PPM1D

Gene Summary

Gene:PPM1D; protein phosphatase, Mg2+/Mn2+ dependent 1D
Aliases: JDVS, WIP1, IDDGIP, 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:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein phosphatase 1D
Source:NCBIAccessed: 30 August, 2019

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 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 30 August, 2019 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)

Mendoza-Rodríguez MG, Ayala-Sumuano JT, García-Morales L, et al.
IL-1β Inflammatory Cytokine-Induced
Int J Mol Sci. 2019; 20(2) [PubMed] Free Access to Full Article Related Publications
The mechanisms behind the induction of malignancy and chemoresistance in breast cancer cells are still not completely understood. Inflammation is associated with the induction of malignancy in different types of cancer and is highlighted as an important factor for chemoresistance. In previous work, we demonstrated that the inflammatory cytokine interleukin 1β (IL-1β)-induced upregulation of genes was associated with chemoresistance in breast cancer cells. Here, we evaluated the participation and the expression profile of

Yokoyama A, Kakiuchi N, Yoshizato T, et al.
Age-related remodelling of oesophageal epithelia by mutated cancer drivers.
Nature. 2019; 565(7739):312-317 [PubMed] Related Publications
Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire oesophageal epithelium in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal oesophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which-depending on lifestyle risks-may affect cancer development.

Ogasawara S, Chuman Y, Michiba T, et al.
Inhibition of protein phosphatase PPM1D enhances retinoic acid-induced differentiation in human embryonic carcinoma cell line.
J Biochem. 2019; 165(6):471-477 [PubMed] Related Publications
The protein phosphatase PPM1D (Wip1) was originally identified as a p53 target product. Activation of PPM1D through various mechanism promotes the tumorigenic potential of various cancers by suppressing p53 and other DNA damage response proteins. New functions of PPM1D have recently been revealed in physiological processes such as cell differentiation. However, the regulatory mechanisms of signalling pathway to maintain stemness and induce cell differentiation are still unclear. Here we report that PPM1D modulates retinoic acid (RA) signalling. PPM1D knockdown resulted in decreased alkaline phosphatase activity of the human teratocarcinoma cell line NT2/D1. Inhibition of PPM1D-induced cell differentiation and decreased gene expression of the stem cell marker Oct-4 (POU5F1). RA-induced cell differentiation was promoted by reducing PPM1D activity. RA treatment elicited activation of the MEK-ERK pathway and induced rapid and transient activation of the extracellular signal-regulated kinase 1/2 (ERK-1/2). PPM1D dephosphorylated a phosphopeptide with the TEY motif in ERK-1/2 in vitro. Moreover, phosphorylation of ERK-1/2 was facilitated by PPM1D inhibition. Our study shows that PPM1D plays an important role in maintaining the undifferentiation state and a new function in RA-induced ERK regulation and cell differentiation.

Liu Y, Xu J, Choi HH, et al.
Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer.
Nat Commun. 2018; 9(1):4718 [PubMed] Free Access to Full Article Related Publications
Chromosome 17q23 amplification occurs in ~11% of human breast cancers. Enriched in HER2+ breast cancers, the 17q23 amplification is significantly correlated with poor clinical outcomes. In addition to the previously identified oncogene WIP1, we uncover an oncogenic microRNA gene, MIR21, in a majority of the WIP1-containing 17q23 amplicons. The 17q23 amplification results in aberrant expression of WIP1 and miR-21, which not only promotes breast tumorigenesis, but also leads to resistance to anti-HER2 therapies. Inhibiting WIP1 and miR-21 selectively inhibits the proliferation, survival and tumorigenic potential of the HER2+ breast cancer cells harboring 17q23 amplification. To overcome the resistance of trastuzumab-based therapies in vivo, we develop pH-sensitive nanoparticles for specific co-delivery of the WIP1 and miR-21 inhibitors into HER2+ breast tumors, leading to a profound reduction of tumor growth. These results demonstrate the great potential of the combined treatment of WIP1 and miR-21 inhibitors for the trastuzumab-resistant HER2+ breast cancers.

