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https://www.readbyqxmd.com/read/30051366/defining-non-inferiority-margins-for-quality-of-surgical-resection-for-rectal-cancer-a-delphi-consensus-study
#1
Sergio A Acuna, Tyler R Chesney, Sonali T Amarasekera, Nancy N Baxter
INTRODUCTION: Quality of surgical resection metrics (QSRMs) have been used as surrogates for long-term oncologic outcomes in non-inferiority randomized clinical trials (RCTs) comparing laparoscopic and open surgery for rectal cancer. However, non-inferiority margins (ΔNI ) for QSRMs have not been previously defined. METHODS: A two-round, web-based Delphi was used to define ΔNI for four QSRMs: positive circumferential resection margin (CRM), incomplete plane of mesorectal excision (PME), positive distal resection margin (DRM), and a composite of these outcomes...
July 26, 2018: Annals of Surgical Oncology
https://www.readbyqxmd.com/read/29997510/cornel-iridoid-glycoside-inhibits-tau-hyperphosphorylation-via-regulating-cross-talk-between-gsk-3%C3%AE-and-pp2a-signaling
#2
Cuicui Yang, Xuelian Li, Wenbin Gao, Qi Wang, Li Zhang, Yali Li, Lin Li, Lan Zhang
Neurofibrillary pathology contributes to neuronal dysfunction and correlates with the clinical progression of Alzheimer's disease (AD). Tau phosphorylation is mainly regulated by a balance of glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) activities. Cornel iridoid glycoside (CIG) is a main component extracted from Cornus officinalis . The purpose of this study was to investigate the effects of CIG on GSK-3β and PP2A, thus to explore the mechanisms of CIG to inhibit tau hyperphosphorylation...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29950985/leucine-carboxyl-methyltransferase-downregulation-and-protein-phosphatase-methylesterase-upregulation-contribute-toward-the-inhibition-of-protein-phosphatase-2a-by-%C3%AE-synuclein
#3
Hao Tian, Yongquan Lu, Jia Liu, Weijin Liu, Lingling Lu, Chunli Duan, Ge Gao, Hui Yang
The pathology of Parkinson's disease (PD) is characterized by intracellular neurofibrillary tangles of phosphorylated α-synuclein (α-syn). Protein phosphatase 2A (PP2A) is responsible for α-syn dephosphorylation. Previous work has demonstrated that α-syn can regulate PP2A activity. However, the mechanisms underlying α-syn regulation of PP2A activity are not well understood. In this study, we found that α-syn overexpression induced increased α-syn phosphorylation at serine 129 (Ser129), and PP2A inhibition, in vitro and in vivo ...
2018: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29752834/h-2-o-2-induces-pp2a-demethylation-to-downregulate-mtorc1-signaling-in-hek293-cells
#4
Shen Tang, Fu Qin, Xinhang Wang, Ziwei Liang, Haiqing Cai, Laiming Mo, Yue Huang, Boyin Liang, Xuejing Wei, Qingqing Ao, Yilu Xu, Yuyang Liu, Deqiang Xiao, Songchao Guo, Cailing Lu, Xiyi Li
Mammalian target of rapamycin (mTOR) is a Ser/Thr protein kinase that functions as an ATP and amino acid sensor to govern cell growth and proliferation by mediating mitogen- and nutrient-dependent signal transduction. Protein phosphatase 2A (PP2A), a ubiquitously expressed serine/threonine phosphatase, negatively regulates mTOR signaling. Methylation of PP2A is catalyzed by leucine carboxyl methyltransferase-1 (LCMT1) and reversed by protein phosphatase methylesterase 1 (PME-1), which regulates PP2A activity and substrate specificity...
May 12, 2018: Cell Biology International
https://www.readbyqxmd.com/read/29281045/protein-phosphatase-2a-and-its-methylation-modulating-enzymes-lcmt-1-and-pme-1-are-dysregulated-in-tauopathies-of-progressive-supranuclear-palsy-and-alzheimer-disease
#5
Hye-Jin Park, Kang-Woo Lee, Stephanie Oh, Run Yan, Jie Zhang, Thomas G Beach, Charles H Adler, Michael Voronkov, Steven P Braithwaite, Jeffry B Stock, M Maral Mouradian
Hyperphosphorylated tau aggregates are characteristic of tauopathies including progressive supranuclear palsy (PSP) and Alzheimer disease (AD), but factors contributing to pathologic tau phosphorylation are not well understood. Here, we studied the regulation of the major tau phosphatase, the heterotrimeric AB55αC protein phosphatase 2 A (PP2A), in PSP and AD. The assembly and activity of this PP2A isoform are regulated by reversible carboxyl methylation of its catalytic C subunit, while the B subunit confers substrate specificity...
