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pp2a AND T cell

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https://www.readbyqxmd.com/read/28137908/the-pp2a-b56-phosphatase-opposes-cyclin-e-autocatalytic-degradation-via-site-specific-dephosphorylation
#1
Ryan J Davis, Jherek Swanger, Bridget T Hughes, Bruce E Clurman
Cyclin E, in conjunction with its catalytic partner cyclin-dependent kinase 2 (CDK2), regulates cell cycle progression as cells exit quiescence and enter S-phase. Multiple mechanisms control cyclin E periodicity during the cell cycle, including phosphorylation-dependent cyclin E ubiquitylation by the SCF(Fbw7) ubiquitin ligase. Serine 384 (S384) is the critical cyclin E phosphorylation site that stimulates Fbw7 binding and cyclin E ubiquitylation and degradation. Because S384 is autophosphorylated by bound CDK2, this presents a paradox as to how cyclin E can evade autocatalytically induced degradation in order to phosphorylate its other substrates...
January 30, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28090813/effects-of-fostriecin-on-%C3%AE-2-adrenoceptor-driven-responses-in-human-mast-cells
#2
Reza Bastan, Nahid Eskandari, Hamidrez J Ardakani, Peter T Peachell
As part of the intracellular processes leading to mast cell and basophil activation, phosphorylation of key substrates is likely to be important. These processes, mediated by phosphatases, are responsible for regulating phosphorylation. The aim of the present study was to determine effects fostriecin - a selective inhibitor of PP2A (protein phosphatase-2) - on β2-adrenoceptor-driven responses in human mast cells. Here, the effects of fostriecin (PP inhibitors) on the inhibition of histamine release from HLMC, on β-adrenoceptor-driven responses in mast cells and on desensitization were investigated...
December 2017: Journal of Immunotoxicology
https://www.readbyqxmd.com/read/27998769/passive-immunization-targeting-the-n-terminal-region-of-phosphorylated-tau-residues-68-71-improves-spatial-memory-in-okadaic-acid-induced-tauopathy-model-rats
#3
Sarada Subramanian, Ganesh Savanur, Sowmya Madhavadas
Alzheimer's disease (AD) is the leading cause of dementia, characterized by progressive loss of memory and other cognitive functions. The cognitive impairment in patients with AD is closely associated with loss of synapses and the formation of neurofibrillary tangles (NFT) containing hyperphosphorylated tau in the hippocampus. Effective treatment for AD is still not available. In this study, the sequence comprising of residues 50-71 in the N-terminal region of tau, containing theoretically predicted B- and T-cell epitopes in close proximity to pathologically relevant phospho-serine (residue 68) and phospho-threonine (residues 69, 71) was selected as a potential immunotherapeutic peptide...
January 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27987522/-interleukin-2-signaling-pathway-regulating-molecules-in-systemic-lupus-erythematosus
#4
Q Guo, X Y Chen, Y Su
Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease, which characterized by complex immunological abnormalities and multiple tissue and organ damages. The etiology and pathogenesis of SLE have not been entirely recognized. Genetic, environmental and viral infections and other factors might be related to the pathogenetic mechanisms of SLE. Interleukin-2 (IL-2) is a critical cytokine produced by T cells upon activation and is important for the generation of T regulatory cells and activation-induced cell death...
December 18, 2016: Beijing da Xue Xue Bao. Yi Xue Ban, Journal of Peking University. Health Sciences
https://www.readbyqxmd.com/read/27872207/myeloid-specific-gene-deletion-of-protein-phosphatase-2a-magnifies-myd88-and-trif-dependent-inflammation-following-endotoxin-challenge
#5
Lei Sun, Tiffany T Pham, Timothy T Cornell, Kelli L McDonough, Walker M McHugh, Neal B Blatt, Mary K Dahmer, Thomas P Shanley
Protein phosphatase 2A (PP2A) is a member of the intracellular serine/threonine phosphatases. Innate immune cell activation triggered by pathogen-associated molecular patterns is mediated by various protein kinases, and PP2A plays a counter-regulatory role by deactivating these kinases. In this study, we generated a conditional knockout of the α isoform of the catalytic subunit of PP2A (PP2ACα). After crossing with myeloid-specific cre-expressing mice, effective gene knockout was achieved in various myeloid cells...