Chen W, Tan Y, Zhang Y
p38 MAPK signaling pathway activation by phenyl benzoxime in SNU-306 cells causes induction of apoptosis.
Microb Pathog. 2019; 126:74-78 [PubMed] Related Publications
The present study was aimed to investigate and understand the mechanism of inhibitory effect of phenyl benzoxime on proliferation of SNU-306 cells. Proliferation of SNU-306 cells transfected with wild-type p53-induced phosphatase 1 (Wip1)-siRNA or treated with phenyl benzoxime was examined by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Induction of apoptosis was examined by flow cytometry using annexin V-fluorescein isothiocyanate/propidium iodide staining. In SNU-306 cells Wip1 mRNA and protein expression was found to be significantly (p < 0.05) higher compared to normal cells. However, Wip1-siRNA transfection significantly (p < 0.02) inhibited the expression of Wip1 at 60 nmol/l. The proliferation of SNU-306 cells was inhibited to 3.7% on transfection with Wip1-siRNA. Phenyl benzoxime reduced proliferation to 92.0, 75.0, 49.0, 19.0 and 4.0% at 1, 2, 4, 8 and 10 μM doses, respectively. The expression of Wip1 was significantly (p < 0.01) suppressed in SNU-306 cells on phenyl benzoxime treatment. Phenyl benzoxime induced apoptosis in 74.73% cells at 10 μM doses compared to 1.34% in control. Treatment with phenyl benzoxime markedly increased the expression of Bax, caspase-3 and p53 and decreased Bcl-2 mRNA. Moreover, addition of SB203580 to cultures of SNU-306 cells significantly (p < 0.01) prevented phenyl benzoxime mediated inhibition of cell proliferation. Phenyl benzoxime induces apoptosis and inhibits SNU-306 cell proliferation by silencing Wip1 expression through p38 MAPK signaling pathway activation. Therefore, phenyl benzoxime can act as an important chemotherapeutic agent for breast cancer treatment.

Bonache S, Esteban I, Moles-Fernández A, et al.
Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings.
J Cancer Res Clin Oncol. 2018; 144(12):2495-2513 [PubMed] Related Publications
PURPOSE: Few and small studies have been reported about multigene testing usage by massively parallel sequencing in European cancer families. There is an open debate about what genes should be tested, and the actionability of some included genes is under research.
METHODS: We investigated a panel of 34 known high/moderate-risk cancer genes, including 16 related to breast or ovarian cancer (BC/OC) genes, and 63 candidate genes to BC/OC in 192 clinically suspicious of hereditary breast/ovarian cancer (HBOC) Spanish families without pathogenic variants in BRCA1 or BRCA2 (BRCA1/2).
RESULTS: We identified 16 patients who carried a high- or moderate-risk pathogenic variant in eight genes: 4 PALB2, 3 ATM, 2 RAD51D, 2 TP53, 2 APC, 1 BRIP1, 1 PTEN and 1 PMS2. These findings led to increased surveillance or prevention options in 12 patients and predictive testing in their family members. We detected 383 unique variants of uncertain significance in known cancer genes, of which 35 were prioritized in silico. Eighteen loss-of-function variants were detected in candidate BC/OC genes in 17 patients (1 BARD1, 1 ERCC3, 1 ERCC5, 2 FANCE, 1 FANCI, 2 FANCL, 1 FANCM, 1 MCPH1, 1 PPM1D, 2 RBBP8, 3 RECQL4 and 1 with SLX4 and XRCC2), three of which also carry pathogenic variants in known cancer genes.
CONCLUSIONS: Eight percent of the BRCA1/2 negative patients carry pathogenic variants in other actionable genes. The multigene panel usage improves the diagnostic yield in HBOC testing and it is an effective tool to identify potentially new candidate genes.