February 1, 2018: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/27913678/regulation-of-protein-phosphatase-2a-pp2a-tumor-suppressor-function-by-pme-1
#6
REVIEW
Amanpreet Kaur, Jukka Westermarck
Protein phosphatase 2A (PP2A) plays a major role in maintaining cellular signaling homeostasis by dephosphorylation of a variety of signaling proteins and acts as a tumor suppressor. Protein phosphatase methylesterase-1 (PME-1) negatively regulates PP2A activity by highly complex mechanisms that are reviewed here. Importantly, recent studies have shown that PME-1 promotes oncogenic MAPK/ERK and AKT pathway activities in various cancer types. In human glioma, high PME-1 expression correlates with tumor progression and kinase inhibitor resistance...
December 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27752512/dysregulation-of-protein-phosphatase-2a-in-parkinson-disease-and-dementia-with-lewy-bodies
#7
Hye-Jin Park, Kang-Woo Lee, Eun S Park, Stephanie Oh, Run Yan, Jie Zhang, Thomas G Beach, Charles H Adler, Michael Voronkov, Steven P Braithwaite, Jeffry B Stock, M Maral Mouradian
OBJECTIVE: Protein phosphatase 2A (PP2A) is a heterotrimeric holoenzyme composed of a catalytic C subunit, a structural A subunit, and one of several regulatory B subunits that confer substrate specificity. The assembly and activity of PP2A are regulated by reversible methylation of the C subunit. α -Synuclein, which aggregates in Parkinson disease (PD) and dementia with Lewy bodies (DLB), is phosphorylated at Ser129 , and PP2A containing a B55 α subunit is a major phospho-Ser129 phosphatase...
October 2016: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/27671680/pp2a-inhibitor-pme-1-drives-kinase-inhibitor-resistance-in-glioma-cells
#8
Amanpreet Kaur, Oxana V Denisova, Xi Qiao, Mikael Jumppanen, Emilia Peuhu, Shafiq U Ahmed, Olayinka Raheem, Hannu Haapasalo, John Eriksson, Anthony J Chalmers, Pirjo Laakkonen, Jukka Westermarck
Glioblastoma multiforme lacks effective therapy options. Although deregulated kinase pathways are drivers of malignant progression in glioblastoma multiforme, glioma cells exhibit intrinsic resistance toward many kinase inhibitors, and the molecular basis of this resistance remains poorly understood. Here, we show that overexpression of the protein phosphatase 2A (PP2A) inhibitor protein PME-1 drives resistance of glioma cells to various multikinase inhibitors. The PME-1-elicited resistance was dependent on specific PP2A complexes and was mediated by a decrease in cytoplasmic HDAC4 activity...
December 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27573413/structural-and-biomechanical-corneal-differences-between-patients-suffering-from-primary-congenital-glaucoma-and-healthy-volunteers
#9
Lucía Perucho-González, Federico Sáenz-Francés, Laura Morales-Fernández, José María Martínez-de-la-Casa, Carmen D Méndez-Hernández, Enrique Santos-Bueso, John L Brookes, Julián García-Feijoó
PURPOSE: To determine whether a set of ocular morphometric and biomechanical variables are able to discriminate between healthy volunteers and patients suffering from primary congenital glaucoma (PCG). METHODS: Case-control study in which 66 patients with PCG and 94 age-matched healthy subjects were evaluated using ocular response analyser (ORA) to record corneal biomechanical properties. Topographic corneal variables were obtained using the Pentacam in both groups...
March 2017: Acta Ophthalmologica
https://www.readbyqxmd.com/read/27507813/leucine-carboxyl-methyltransferase-1-lcmt-1-methylates-protein-phosphatase-4-pp4-and-protein-phosphatase-6-pp6-and-differentially-regulates-the-stable-formation-of-different-pp4-holoenzymes
#10
Juyeon Hwang, Jocelyn A Lee, David C Pallas
The protein phosphatase 2A (PP2A) subfamily of phosphatases, PP2A, PP4, and PP6, are multifunctional serine/threonine protein phosphatases involved in many cellular processes. Carboxyl methylation of the PP2A catalytic subunit (PP2Ac) C-terminal leucine is regulated by the opposing activities of leucine carboxyl methyltransferase 1 (LCMT-1) and protein phosphatase methylesterase 1 (PME-1) and regulates PP2A holoenzyme formation. The site of methylation on PP2Ac is conserved in the catalytic subunits of PP4 and PP6, and PP4 is also methylated on that site, but the identities of the methyltransferase enzyme for PP4 are not known...
