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PPM1D

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https://www.readbyqxmd.com/read/28486685/inhibition-of-ser-thr-phosphatase-ppm1d-induces-neutrophil-differentiation-in-hl-60-cells
#1
Rui Kamada, Fuki Kudoh, Fumihiko Yoshimura, Keiji Tanino, Kazuyasu Sakaguchi
Protein phosphatase Magnesium-dependent 1, Delta (PPM1D) is a wild-type p53-inducible Ser/Thr phosphatase that acts as a negative regulator of the p53 tumor suppressor. Gene amplification and overexpression of PPM1D have been reported in various cancers including leukemia and neuroblastoma. Therefore, PPM1D is a promising target in cancer therapy. It has been reported that PPM1D knockout mice exhibit neutrophilia in blood and show a defective immune response. Here, we found that inhibition of PPM1D induced neutrophil differentiation of human promyelocytic leukemia cell line HL-60...
May 9, 2017: Journal of Biochemistry
https://www.readbyqxmd.com/read/28483762/clonal-hematopoiesis-with-and-without-candidate-driver-mutations-is-common-in-the-elderly
#2
Florian Zink, Simon N Stacey, Gudmundur L Norddahl, Michael L Frigge, Olafur T Magnusson, Ingileif Jonsdottir, Thorgeir E Thorgeirsson, Asgeir Sigurdsson, Sigurjon A Gudjonsson, Julius Gudmundsson, Jon G Jonasson, Laufey Tryggvadottir, Thorvaldur Jonsson, Agnar Helgason, Arnaldur Gylfason, Patrick Sulem, Thorunn Rafnar, Unnur Thorsteinsdottir, Daniel F Gudbjartsson, Gisli Masson, Augustine Kong, Kari Stefansson
Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells are 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 1,403 cases of CH by using barcodes of mosaic somatic mutations in peripheral blood, irrespective of whether or not they have a mutation in a CD gene. We find that CH is very common in the elderly, trending towards inevitability...
May 8, 2017: Blood
https://www.readbyqxmd.com/read/28423363/multiple-gene-panel-analysis-in-a-case-series-of-255-women-with-hereditary-breast-and-ovarian-cancer
#3
Gianluca Tedaldi, Michela Tebaldi, Valentina Zampiga, Rita Danesi, Valentina Arcangeli, Mila Ravegnani, Ilaria Cangini, Francesca Pirini, Elisabetta Petracci, Andrea Rocca, Fabio Falcini, Dino Amadori, Daniele Calistri
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...
April 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28417018/dna-damage-induced-phosphatase-wip1-in-regulation-of-hematopoiesis-immune-system-and-inflammation
#4
REVIEW
B Uyanik, B B Grigorash, A R Goloudina, O N Demidov
PP2C serine-threonine phosphatase, Wip1, is an important regulator of stress response. Wip1 controls a number of critical cellular functions: proliferation, cell cycle arrest, senescence and programmed cell death, apoptosis or autophagy. Ppm1d, the gene encoding Wip1 phosphatase, is expressed in hematopoietic progenitors, stem cells, neutrophils, macrophages B and T lymphocytes in bone marrow and peripheral blood. The Wip1-/- mice display immunodeficiency, abnormal lymphoid histopathology in thymus and spleen, defects in B- and T-cell differentiation, as well as susceptibility to viral infection...
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/28343630/de-novo-truncating-mutations-in-the-last-and-penultimate-exons-of-ppm1d-cause-an-intellectual-disability-syndrome
#5
Sandra Jansen, Sinje Geuer, Rolph Pfundt, Rachel Brough, Priyanka Ghongane, Johanna C Herkert, Elysa J Marco, Marjolein H Willemsen, Tjitske Kleefstra, Mark Hannibal, Joseph T Shieh, Sally Ann Lynch, Frances Flinter, David R FitzPatrick, Alice Gardham, Birgitta Bernhard, Nicola Ragge, Ruth Newbury-Ecob, Raphael Bernier, Malin Kvarnung, E A Helena Magnusson, Marja W Wessels, Marjon A van Slegtenhorst, Kristin G Monaghan, Petra de Vries, Joris A Veltman, Christopher J Lord, Lisenka E L M Vissers, Bert B A de Vries
Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis...
April 6, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28248986/cellular-responses-and-gene-expression-profile-changes-due-to-bleomycin-induced-dna-damage-in-human-fibroblasts-in-space
#6
Tao Lu, Ye Zhang, Yared Kidane, Alan Feiveson, Louis Stodieck, Fathi Karouia, Govindarajan Ramesh, Larry Rohde, Honglu Wu
Living organisms in space are constantly exposed to radiation, toxic chemicals or reactive oxygen species generated due to increased levels of environmental and psychological stresses. Understanding the impact of spaceflight factors, microgravity in particular, on cellular responses to DNA damage is essential for assessing the radiation risk for astronauts and the mutation rate in microorganisms. In a study conducted on the International Space Station, confluent human fibroblasts in culture were treated with bleomycin for three hours in the true microgravity environment...
2017: PloS One
https://www.readbyqxmd.com/read/28177873/prognostic-mutations-in-myelodysplastic-syndrome-after-stem-cell-transplantation
#7
R Coleman Lindsley, Wael Saber, Brenton G Mar, Robert Redd, Tao Wang, Michael D Haagenson, Peter V Grauman, Zhen-Huan Hu, Stephen R Spellman, Stephanie J Lee, Michael R Verneris, Katharine Hsu, Katharina Fleischhauer, Corey Cutler, Joseph H Antin, Donna Neuberg, Benjamin L Ebert
BACKGROUND: Genetic mutations drive the pathogenesis of the myelodysplastic syndrome (MDS) and are closely associated with clinical phenotype. Therefore, genetic mutations may predict clinical outcomes after allogeneic hematopoietic stem-cell transplantation. METHODS: We performed targeted mutational analysis on samples obtained before transplantation from 1514 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research Repository between 2005 and 2014...
February 9, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28105167/cisplatin-induces-hepg2-cell-cycle-arrest-through-targeting-specific-long-noncoding-rnas-and-the-p53-signaling-pathway
#8
Ping Wang, Jiayue Cui, Jihong Wen, Yunhui Guo, Liangzi Zhang, Xia Chen
Cisplatin has been used effectively in the treatment of hepatocellular carcinoma (HCC). Long noncoding RNAs (lncRNAs) were recently reported to contribute to the pathogenesis and progression of HCC. Their molecular mechanism related to cisplatin treatment remains unclear. The purpose of this study is to identify specific lncRNAs and to clarify their functions in HCC after cisplatin exposure. Reannotation and identification of differentially expressed lncRNAs were performed using the microarray data set GSE38122 in the Gene Expression Omnibus database...
December 2016: Oncology Letters
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
#9
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
#10
EDITORIAL
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
#11
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...
November 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
#12
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...
November 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
#13
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...
October 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27619510/ppm1d-controls-nucleolar-formation-by-up-regulating-phosphorylation-of-nucleophosmin
#14
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
#15
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
#16
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...
October 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
#17
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
#18
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
#19
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
#20
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
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