Alzahrani AS, Murugan AK, Qasem E, et al.
Absence of EIF1AX, PPM1D, and CHEK2 mutations reported in Thyroid Cancer Genome Atlas (TCGA) in a large series of thyroid cancer.
Endocrine. 2019; 63(1):94-100 [PubMed] Related Publications
INTRODUCTION: The Thyroid Cancer Genome Atlas (TCGA) was a major project that significantly clarified the key underlying genetic aberrations in papillary thyroid cancer. It confirmed the previously known somatic mutations and gene fusions and disclosed additional genetic alterations that were previously unknown. Among the most significant novel genetic mutations were those in EIF1AX, PPM1D, and CHEK2.
OBJECTIVES: We sought to determine the rates of these novel genetic alterations in a large sample of our patients to test the prevalence, reproducibility, and significance of these findings.
PATIENTS AND METHODS: We studied thyroid cancer (TC) tumor tissues from 301 unselected patients using polymerase chain reaction (PCR) and direct Sanger sequencing. DNA was isolated from paraffin-embedded formalin-fixed tumor tissue. Exons and exon-intron boundaries harboring the previously reported mutations in TCGA were amplified using PCR and directly sequenced.
RESULTS: We found only one of the 301 tumors (0.3%) harboring A113_splice site mutation at the intron 5/exon 6 splice site of EIF1AX gene. Apart from this single mutation, none of the 301 tumors harbored any of the previously reported mutations in any of the three genes, EIF1AX, PPM1D, and CHEK2. A number of previously reported single nucleotide polymorphisms (SNP) were found in CHEK2, PPM1D but not in EIF1AX. These include CHEK2 SNPs, rs375130261, rs200928781, rs540635787, rs142763740, and rs202104749. The PPM1D SNPs rs771831676 and rs61757742 were present in 1.49% and 0.74%, respectively. Each of these SNPs was present in a heterozygous form in 100% of the tumors. An additional analysis of these samples for the most frequently reported mutations in DTC such as BRAF
CONCLUSIONS: Except for a rare A113_splice site mutation in EIF1AX, other recently described somatic mutations in EIF1AX, PPM1D, and CHEK2 were absent in this large series of patients with TC from a different racial group (Saudi Arabia). This might be related to the different techniques used (PCR and direct sequencing) or low density of the mutants. It might also reflect racial differences in the rate of these mutations.

Schoch S, Sen V, Gajewski S, et al.
Activity profile of the cisplatin analogue PN149 in different tumor cell lines.
Biochem Pharmacol. 2018; 156:109-119 [PubMed] Related Publications
The efficacy of the anticancer drug cisplatin is restricted by tumor cell resistance and occurrence of severe side effects. One strategy to overcome these limitations is the development of new, improved platinum drugs. Previous investigations showed that platinum(IV)-nitroxyl complexes are able to circumvent cisplatin resistance in bladder cancer cells. In the present study the mode of action of the platinum(IV)-nitroxyl complex PN149 was investigated in the bladder cancer cell line RT112 and the renal cell carcinoma cell line A498 on the molecular and cellular level. Gene expression analysis showed that PN149 induced genes related to DNA damage response (RRM2B, GADD45A), cell cycle regulation (CDKN1A, PLK3, PPM1D) as well as those coding for the pro-apoptotic factors PUMA and Noxa. These findings on the transcriptional level were confirmed on the functional level revealing that PN149 treatment increased levels of p53 and resulted in cell cycle arrest and drug-induced cytotoxicity via induction of apoptosis. Regarding the expression of oxidative-stress sensitive genes, PN149 induced FTH1, GCLC, HMOX1 and TXNRD1 but relevant effects were restricted to RT112 cells treated with 50 µM. The pro-inflammatory IL-8 was induced by PN149 in RT112 but not A498 cells indicating a cell-type specific activation. Taken together, PN149 possessed promising activity in different tumor cell lines rendering it an interesting alternative to cisplatin in chemotherapy.

Adams O, Janser FA, Dislich B, et al.
A specific expression profile of LC3B and p62 is associated with nonresponse to neoadjuvant chemotherapy in esophageal adenocarcinomas.
PLoS One. 2018; 13(6):e0197610 [PubMed] Free Access to Full Article Related Publications
Paclitaxel is a powerful chemotherapeutic drug, used for the treatment of many cancer types, including esophageal adenocarcinomas (EAC). Autophagy is a lysosome-dependent degradation process maintaining cellular homeostasis. Defective autophagy has been implicated in cancer biology and therapy resistance. We aimed to assess the impact of autophagy on chemotherapy response in EAC, with a special focus on paclitaxel. Responsiveness of EAC cell lines, OE19, FLO-1, OE33 and SK-GT-4, to paclitaxel was assessed using Alamar Blue assays. Autophagic flux upon paclitaxel treatment in vitro was assessed by immunoblotting of LC3B-II and quantitative assessment of WIP1 mRNA. Immunohistochemistry for the autophagy markers LC3B and p62 was applied on tumor tissue from 149 EAC patients treated with neoadjuvant chemotherapy, including pre- and post-therapeutic samples (62 matched pairs). Tumor response was assessed by histology. For comparison, previously published data on 114 primary resected EAC cases were used. EAC cell lines displayed differing responsiveness to paclitaxel treatment; however this was not associated with differential autophagy regulation. High p62 cytoplasmic expression on its own (p ≤ 0.001), or in combination with low LC3B (p = 0.034), was associated with nonresponse to chemotherapy, regardless of whether or not the regiments contained paclitaxel, but there was no independent prognostic value of LC3B or p62 expression patterns for EAC after neoadjuvant treatment. p62 and related pathways, most likely other than autophagy, play a role in chemotherapeutic response in EAC in a clinical setting. Therefore p62 could be a novel therapeutic target to overcome chemoresistance in EAC.

