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PPM1D

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https://www.readbyqxmd.com/read/27802111/identification-of-differential-gene-expression-patterns-after-acute-exposure-to-high-and-low-doses-of-low-let-ionizing-radiation-in-a-reconstituted-human-skin-tissue
#1
Susan C Tilton, Lye Meng Markillie, Spencer Hays, Ronald C Taylor, David L Stenoien
In this study we utilized a systems biology approach to identify dose- (0.1, 2.0 and 10 Gy) and time- (3 and 8 h) dependent responses to acute ionizing radiation exposure in a complex tissue, reconstituted human skin. The low dose used here (0.1 Gy) falls within the range of certain medical diagnostic procedures. Of the two higher doses used, 2.0 Gy is typically administered for radiotherapy, while 10 Gy is lethal. Because exposure to any of these doses is possible after an intentional or accidental radiation events, biomarkers are needed to rapidly and accurately triage potentially exposed individuals...
November 2016: Radiation Research
https://www.readbyqxmd.com/read/27713908/ppm1d-wip1-in-medulloblastoma
#2
Mwangala P Akamandisa, Rita Nahta, Robert C Castellino
No abstract text is available yet for this article.
2016: Oncoscience
https://www.readbyqxmd.com/read/27670885/identification-of-ppm1d-as-an-essential-ulk1-phosphatase-for-genotoxic-stress-induced-autophagy
#3
Satoru Torii, Tatsushi Yoshida, Satoko Arakawa, Shinya Honda, Akira Nakanishi, Shigeomi Shimizu
Autophagy is an evolutionary conserved process that degrades subcellular constituents. Unlike starvation-induced autophagy, the molecular mechanism of genotoxic stress-induced autophagy has not yet been fully elucidated. In this study, we analyze the molecular mechanism of genotoxic stress-induced autophagy and identify an essential role of dephosphorylation of the Unc51-like kinase 1 (Ulk1) at Ser(637), which is catalyzed by the protein phosphatase 1D magnesium-dependent delta isoform (PPM1D). We show that after exposure to genotoxic stress, PPM1D interacts with and dephosphorylates Ulk1 at Ser(637) in a p53-dependent manner...
September 26, 2016: EMBO Reports
https://www.readbyqxmd.com/read/27633132/combination-of-lentivirus-mediated-silencing-of-ppm1d-and-temozolomide-chemotherapy-eradicates-malignant-glioma-through-cell-apoptosis-and-cell-cycle-arrest
#4
Peng Wang, Jing-An Ye, Chong-Xian Hou, Dong Zhou, Sheng-Quan Zhan
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...
September 14, 2016: Oncology Reports
https://www.readbyqxmd.com/read/27626308/the-pathophysiological-significance-of-ppm1d-and-therapeutic-targeting-of-ppm1d-mediated-signaling-by-gsk2830371-in-mantle-cell-lymphoma
#5
Kensuke Kojima, Aya Maeda, Mariko Yoshimura, Yuki Nishida, Shinya Kimura
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...
September 8, 2016: Oncotarget
https://www.readbyqxmd.com/read/27619510/ppm1d-controls-nucleolar-formation-by-up-regulating-phosphorylation-of-nucleophosmin
#6
Yuuki Kozakai, Rui Kamada, Junya Furuta, Yuhei Kiyota, Yoshiro Chuman, Kazuyasu Sakaguchi
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...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27565380/phosphorylated-tandembp-a-unique-protein-substrate-for-protein-phosphatase-assay
#7
Yasunori Sugiyama, Sho Yamashita, Yuuki Uezato, Yukako Senga, Syouichi Katayama, Naoki Goshima, Yasushi Shigeri, Noriyuki Sueyoshi, Isamu Kameshita
To analyze a variety of protein phosphatases, we developed phosphorylated TandeMBP (P-TandeMBP), in which two different mouse myelin basic protein isoforms were fused in tandem, as a protein phosphatase substrate. P-TandeMBP was prepared efficiently in four steps: (1) phosphorylation of TandeMBP by a protein kinase mixture (Ca(2+)/calmodulin-dependent protein kinase Iδ, casein kinase 1δ, and extracellular signal-regulated kinase 2); (2) precipitation of both P-TandeMBP and protein kinases to remove ATP, Pi, and ADP; (3) acid extraction of P-TandeMBP with HCl to remove protein kinases; and (4) neutralization of the solution that contains P-TandeMBP with Tris...