January 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27866533/-lb100-reverses-the-acquired-resistance-to-gefitinib-in-lung-adenocarcinoma-cells-with-egfr-mutation
#6
S Shan, Y D Wang, T Ren
Objective: To investigate the possibility of the Protein Phosphatase 2A (PP2A) inhibitor, LB100, in reversing acquired resistance to gefitinib in lung adenocarcinoma with epidermal growth factor receptor (EGFR) gene mutation. Methods: Cell line NCI-H1975 and established primary culture cell line 44-1 with gefitinib resistance were sequenced to determine the mutation type of EGFR gene. Cells were treated with gefitinib alone or combined with LB100 to determine the half maximal inhibitory concentration (IC50), and sensitivity of 44-1 and NCI-1975 to gefitinib alone or combined with LB100 was compared...
November 15, 2016: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/27852846/a-transformation-defective-polyomavirus-middle-t-antigen-with-a-novel-defect-in-pi3-kinase-signaling
#7
Deborah Denis, Cecile Rouleau, Brian S Schaffhausen
: Middle T antigen (MT), the principal oncoprotein of murine polyomavirus, transforms by association with cellular proteins. Protein phosphatase 2A (PP2A), YAP, Src family tyrosine kinases, Shc, phosphatidylinositol 3-kinase (PI3K), and phospholipase C-γ1 (PLCγ1) have all been implicated in MT transformation. Mutant dl1015, with deletion of residues 338 to 347 in the C-terminal region, has been an enigma, because the basis for its transformation defect has not been apparent. This work probes the dl1015 region of MT...
January 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/27810903/nnmt-silencing-activates-tumor-suppressor-pp2a-inactivates-oncogenic-stks-and-inhibits-tumor-forming-ability
#8
Kamalakannan Palanichamy, Suman Kanji, Nicolaus Gordon, Krishnan Thirumoorthy, John R Jacob, Kevin T Litzenberg, Disha Patel, Arnab Chakravarti
PURPOSE: To identify potential molecular hubs that regulate oncogenic kinases and target them to improve treatment outcomes for glioblastoma (GBM) patients. EXPERIMENTAL DESIGN: Data mining of The Cancer Genome Atlas (TCGA) datasets identified Nicotinamide-N-methyl transferase (NNMT) as a prognostic marker for GBM, an enzyme linked to the reorganization of the methylome. We tested our hypothesis that NNMT plays a crucial role by modulating protein methylation leading to inactivation of tumor suppressors and activation of oncogenes...
November 3, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27784696/serine-threonine-phosphatases-and-aquaporin-2-regulation-in-renal-collecting-duct
#9
Sophia M LeMaire, Viswanathan Raghuram, Cameron R Grady, Christina M Pickering, Chung-Lin Chou, Ezigbobiara N Umejiego, Mark A Knepper
Phosphorylation of the aquaporin-2 (AQP2) water channel at four COOH-terminal serines plays a central role in the regulation of water permeability of the renal collecting duct. The level of phosphorylation at these sites is determined by a balance between phosphorylation by protein kinases and dephosphorylation by phosphatases. The phosphatases that dephosphorylate AQP2 have not been identified. Here, we use large-scale data integration techniques to identify serine-threonine phosphatases likely to interact with AQP2 in renal collecting duct principal cells...
January 1, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/27705940/combined-targeting-of-set-and-tyrosine-kinases-provides-an-effective-therapeutic-approach-in-human-t-cell-acute-lymphoblastic-leukemia
#10
Nameeta P Richard, Raffaella Pippa, Megan M Cleary, Alka Puri, Deanne Tibbitts, Shawn Mahmood, Dale J Christensen, Sophia Jeng, Shannon McWeeney, A Thomas Look, Bill H Chang, Jeffrey W Tyner, Michael P Vitek, María D Odero, Rosalie Sears, Anupriya Agarwal
Recent evidence suggests that inhibition of protein phosphatase 2A (PP2A) tumor suppressor activity via the SET oncoprotein contributes to the pathogenesis of various cancers. Here we demonstrate that both SET and c-MYC expression are frequently elevated in T-ALL cell lines and primary samples compared to healthy T cells. Treatment of T-ALL cells with the SET antagonist OP449 restored the activity of PP2A and reduced SET interaction with the PP2A catalytic subunit, resulting in a decrease in cell viability and c-MYC expression in a dose-dependent manner...