Wong TN, Miller CA, Jotte MRM, et al.
Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential.
Nat Commun. 2018; 9(1):455 [PubMed] Free Access to Full Article Related Publications
Hematopoietic clones harboring specific mutations may expand over time. However, it remains unclear how different cellular stressors influence this expansion. Here we characterize clonal hematopoiesis after two different cellular stressors: cytotoxic therapy and hematopoietic transplantation. Cytotoxic therapy results in the expansion of clones carrying mutations in DNA damage response genes, including TP53 and PPM1D. Analyses of sorted populations show that these clones are typically multilineage and myeloid-biased. Following autologous transplantation, most clones persist with stable chimerism. However, DNMT3A mutant clones often expand, while PPM1D mutant clones often decrease in size. To assess the leukemic potential of these expanded clones, we genotyped 134 t-AML/t-MDS samples. Mutations in non-TP53 DNA damage response genes are infrequent in t-AML/t-MDS despite several being commonly identified after cytotoxic therapy. These data suggest that different hematopoietic stressors promote the expansion of distinct long-lived clones, carrying specific mutations, whose leukemic potential depends partially on the mutations they harbor.

Bai F, Zhou H, Fu Z, et al.
NF-κB-induced WIP1 expression promotes colorectal cancer cell proliferation through mTOR signaling.
Biomed Pharmacother. 2018; 99:402-410 [PubMed] Related Publications
Colorectal cancer (CRC) is one of the major causes of cancer deaths worldwide. Wild-type p53-induced protein 1 (WIP1) is overexpressed in multiple human cancers and acted as an oncogene. This study was aimed to investigate the effect of WIP1 in colorectal cancer growth and analyzed underlying mechanisms. Herein, we determined WIP1 expression in CRC tissues and cell lines, as well as evaluated its detailed function in CRC cell proliferation. Several factors have been reported to mediate WIP1 effects; herein, we examined the involvement of mTOR and p21 in WIP1 regulation of CRC cell proliferation. Moreover, NF-κB has been regarded as a positive transcriptional regulator of WIP1 to activate its expression. NF-κB knockdown suppressed CRC cell proliferation, which could be reversed by WIP1 overexpression, through p21 and mTOR. Further, we examined the binding of NF-κB to the promoter region of WIP1. In CRC tissues, NF-κB expression was significantly up-regulated, and positively correlated with WIP1 expression, suggesting that inhibiting NF-κB expression to attenuate its activating effect on WIP1 expression presented a promising strategy of controlling excess proliferation of CRC cell. In summary, WIP1 promotes CRC proliferation through p21 and mTOR, both downstream targets of p53; NF-κB served as a positive transcriptional regulator of WIP1 to activate its expression and affect its function in CRC cells. Our finding provided a novel strategy for treatment for CRC.

Fox CR, Parks GD
Parainfluenza Virus Infection Sensitizes Cancer Cells to DNA-Damaging Agents: Implications for Oncolytic Virus Therapy.
J Virol. 2018; 92(7) [PubMed] Free Access to Full Article Related Publications
A parainfluenza virus 5 (PIV5) with mutations in the P/V gene (P/V-CPI