November 15, 2016: Analytical Biochemistry
https://www.readbyqxmd.com/read/27485113/identification-of-novel-biomarkers-associated-with-poor-patient-outcomes-in-invasive-breast-carcinoma
#8
Renata A Canevari, Fabio A Marchi, Maria A C Domingues, Victor Piana de Andrade, José R F Caldeira, Sergio Verjovski-Almeida, Silvia R Rogatto, Eduardo M Reis
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...
August 2, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/27479843/meta-analysis-of-2-104-trios-provides-support-for-10-new-genes-for-intellectual-disability
#9
Stefan H Lelieveld, Margot R F Reijnders, Rolph Pfundt, Helger G Yntema, Erik-Jan Kamsteeg, Petra de Vries, Bert B A de Vries, Marjolein H Willemsen, Tjitske Kleefstra, Katharina Löhner, Maaike Vreeburg, Servi J C Stevens, Ineke van der Burgt, Ernie M H F Bongers, Alexander P A Stegmann, Patrick Rump, Tuula Rinne, Marcel R Nelen, Joris A Veltman, Lisenka E L M Vissers, Han G Brunner, Christian Gilissen
To identify candidate genes for intellectual disability, we performed a meta-analysis on 2,637 de novo mutations, identified from the exomes of 2,104 patient-parent trios. Statistical analyses identified 10 new candidate ID genes: DLG4, PPM1D, RAC1, SMAD6, SON, SOX5, SYNCRIP, TCF20, TLK2 and TRIP12. In addition, we show that these genes are intolerant to nonsynonymous variation and that mutations in these genes are associated with specific clinical ID phenotypes.
September 2016: Nature Neuroscience
https://www.readbyqxmd.com/read/27401275/truncating-and-missense-ppm1d-mutations-in-early-onset-and-or-familial-hereditary-prostate-cancer-patients
#10
Marta Cardoso, Paula Paulo, Sofia Maia, Manuel R Teixeira
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...
July 12, 2016: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/27183917/cooperation-of-nutlin-3a-and-a-wip1-inhibitor-to-induce-p53-activity
#11
Anusha Sriraman, Marija Radovanovic, Magdalena Wienken, Zeynab Najafova, Yizhu Li, Matthias Dobbelstein
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...
May 31, 2016: Oncotarget
https://www.readbyqxmd.com/read/27086929/wip1-modulates-responsiveness-to-sonic-hedgehog-signaling-in-neuronal-precursor-cells-and-medulloblastoma
#12
J Wen, J Lee, A Malhotra, R Nahta, A R Arnold, M C Buss, B D Brown, C Maier, A M Kenney, M Remke, V Ramaswamy, M D Taylor, R C Castellino
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)...
April 18, 2016: Oncogene
https://www.readbyqxmd.com/read/27073481/association-between-overexpression-of-wip1-and-prognosis-of-patients-with-non-small-cell-lung-cancer
#13
Min Zhao, Hongbin Zhang, Guiyun Zhu, Jian Liang, Ning Chen, Yonghui Yang, Xiangcun Liang, Hongmei Cai, Wei Liu
Wild-type p53-induced phosphatase 1 (Wip1), also termed PPM1D, is a member of the protein phosphatase 2C family, which is characterized by distinctive oncogenic properties. Overexpression of Wip1 is observed in certain types of human tumors that are associated with significantly poor prognosis. The present study aimed to detect the expression of Wip1 in non-small cell lung cancer (NSCLC) and to analyze its prognostic value in such patients. The protein expression level of Wip1 was compared between NSCLC and normal lung tissue specimens using by immunohistochemistry, and it was found that Wip1 was highly expressed in NSCLCs but was absent or weakly expressed in normal lung tissues...
April 2016: Oncology Letters
https://www.readbyqxmd.com/read/27048880/spatial-and-temporal-homogeneity-of-driver-mutations-in-diffuse-intrinsic-pontine-glioma
#14
Hamid Nikbakht, Eshini Panditharatna, Leonie G Mikael, Rui Li, Tenzin Gayden, Matthew Osmond, Cheng-Ying Ho, Madhuri Kambhampati, Eugene I Hwang, Damien Faury, Alan Siu, Simon Papillon-Cavanagh, Denise Bechet, Keith L Ligon, Benjamin Ellezam, Wendy J Ingram, Caedyn Stinson, Andrew S Moore, Katherine E Warren, Jason Karamchandani, Roger J Packer, Nada Jabado, Jacek Majewski, Javad Nazarian
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...
