0.05). Meanwhile, Increased expression of Wip1 was significantly with poor overall survival time by Kaplan-Meier analysis (P < 0.05). Wip1 expression deletion determines independent risk factors for prognosis of patients with nasopharyngeal carcinoma in addition to tumor T stage, clinical stage, histological grade and lymph node metastasis outside by Cox-2 in the regression analysis (P < 0.05). qRT-PCR and Western blot showed that CNE2 cell transfected Wip1 siRNA had a lower relative expressive content than normal cell (P < 0.05). MTT assay, cell apoptosis, cell cycles demonstrated that CNE2 cell transfected Wip1 siRNA had a lower survival fraction, higher cell apoptosis, more percentage of the G0/G1 phases, significant decrease in migration and invasion, and higher P53 and P16 protein expression compared with CNE2 cell untransfected Wip1 siRNA (P < 0.05). Wip1 protein was increased in nasopharyngeal carcinoma, specifically in T stages, lymph node metastasis, clinical stages and tumor differentiation. Wip1 may involved in the biological processes of nasopharyngeal cancer cell proliferation, apoptosis, and migration and invasion by regulation P53 and P16 protein expression.

Zhang L, Chen LH, Wan H, et al.
Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas.
Nat Genet. 2014; 46(7):726-30 [PubMed] Free Access to Full Article Related Publications
Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.

Lin J, Zhang Q, Lu Y, et al.
Downregulation of HIPK2 increases resistance of bladder cancer cell to cisplatin by regulating Wip1.
PLoS One. 2014; 9(5):e98418 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Cisplatin-based combination chemotherapy regimen is a reasonable alternative to cystectomy in advanced/metastatic bladder cancer, but acquisition of cisplatin resistance is common in patients with bladder cancer. Previous studies showed that loss of homeodomain-interacting protein kinase-2 (HIPK2) contributes to cell proliferation and tumorigenesis. However, the role of HIPK2 in regulating chemoresistance of cancer cell is not fully understood. In the present study, we found that HIPK2 mRNA and protein levels are significantly decreased in cisplatin-resistant bladder cancer cell in vivo and in vitro. Downregulation of HIPK2 increases the cell viability in a dose- and time-dependent manner during cisplatin treatment, whereas overexpression of HIPK2 reduces the cell viability. HIPK2 overexpression partially overcomes cisplatin resistance in RT4-CisR cell. Furthermore, we showed that Wip1 (wild-type p53-induced phosphatase 1) expression is upregulated in RT4-CisR cell compared with RT4 cell, and HIPK2 negatively regulates Wip1 expression in bladder cancer cell. HIPK2 and Wip1 expression is also negatively correlated after cisplatin-based combination chemotherapy in vivo. Finally, we demonstrated that overexpression of HIPK2 sensitizes chemoresistant bladder cancer cell to cisplatin by regulating Wip1 expression.
CONCLUSIONS: These data suggest that HIPK2/Wip1 signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of bladder cancer.

Buss MC, Remke M, Lee J, et al.
The WIP1 oncogene promotes progression and invasion of aggressive medulloblastoma variants.
Oncogene. 2015; 34(9):1126-40 [PubMed] Free Access to Full Article Related Publications
Recent studies suggest that medulloblastoma, the most common malignant brain tumor of childhood, is comprised of four disease variants. The WIP1 oncogene is overexpressed in Group 3 and 4 tumors, which contain medulloblastomas with the most aggressive clinical behavior. Our data demonstrate increased WIP1 expression in metastatic medulloblastomas, and inferior progression-free and overall survival of patients with WIP1 high-expressing medulloblastoma. Microarray analysis identified upregulation of genes involved in tumor metastasis, including the G protein-coupled receptor CXCR4, in medulloblastoma cells with high WIP1 expression. Stimulation with the CXCR4 ligand SDF1α activated PI-3 kinase signaling, and promoted growth and invasion of WIP1 high-expressing medulloblastoma cells in a p53-dependent manner. When xenografted into the cerebellum of immunodeficient mice, medulloblastoma cells with stable or endogenous high WIP1 expression exhibited strong expression of CXCR4 and activated AKT in primary and invasive tumor cells. WIP1 or CXCR4 knockdown inhibited medulloblastoma growth and invasion. WIP1 knockdown also improved the survival of mice xenografted with WIP1 high-expressing medulloblastoma cells. WIP1 knockdown inhibited cell surface localization of CXCR4 by suppressing expression of the G protein receptor kinase 5, GRK5. Restoration of wild-type GRK5 promoted Ser339 phosphorylation of CXCR4 and inhibited the growth of WIP1-stable medulloblastoma cells. Conversely, GRK5 knockdown inhibited Ser339 phosphorylation of CXCR4, increased cell surface localization of CXCR4 and promoted the growth of medulloblastoma cells with low WIP1 expression. These results demonstrate crosstalk among WIP1, CXCR4 and GRK5, which may be important for the aggressive phenotype of a subclass of medulloblastomas in children.

Fu Z, Sun G, Gu T
Proto-oncogene Wip1, a member of a new family of proliferative genes in NSCLC and its clinical significance.
Tumour Biol. 2014; 35(4):2975-81 [PubMed] Related Publications
This study aimed to analyze the expression, clinical significance of proto-oncogene in non small cell lung cancer (NSCLC), and the biological effect in its cell line by siRNA targeting wild-type p53-induced phosphatase 1 (Wip1). Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) were, respectively, used to analyze Wip1 protein expression in 75 cases of NSCLC and normal tissues to study the relationship between Wip1 expression and clinical parameters. Wip1 siRNA was transiently transfected into papillary NSCLC H1299 cell by liposome-mediated method and was detected by RT-PCR and Western blot. MTT assay, cell apoptosis, and cell cycle were also conducted as to the influence of the downregulated expression of Wip1 that might be found on H1299 cells biological effect. The positive rates of Wip1 protein was 69.3% in NSCLC tissues but 16.0% expressed in normal tissues (P < 0.05). The relative content of Wip1 mRNA was 0.785 ± 0.062 and 0.147 ± 0.020 in NSCLC tissues and normal tissues, respectively, with significant differences between the two types (P < 0.05). There were no significant differences between Wip1 expression and sex, age, tumor size, and pathological types (P > 0.05). However, there were significant differences between Wip1 expression and lymph node metastasis, clinical stages, and tumor differentiation (P < 0.05). Individuals with positive and negative levels of Wip1 expression showed were statistically significant differences in the 5-year overall survival rate (P < 0.05). RT-PCR and Western blot showed that H1299 cell transfected Wip1 siRNA had a lower relative expressive content than normal cell (P < 0.05). MTT assay, cell apoptosis, and cell cycles demonstrated that H1299 cell transfected Wip1 siRNA had a lower survival fraction, higher cell apoptosis, more percentage of the G0/G1 phases, and lower cells in the S phases (P < 0.05). Wip1 protein and mRNA were increased in NSCLC, specifically in lymph node metastasis, clinical stages, and tumor differentiation. Wip1 may be involved in the biological processes of NSCLC cell proliferation, cell apoptosis, and cell cycle.

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