Wang YW, Zhang W, Ma R
Bioinformatic identification of chemoresistance-associated microRNAs in breast cancer based on microarray data.
Oncol Rep. 2018; 39(3):1003-1010 [PubMed] Free Access to Full Article Related Publications
Breast cancer is the most commonly diagnosed cancer among females, and chemoresistance constitutes a major clinical obstacle to the treatment of this disease. MicroRNAs (miRNAs) are related to human cancer development, progression and drug resistance. To identify breast cancer chemoresistance-associated miRNAs, miRNA microarray dataset GSE71142, including five chemoresistant breast cancer tissues and five chemosensitive tissues, was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed miRNAs (DE-miRNAs) were obtained by t-test and the potential target genes were predicted by miRWalk2.0. Functional and pathway enrichment analysis by WebGestalt was performed for the potential target genes of DE-miRNAs. Protein-protein interaction (PPI) network was established by STRING database and visualized by Cytoscape software. Enriched transcription factors by the target genes were obtained from FunRich. Breast cancer-associated miRNA‑gene pairs were identified from miRWalk2.0. A total of 22 DE-miRNAs were screened out, including 10 upregulated miRNAs (e.g., miR-196a-5p) and 12 downregulated miRNAs (e.g., miR-4472) in the chemoresistant breast cancer tissues, compared with chemosensitive tissues. In total 1,278 target genes were screened out, and they were involved in breast cancer-related pathways such as pathways in cancer, signaling pathways regulating pluripotency of stem cells, endocrine resistance, breast cancer, mTOR signaling and Hippo signaling pathway. NOTCH1 and MAPK14 were identified as hub genes in the PPI network. EGR1 and SP1 were the most enriched transcription factors by the target genes. Several breast cancer-associated miRNA-gene pairs including miR-214-TP53 and miR-16-PPM1D were identified. The current bioinformatics study of miRNAs based on microarray may offer a new understanding into the mechanisms of breast cancer chemoresistance, and may identify novel miRNA therapeutic targets.

Wu CE, Esfandiari A, Ho YH, et al.
Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma.
Br J Cancer. 2018; 118(4):495-508 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cutaneous melanoma is the most serious skin malignancy and new therapeutic strategies are needed for advanced melanoma. TP53 mutations are rare in cutaneous melanoma and hence activation of wild-type p53 is a potential therapeutic strategy in cutaneous melanoma. Here, we investigated the WIP1 inhibitor, GSK2830371, and MDM2-p53 binding antagonists (nutlin-3, RG7388 and HDM201) alone and in combination treatment in cutaneous melanoma cell lines and explored the mechanistic basis of these responses in relation to the genotype and induced gene expression profile of the cells.
METHODS: A panel of three p53
RESULTS: GSK2830371, at doses (⩽10 μM) that alone had no growth-inhibitory or cytotoxic effects on the cells, nevertheless significantly potentiated the growth-inhibitory and clonogenic cell killing effects of MDM2 inhibitors in p53
CONCLUSIONS: GSK2830371, a WIP1 inhibitor, at doses with no growth-inhibitory activity alone, potentiated the growth-inhibitory and cytotoxic activity of MDM2 inhibitors by increasing phosphorylation, acetylation and stabilisation of p53 in cutaneous melanoma cells in a functional p53-dependent manner.

Nomura M, Mukasa A, Nagae G, et al.
Distinct molecular profile of diffuse cerebellar gliomas.
Acta Neuropathol. 2017; 134(6):941-956 [PubMed] Free Access to Full Article Related Publications
Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the "RTK I (PDGFRA)" group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.

Coombs CC, Zehir A, Devlin SM, et al.
Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes.
Cell Stem Cell. 2017; 21(3):374-382.e4 [PubMed] Free Access to Full Article Related Publications
Clonal hematopoiesis (CH), as evidenced by recurrent somatic mutations in leukemia-associated genes, commonly occurs among aging human hematopoietic stem cells. We analyzed deep-coverage, targeted, next-generation sequencing (NGS) data of paired tumor and blood samples from 8,810 individuals to assess the frequency and clinical relevance of CH in patients with non-hematologic malignancies. We identified CH in 25% of cancer patients, with 4.5% harboring presumptive leukemia driver mutations (CH-PD). CH was associated with increased age, prior radiation therapy, and tobacco use. PPM1D and TP53 mutations were associated with prior exposure to chemotherapy. CH and CH-PD led to an increased incidence of subsequent hematologic cancers, and CH-PD was associated with shorter patient survival. These data suggest that CH occurs in an age-dependent manner and that specific perturbations can enhance fitness of clonal hematopoietic stem cells, which can impact outcome through progression to hematologic malignancies and through cell-non-autonomous effects on solid tumor biology.