April 6, 2016: Nature Communications
https://www.readbyqxmd.com/read/26942600/expression-and-gene-doses-changes-of-the-p53-regulator-ppm1d-in-meningiomas-a-role-in-meningioma-progression
#15
Shinjiro Fukami, Markus J Riemenschneider, Michihiro Kohno, Hans Jakob Steiger
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...
July 2016: Brain Tumor Pathology
https://www.readbyqxmd.com/read/26883108/inhibition-of-wip1-phosphatase-sensitizes-breast-cancer-cells-to-genotoxic-stress-and-to-mdm2-antagonist-nutlin-3
#16
Sona Pechackova, Kamila Burdova, Jan Benada, Petra Kleiblova, Gabriela Jenikova, Libor Macurek
PP2C family serine/threonine phosphatase WIP1 acts as a negative regulator of the tumor suppressor p53 and is implicated in silencing of cellular responses to genotoxic stress. Chromosomal locus 17q23 carrying the PPM1D (coding for WIP1) is commonly amplified in breast carcinomas and WIP1 was proposed as potential pharmacological target. Here we employed a cellular model with knocked out PPM1D to validate the specificity and efficiency of GSK2830371, novel small molecule inhibitor of WIP1. We have found that GSK2830371 increased activation of the DNA damage response pathway to a comparable level as the loss of PPM1D...
March 22, 2016: Oncotarget
https://www.readbyqxmd.com/read/26847329/somatic-mosaic-mutations-in-ppm1d-and-tp53-in-the-blood-of-women-with-ovarian-carcinoma
#17
Elizabeth M Swisher, Maria I Harrell, Barbara M Norquist, Tom Walsh, Mark Brady, Ming Lee, Robert Hershberg, Kimberly R Kalli, Heather Lankes, Eric Q Konnick, Colin C Pritchard, Bradley J Monk, John K Chan, Robert Burger, Scott H Kaufmann, Michael J Birrer
IMPORTANCE: Somatic mosaic mutations in PPM1D have been reported in patients with breast cancer, lung cancer, and ovarian cancer (OC), but cause or effect has not been established. OBSERVATIONS: To test the hypothesis that somatic mosaic mutations are associated with chemotherapy exposure, we used massively parallel sequencing to quantitate mutations in peripheral blood mononuclear cells (PBMCs) of 686 women with primary OC (n = 412) or relapsed OC (n = 274). The frequency of somatic mosaic PPM1D mutations in PBMCs was significantly associated with prior chemotherapy (P < ...
March 2016: JAMA Oncology
https://www.readbyqxmd.com/read/26832796/chemical-inhibition-of-wild-type-p53-induced-phosphatase-1-wip1-ppm1d-by-gsk2830371-potentiates-the-sensitivity-to-mdm2-inhibitors-in-a-p53-dependent-manner
#18
Arman Esfandiari, Thomas A Hawthorne, Sirintra Nakjang, John Lunec
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...
March 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/26823519/ppm1d-mosaic-truncating-variants-in-ovarian-cancer-cases-may-be-treatment-related-somatic-mutations
#19
Paul D P Pharoah, Honglin Song, Ed Dicks, Maria P Intermaggio, Patricia Harrington, Caroline Baynes, Kathryn Alsop, Natalia Bogdanova, Mine S Cicek, Julie M Cunningham, Brooke L Fridley, Aleksandra Gentry-Maharaj, Peter Hillemanns, Shashi Lele, Jenny Lester, Valerie McGuire, Kirsten B Moysich, Samantha Poblete, Weiva Sieh, Lara Sucheston-Campbell, Martin Widschwendter, Alice S Whittemore, Thilo Dörk, Usha Menon, Kunle Odunsi, Ellen L Goode, Beth Y Karlan, David D Bowtell, Simon A Gayther, Susan J Ramus
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...
March 2016: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/26809466/protein-phosphatase-magnesium-dependent-1%C3%AE-is-a-novel-tumor-marker-and-target-in-hepatocellular-carcinoma
#20
Zhi Xu, Chunxiang Cao, Haiyan Xia, Shujing Shi, Lingzhi Hong, Xiaowei Wei, Dongying Gu, Jianmin Bian, Zijun Liu, Wenbin Huang, Yixin Zhang, Song He, Nikki Pui-Yue Lee, Jinfei Chen
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...
March 2016: Frontiers of Medicine
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