September 30, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27459928/knockdown-of-microrna-195-contributes-to-protein-phosphatase-2a-inactivation-in-rats-with-chronic-brain-hypoperfusion
#11
Cheng-Di Liu, Qin Wang, De-Kang Zong, Shuang-Chao Pei, Yan Yan, Mei-Ling Yan, Lin-Lin Sun, Yang-Yang Hao, Meng Mao, Wen-Jing Xing, Huan Ren, Jing Ai
Reduction of protein phosphatase-2A (PP2A) activity is a common clinical feature of Alzheimer's disease and vascular dementia. In this study, we observed that chronic brain hypoperfusion induced by bilateral common carotid artery occlusion of rats led to PP2A inactivation based on the increase in tyrosine-307 phosphorylation and leucine-309 demethylation of PP2AC and the depression in PP2ABα. Knockdown of miR-195 using overexpression of its antisense molecule oligonucleotide (pre-AMO-miR-195) delivered by a lentivirus (lenti-pre-AMO-miR-195) increased tyrosine-307 phosphorylation and decreased both PP2ABα expression and leucine-309 methylation; these effects were prevented by the overexpression of miR-195 using lenti-pre-miR-195 and controlled by an increase in methylesterase (PME-1) and a decrease in leucine carboxyl methyltransferase-1...
September 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/27048286/inhibition-of-protein-methylesterase-1-decreased-cancerous-phenotypes-in-endometrial-adenocarcinoma-cell-lines-and-xenograft-tumor-models
#12
Michelle Pusey, Sophie Bail, Yan Xu, Olesia Buiakova, Mariya Nestor, Jing-Jing Yang, Lyndi M Rice
Protein methylesterase 1 (PME-1) promotes cancerous phenotypes through the demethylation and inactivation of protein phosphatase 2A. We previously demonstrated that PME-1 overexpression promotes Akt, ERK, and may promote Wnt signaling and increases tumor burden in a xenograft model of endometrial cancer. Here, we show that covalent PME-1 inhibitors decrease cell proliferation and invasive growth in vitro but have no effect in vivo at the concentrations tested; however, depletion of PME-1 with shRNA in an endometrial cancer xenograft model significantly reduced tumor growth...
September 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/26951658/pp2a-methylation-controls-sensitivity-and-resistance-to-%C3%AE-amyloid-induced-cognitive-and-electrophysiological-impairments
#13
Russell E Nicholls, Jean-Marie Sontag, Hong Zhang, Agnieszka Staniszewski, Shijun Yan, Carla Y Kim, Michael Yim, Caitlin M Woodruff, Erland Arning, Brandi Wasek, Deqi Yin, Teodoro Bottiglieri, Estelle Sontag, Eric R Kandel, Ottavio Arancio
Elevated levels of the β-amyloid peptide (Aβ) are thought to contribute to cognitive and behavioral impairments observed in Alzheimer's disease (AD). Protein phosphatase 2A (PP2A) participates in multiple molecular pathways implicated in AD, and its expression and activity are reduced in postmortem brains of AD patients. PP2A is regulated by protein methylation, and impaired PP2A methylation is thought to contribute to increased AD risk in hyperhomocysteinemic individuals. To examine further the link between PP2A and AD, we generated transgenic mice that overexpress the PP2A methylesterase, protein phosphatase methylesterase-1 (PME-1), or the PP2A methyltransferase, leucine carboxyl methyltransferase-1 (LCMT-1), and examined the sensitivity of these animals to behavioral and electrophysiological impairments caused by exogenous Aβ exposure...
March 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26836014/morroniside-induced-pp2a-activation-antagonizes-tau-hyperphosphorylation-in-a-cellular-model-of-neurodegeneration
#14
Cui-cui Yang, Xue-xian Kuai, Wen-bin Gao, Jian-chun Yu, Qi Wang, Lin Li, Lan Zhang
BACKGROUND: An accumulation of hyperphosphorylated tau in the brain is a hallmark of Alzheimer's disease (AD). Deficits in protein phosphatase 2A (PP2A) are associated with tau hyperphosphorylation in AD. OBJECTIVE: To investigate the effects of morroniside (MOR), isolated from Cornus officinalis, on tau hyperphosphorylation and its underlying mechanisms related to PP2A. METHODS: SK-N-SH cells were pretreated with 50-200 μM MOR for 24 h followed by 20 nM okadaic acid (OA) for 6 h...
2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/26718045/11-reversible-methylation-of-protein-phosphatase-2a
#15
Sari Longin, Jozef Goris
PP2A has been shown to be methylated at the C-terminal leucine residue of the catalytic subunit by a specific 38 kDa methyltransferase (LCMT1) and demethylated by a specific 44-kDa methylesterase (PME-1). This reversible methylation does not seem to drastically change the PP2A activity but is shown to be a modulating factor in the binding of the third regulatory subunit. The structure of LCMT1 is solved and a model for the catalysis of the methylation reaction is presented. By purifying the PP2A-methylesterase, inactive dimeric (PP2AiD) and trimeric (PP2AiT55) holoenzymes were found to be associated with PME-1...