Zink F, Stacey SN, Norddahl GL, et al.
Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly.
Blood. 2017; 130(6):742-752 [PubMed] Free Access to Full Article Related Publications
Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single dominant hematopoietic stem cell lineage. Somatic mutations in candidate driver (CD) genes are thought to be responsible for at least some cases of CH. Using whole-genome sequencing of 11 262 Icelanders, we found 1403 cases of CH by using barcodes of mosaic somatic mutations in peripheral blood, whether or not they have a mutation in a CD gene. We find that CH is very common in the elderly, trending toward inevitability. We show that somatic mutations in

Pecháčková S, Burdová K, Macurek L
WIP1 phosphatase as pharmacological target in cancer therapy.
J Mol Med (Berl). 2017; 95(6):589-599 [PubMed] Free Access to Full Article Related Publications
DNA damage response (DDR) pathway protects cells from genome instability and prevents cancer development. Tumor suppressor p53 is a key molecule that interconnects DDR, cell cycle checkpoints, and cell fate decisions in the presence of genotoxic stress. Inactivating mutations in TP53 and other genes implicated in DDR potentiate cancer development and also influence the sensitivity of cancer cells to treatment. Protein phosphatase 2C delta (referred to as WIP1) is a negative regulator of DDR and has been proposed as potential pharmaceutical target. Until recently, exploitation of WIP1 inhibition for suppression of cancer cell growth was compromised by the lack of selective small-molecule inhibitors effective at cellular and organismal levels. Here, we review recent advances in development of WIP1 inhibitors and discuss their potential use in cancer treatment.

Tedaldi G, Tebaldi M, Zampiga V, et al.
Multiple-gene panel analysis in a case series of 255 women with hereditary breast and ovarian cancer.
Oncotarget. 2017; 8(29):47064-47075 [PubMed] Free Access to Full Article Related Publications
As new genes predisposing to breast (BC) and ovarian cancer (OC) are constantly emerging, the use of panels of genes analyzed by Next-Generation Sequencing (NGS) is increasing in clinical diagnostics. The identification of a large number of new germline mutations allows for deeper knowledge of cancer predisposition, although raising many questions about patient management.BC and OC patients recruited by our counseling service between 2012-2015 were included in this study. DNA was extracted from peripheral blood and a panel of 94 genes involved in hereditary tumors was analyzed by NGS. Patient clinical features of BC and OC and cancer family history were collected and compared to the patient genetic profile.A total of 255 women were analyzed, 57 of whom had a pathogenic mutation in BRCA1/2 genes, and 17 carried pathogenic mutations in other genes, such as PALB2, ATM, BRIP1, RAD51D, MSH6, PPM1D, RECQL4, ERCC3, TSC2, SLX4 and other Fanconi anemia genes.Patients with a pathogenic mutation in genes other than BRCA1 and BRCA2 showed no significant difference from the BRCA1/2-mutated carriers with respect to age at diagnosis and clinical features, suggesting that mutations in other genes could pose a high risk of cancer development.These patients had a much higher percentage of bilateral breast cancer (BBC) and a lower rate of OC than BRCA-mutated patients and patients with no pathogenic mutations: as a consequence, the surveillance protocol should be customized to the patient genetic characteristics.

Chen Z, Wang L, Yao D, et al.
Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis.
Sci Rep. 2016; 6:38011 [PubMed] Free Access to Full Article Related Publications
Neuroblastoma (NB) is the most common extracranial tumor in children. Unlike in most adult tumors, tumor suppressor protein 53 (p53) mutations occur with a relatively low frequency in NB and the downstream function of p53 is intact in NB cell lines. Wip1 is a negative regulator of p53 and hindrance of Wip1 activity by novel inhibitor GSK2830371 is a potential strategy to activate p53's tumor suppressing function in NB. Yet, the in vivo efficacy and the possible mechanisms of GSK2830371 in NB have not yet been elucidated. Here we report that novel Wip1 inhibitor GSK2830371 induced Chk2/p53-mediated apoptosis in NB cells in a p53-dependent manner. In addition, GSK2830371 suppressed the colony-formation potential of p53 wild-type NB cell lines. Furthermore, GSK2830371 enhanced doxorubicin- (Dox) and etoposide- (VP-16) induced cytotoxicity in a subset of NB cell lines, including the chemoresistant LA-N-6 cell line. More importantly, GSK2830371 significantly inhibited tumor growth in an orthotopic xenograft NB mouse model by inducing Chk2/p53-mediated apoptosis in vivo. Taken together, this study suggests that GSK2830371 induces Chk2/p53-mediated apoptosis both in vitro and in vivo in a p53 dependent manner.