October 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27669461/targeting-cancer-metabolism-by-simultaneously-disrupting-parallel-nutrient-access-pathways
#11
Seong M Kim, Saurabh G Roy, Bin Chen, Tiffany M Nguyen, Ryan J McMonigle, Alison N McCracken, Yanling Zhang, Satoshi Kofuji, Jue Hou, Elizabeth Selwan, Brendan T Finicle, Tricia T Nguyen, Archna Ravi, Manuel U Ramirez, Tim Wiher, Garret G Guenther, Mari Kono, Atsuo T Sasaki, Lois S Weisman, Eric O Potma, Bruce J Tromberg, Robert A Edwards, Stephen Hanessian, Aimee L Edinger
Oncogenic mutations drive anabolic metabolism, creating a dependency on nutrient influx through transporters, receptors, and macropinocytosis. While sphingolipids suppress tumor growth by downregulating nutrient transporters, macropinocytosis and autophagy still provide cancer cells with fuel. Therapeutics that simultaneously disrupt these parallel nutrient access pathways have potential as powerful starvation agents. Here, we describe a water-soluble, orally bioavailable synthetic sphingolipid, SH-BC-893, that triggers nutrient transporter internalization and also blocks lysosome-dependent nutrient generation pathways...
November 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27638902/protein-phosphatase-2a-activation-attenuates-inflammation-in-murine-models-of-acute-lung-injury
#12
Walker M McHugh, William W Russell, Andrew J Fleszar, Paul E Rodenhouse, Skyler P Rietberg, Lei Sun, Thomas P Shanley, Timothy T Cornell
Acute respiratory distress syndrome (ARDS) remains a leading cause of morbidity and mortality in both adult and pediatric intensive care units. A key event in the development of ARDS is neutrophil recruitment into the lungs leading to tissue damage and destruction. Interleukin-8 (IL-8) is the major human chemokine responsible for neutrophil recruitment into the lungs. Protein phosphatase 2A (PP2A) has been shown to be a key regulator of the mitogen-activated protein kinase (MAPK) cascades, which control the production of IL-8...
November 1, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/27632801/molecular-mechanisms-supporting-a-pathogenic-role-for-human-polyomavirus-6-small-t-antigen-protein-phosphatase-2a-targeting-and-mapk-cascade-activation
#13
Julie H Wu, Rebecca A Simonette, Harrison P Nguyen, Peter L Rady, Stephen K Tyring
BRAF inhibitors are highly effective therapies in treating a subset of melanomas but are associated with induction of secondary cutaneous squamous cell carcinoma (cSCC). Recently, Human Polyomavirus 6 (HPyV6) was found to actively express viral proteins in BRAF inhibitor-induced cSCCs; however, the specific cellular mechanisms by which HPyV6 may facilitate neoplastic cell growth require further investigation. The current study describes a novel pathogenic mechanism of action for HPyV6 small tumor (sT) antigen which involves binding to protein phosphatase 2A (PP2A) via its WFG motif and zinc binding sites...
September 15, 2016: Journal of Medical Virology
https://www.readbyqxmd.com/read/27626381/ionic-immune-suppression-within-the-tumour-microenvironment-limits-t-cell-effector-function
#14
Robert Eil, Suman K Vodnala, David Clever, Christopher A Klebanoff, Madhusudhanan Sukumar, Jenny H Pan, Douglas C Palmer, Alena Gros, Tori N Yamamoto, Shashank J Patel, Geoffrey C Guittard, Zhiya Yu, Valentina Carbonaro, Klaus Okkenhaug, David S Schrump, W Marston Linehan, Rahul Roychoudhuri, Nicholas P Restifo
Tumours progress despite being infiltrated by tumour-specific effector T cells. Tumours contain areas of cellular necrosis, which are associated with poor survival in a variety of cancers. Here, we show that necrosis releases intracellular potassium ions into the extracellular fluid of mouse and human tumours, causing profound suppression of T cell effector function. Elevation of the extracellular potassium concentration ([K(+)]e) impairs T cell receptor (TCR)-driven Akt-mTOR phosphorylation and effector programmes...
September 22, 2016: Nature
https://www.readbyqxmd.com/read/27597652/treatment-of-inflammatory-arthritis-via-targeting-of-tristetraprolin-a-master-regulator-of-pro-inflammatory-gene-expression
#15
E A Ross, A J Naylor, J D O'Neil, T Crowley, M L Ridley, J Crowe, T Smallie, T J Tang, J D Turner, L V Norling, S Dominguez, H Perlman, N M Verrills, G Kollias, M P Vitek, A Filer, C D Buckley, J L Dean, A R Clark
OBJECTIVES: Tristetraprolin (TTP), a negative regulator of many pro-inflammatory genes, is strongly expressed in rheumatoid synovial cells. The mitogen-activated protein kinase (MAPK) p38 pathway mediates the inactivation of TTP via phosphorylation of two serine residues. We wished to test the hypothesis that these phosphorylations contribute to the development of inflammatory arthritis, and that, conversely, joint inflammation may be inhibited by promoting the dephosphorylation and activation of TTP...