2006: Enzymes
https://www.readbyqxmd.com/read/26678046/protein-phosphatase-methyl-esterase-pme-1-protects-protein-phosphatase-2a-from-ubiquitin-proteasome-degradation
#16
Ryotaro Yabe, Akane Miura, Tatsuya Usui, Ingrid Mudrak, Egon Ogris, Takashi Ohama, Koichi Sato
Protein phosphatase 2A (PP2A) is a conserved essential enzyme that is implicated as a tumor suppressor based on its central role in phosphorylation-dependent signaling pathways. Protein phosphatase methyl esterase (PME-1) catalyzes specifically the demethylation of the C-terminal Leu309 residue of PP2A catalytic subunit (PP2Ac). It has been shown that PME-1 affects the activity of PP2A by demethylating PP2Ac, but also by directly binding to the phosphatase active site, suggesting loss of PME-1 in cells would enhance PP2A activity...
2015: PloS One
https://www.readbyqxmd.com/read/26499835/relevance-rank-platform-rrp-for-functional-filtering-of-high-content-protein-protein-interaction-data
#17
Yuba Raj Pokharel, Jani Saarela, Agnieszka Szwajda, Christian Rupp, Anne Rokka, Shibendra Lal Kumar Karna, Kaisa Teittinen, Garry Corthals, Olli Kallioniemi, Krister Wennerberg, Tero Aittokallio, Jukka Westermarck
High content protein interaction screens have revolutionized our understanding of protein complex assembly. However, one of the major challenges in translation of high content protein interaction data is identification of those interactions that are functionally relevant for a particular biological question. To address this challenge, we developed a relevance ranking platform (RRP), which consist of modular functional and bioinformatic filters to provide relevance rank among the interactome proteins. We demonstrate the versatility of RRP to enable a systematic prioritization of the most relevant interaction partners from high content data, highlighted by the analysis of cancer relevant protein interactions for oncoproteins Pin1 and PME-1...
December 2015: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/26377365/protein-phosphatase-methylesterase-1-pme-1-expression-predicts-a-favorable-clinical-outcome-in-colorectal-cancer
#18
Amanpreet Kaur, Adam Elzagheid, Eva-Maria Birkman, Tuulia Avoranta, Ville Kytölä, Eija Korkeila, Kari Syrjänen, Jukka Westermarck, Jari Sundström
Colorectal cancer (CRC) accounts for high mortality. So far, there is lack of markers capable of predicting which patients are at risk of aggressive course of the disease. Protein phosphatase-2A (PP2A) inhibitor proteins have recently gained interest as markers of more aggressive disease in certain cancers. Here, we report the role of PP2A inhibitor PME-1 in CRC. PME-1 expression was assessed from a rectal cancer patient cohort by immunohistochemistry, and correlations were performed for various clinicopathological variables and patient survival...
December 2015: Cancer Medicine
https://www.readbyqxmd.com/read/25996669/elemental-bioimaging-of-cisplatin-in-caenorhabditis-elegans-by-la-icp-ms
#19
Barbara Crone, Michael Aschner, Tanja Schwerdtle, Uwe Karst, Julia Bornhorst
cis-Diamminedichloroplatinum(II) (Cisplatin) is one of the most important and frequently used cytostatic drugs for the treatment of various solid tumors. Herein, a laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) method incorporating a fast and simple sample preparation protocol was developed for the elemental mapping of Cisplatin in the model organism Caenorhabditis elegans (C. elegans). The method allows imaging of the spatially-resolved elemental distribution of platinum in the whole organism with respect to the anatomic structure in L4 stage worms at a lateral resolution of 5 μm...
July 2015: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/25839665/a-lcmt1-pme-1-methylation-equilibrium-controls-mitotic-spindle-size
#20
Xiaoyu Xia, Ankur Gholkar, Silvia Senese, Jorge Z Torres
Leucine carboxyl methyltransferase-1 (LCMT1) and protein phosphatase methylesterase-1 (PME-1) are essential enzymes that regulate the methylation of the protein phosphatase 2A catalytic subunit (PP2AC). LCMT1 and PME-1 have been linked to the regulation of cell growth and proliferation, but the underlying mechanisms have remained elusive. We show here an important role for an LCMT1-PME-1 methylation equilibrium in controlling mitotic spindle size. Depletion of LCMT1 or overexpression of PME-1 led to long spindles...
2015: Cell Cycle
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