Yang S, Dong S, Qu X, et al.
Clinical significance of Wip1 overexpression and its association with the p38MAPK/p53/p16 pathway in NSCLC.
Mol Med Rep. 2017; 15(2):719-723 [PubMed] Free Access to Full Article Related Publications
Wip1 is deregulated in numerous human malignancies. However, its roles in non‑small cell lung cancer (NSCLC) remain unclear. In the current study, the expression of Wip1 was investigated in NSCLC and its clinical significance was detected. Immunohistochemical staining was used to measure the expression of (wild‑type p53 induced phosphatase 1) Wip1, p38 mitogen‑activated protein kinase (MAPK), p53, p16 protein in a group of 60 NSCLC and 20 normal lung tissues. In addition, western blotting was performed to detect the Wip1 protein in fresh tissues. The correlations between clinical characteristics and Wip1 expression were analyzed using SPSS, version 16.0 software. The expression of Wip1 was positive in 63.3% (38/60) of NSCLC tissues, and in none of the normal lung tissues (0/20; P<0.01). In addition, Wip1 overexpression was significantly associated with tumor length and differentiation (P=0.008 and 0.03, respectively). The expression of Wip1 was negatively correlated with that of p38MAPK, p53 and p16 (r=‑0.284, ‑0.352 and ‑0.348, respectively). The results of the current study demonstrated that Wip1 was frequently overexpressed in NSCLC, which may serve an essential role in the p38MAPK/p53/p16 signaling pathway.

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.

Wen J, Lee J, Malhotra A, et al.
WIP1 modulates responsiveness to Sonic Hedgehog signaling in neuronal precursor cells and medulloblastoma.
Oncogene. 2016; 35(42):5552-5564 [PubMed] Free Access to Full Article Related Publications
High-level amplification of the protein phosphatase PPM1D (WIP1) is present in a subset of medulloblastomas (MBs) that have an expression profile consistent with active Sonic Hedgehog (SHH) signaling. We found that WIP1 overexpression increased expression of Shh target genes and cell proliferation in response to Shh stimulation in NIH3T3 and cerebellar granule neuron precursor cells in a p53-independent manner. Thus, we developed a mouse in which WIP1 is expressed in the developing brain under control of the Neurod2 promoter (ND2:WIP1). The external granule layer (EGL) in early postnatal ND2:WIP1 mice exhibited increased proliferation and expression of Shh downstream targets. MB incidence increased and survival decreased when ND2:WIP1 mice were crossed with an Shh-activated MB mouse model. Conversely, Wip1 knockout significantly suppressed MB formation in two independent mouse models of Shh-activated MB. Furthermore, Wip1 knockdown or treatment with a WIP1 inhibitor suppressed the effects of Shh stimulation and potentiated the growth inhibitory effects of SHH pathway-inhibiting drugs in Shh-activated MB cells in vitro. This suggests an important cross-talk between SHH and WIP1 pathways that accelerates tumorigenesis and supports WIP1 inhibition as a potential treatment strategy for MB.

Kojima K, Maeda A, Yoshimura M, et al.
The pathophysiological significance of PPM1D and therapeutic targeting of PPM1D-mediated signaling by GSK2830371 in mantle cell lymphoma.
Oncotarget. 2016; 7(43):69625-69637 [PubMed] Free Access to Full Article Related Publications
PPM1D is a serine/threonine phosphatase that negatively regulates key DNA damage response proteins, such as p53, p38 MAPK, histone H2A.X, and ATM. We investigated the pathophysiological significance of PPM1D and its therapeutic targeting by the novel PPM1D inhibitor GSK2830371 in mantle cell lymphoma (MCL). Oncomine-based analyses indicated increased PPM1D mRNA levels in MCL cells compared with their normal counterpart cells. Higher PPM1D expression was associated with higher expression of the proliferation gene signature and poorer prognosis in patients. Eight MCL (three p53 wild-type and five mutant) cell lines were exposed to GSK2830371. GSK2830371 inhibited the cell growth, being prominent in p53 wild-type cells. GSK2830371 induced apoptosis in sensitive cells, as evidenced by induction of phosphatidylserine externalization and loss of mitochondrial membrane potential. p53 knockdown de-sensitized cell sensitivity. GSK2830371 increased the levels of total and Ser15-phosphorylated p53, and p53 targets p21 and PUMA. GSK2830371 and the MDM2 inhibitor Nutlin-3a acted synergistically in p53 wild-type cells. Interestingly, GSK2830371 sensitized MCL cells to bortezomib and doxorubicin in p53 wild-type and mutant cells; p38 signaling appeared to be involved in the GSK2830371/bortezomib lethality. PPM1D inhibition may represent a novel therapeutic strategy for MCL, which can be exploited in combination therapeutic strategies for MCL.