September 5, 2016: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/27595237/interaction-between-integrin-%C3%AE-5-and-pde4d-regulates-endothelial-inflammatory-signalling
#16
Sanguk Yun, Madhusudhan Budatha, James E Dahlman, Brian G Coon, Ryan T Cameron, Robert Langer, Daniel G Anderson, George Baillie, Martin A Schwartz
Atherosclerosis is primarily a disease of lipid metabolism and inflammation; however, it is also closely associated with endothelial extracellular matrix (ECM) remodelling, with fibronectin accumulating in the laminin-collagen basement membrane. To investigate how fibronectin modulates inflammation in arteries, we replaced the cytoplasmic tail of the fibronectin receptor integrin α5 with that of the collagen/laminin receptor integrin α2. This chimaera suppressed inflammatory signalling in endothelial cells on fibronectin and in knock-in mice...
October 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27277081/thioesterase-domain-swapping-of-a-linear-polyketide-tautomycetin-with-a-macrocyclic-polyketide-pikromycin-in-streptomyces-sp-ck4412
#17
Ashootosh Tripathi, Si-Sun Choi, David H Sherman, Eung-Soo Kim
Tautomycetin (TMC) is a linear polyketide metabolite produced by Streptomyces sp. CK4412 that has been reported to possess multiple biological functions including T cell-specific immunosuppressive and anticancer activities that occur through a mechanism of differential inhibition of protein phosphatases such as PP1, PP2A, and SHP2. We previously reported the characterization of the entire TMC biosynthetic gene cluster constituted by multifunctional type I polyketide synthase (PKS) assembly and suggested that the linear form of TMC could be generated via free acid chain termination by a narrow TMC thioesterase (TE) pocket...
August 2016: Journal of Industrial Microbiology & Biotechnology
https://www.readbyqxmd.com/read/27198439/82p-synergistic-antitumor-activity-of-afatinib-and-nintedanib-through-pp2a-reactivation-in-non-small-cell-lung-cancer-cells
#18
T-T Chao, C-H Chen, Z-A Peng, C-Y Wang
No abstract text is available yet for this article.
April 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27150024/anti-tumor-effects-of-perphenazine-on-canine-lymphoma
#19
Shunya Tsuji, Ryotaro Yabe, Tatsuya Usui, Takuya Mizuno, Takashi Ohama, Koichi Sato
Lymphoma is one of the most common malignant tumors in canine. Protein phosphatase 2A (PP2A), a well-conserved serine/threonine phosphatase, plays a critical role as a tumor suppressor. Perphenazine (PPZ) is one of the phenothiazines and widely used as an antipsychotic drug. Recently, it is reported that PPZ directly binds with scaffolding subunit of PP2A complex and exerts anti-tumor effects on human T cell acute lymphoblastic leukemia. However, the effect of PPZ on canine lymphoma has not been studied. Here, we investigated the potential therapeutic role of PPZ and its molecular mechanism in canine T-cell lymphoma...
September 1, 2016: Journal of Veterinary Medical Science
https://www.readbyqxmd.com/read/27100879/cip2a-promotes-t-cell-activation-and-immune-response-to-listeria-monocytogenes-infection
#20
Christophe Côme, Anna Cvrljevic, Mohd Moin Khan, Irina Treise, Thure Adler, Juan Antonio Aguilar-Pimentel, Byron Au-Yeung, Eleonora Sittig, Teemu Daniel Laajala, Yiling Chen, Sebastian Oeder, Julia Calzada-Wack, Marion Horsch, Tero Aittokallio, Dirk H Busch, Markus W Ollert, Frauke Neff, Johannes Beckers, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Zhi Chen, Riitta Lahesmaa, Jukka Westermarck
The oncoprotein Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) is overexpressed in most malignancies and is an obvious candidate target protein for future cancer therapies. However, the physiological importance of CIP2A-mediated PP2A inhibition is largely unknown. As PP2A regulates immune responses, we investigated the role of CIP2A in normal immune system development and during immune response in vivo. We show that CIP2A-deficient mice (CIP2AHOZ) present a normal immune system development and function in unchallenged conditions...
2016: PloS One
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