Kozakai Y, Kamada R, Furuta J, et al.
PPM1D controls nucleolar formation by up-regulating phosphorylation of nucleophosmin.
Sci Rep. 2016; 6:33272 [PubMed] Free Access to Full Article Related Publications
An increase of nucleolar number and size has made nucleoli essential markers for cytology and tumour development. However, the underlying basis for their structural integrity and abundance remains unclear. Protein phosphatase PPM1D was found to be up-regulated in different carcinomas including breast cancers. Here, we demonstrate for the first time that PPM1D regulates nucleolar formation via inducing an increased phosphorylation of the nucleolar protein NPM. We show that PPM1D overexpression induces an increase in the nucleolar number regardless of p53 status. We also demonstrated that specific sequential phosphorylation of NPM is important for nucleolar formation and that PPM1D is a novel upstream regulator of this phosphorylation pathway. These results enhance our understanding of the molecular mechanisms that govern nucleoli formation by demonstrating that PPM1D regulates nucleolar formation by regulating NPM phosphorylation status through a novel signalling pathway, PPM1D-CDC25C-CDK1-PLK1.

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.

Cardoso M, Paulo P, Maia S, Teixeira MR
Truncating and missense PPM1D mutations in early-onset and/or familial/hereditary prostate cancer patients.
Genes Chromosomes Cancer. 2016; 55(12):954-961 [PubMed] Related Publications
Truncating activating mutations in the last exon of PPM1D have been described in patients with breast, ovarian, colorectal and non-small cell lung cancer, but recent data indicate that they may be associated with previous chemotherapy. In this study we evaluated the prevalence of PPM1D mutations in white blood cells (WBC) of 462 patients with early-onset and/or familial/hereditary prostate cancer (PrCa) by sequencing the coding region of exon 6. Two truncating mutations were found in two patients (0.4%), both treated with androgen-ablation therapy but no chemotherapy prior to blood collection. Next generation sequencing analysis showed that the truncating variants were present in 21.4% and 32.4% of the reads, indicating that they were in mosaic in WBC, something that was confirmed by its absence in a different tissue from one of these patients. Additionally, nine patients (1.95%) were found to harbor non-synonymous germline mutations, with three patients sharing the same missense variant, c.1607G > A, p.Arg536Lys. This variant was predicted to be deleterious by different in silico tools and was not found in the 293 male control subjects tested. Large cohorts and/or functional evaluation are needed to clarify the nature of the truncating mosaic mutations in PrCa patients treated with and without androgen-ablation therapy and to evaluate the contribution of the recurrent missense variant to the risk of developing PrCa. © 2016 Wiley Periodicals, Inc.

Sriraman A, Radovanovic M, Wienken M, et al.
Cooperation of Nutlin-3a and a Wip1 inhibitor to induce p53 activity.
Oncotarget. 2016; 7(22):31623-38 [PubMed] Free Access to Full Article Related Publications
Targeting the Mdm2 oncoprotein by drugs has the potential of re-establishing p53 function and tumor suppression. However, Mdm2-antagonizing drug candidates, e. g. Nutlin-3a, often fail to abolish cancer cell growth sustainably. To overcome these limitations, we inhibited Mdm2 and simultaneously a second negative regulator of p53, the phosphatase Wip1/PPM1D. When combining Nutlin-3a with the Wip1 inhibitor GSK2830371 in the treatment of p53-proficient but not p53-deficient cells, we observed enhanced phosphorylation (Ser 15) and acetylation (Lys 382) of p53, increased expression of p53 target gene products, and synergistic inhibition of cell proliferation. Surprisingly, when testing the two compounds individually, largely distinct sets of genes were induced, as revealed by deep sequencing analysis of RNA. In contrast, the combination of both drugs led to an expression signature that largely comprised that of Nutlin-3a alone. Moreover, the combination of drugs, or the combination of Nutlin-3a with Wip1-depletion by siRNA, activated p53-responsive genes to a greater extent than either of the compounds alone. Simultaneous inhibition of Mdm2 and Wip1 enhanced cell senescence and G2/M accumulation. Taken together, the inhibition of Wip1 might fortify p53-mediated tumor suppression by Mdm2 antagonists.

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.

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