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https://www.readbyqxmd.com/read/27872207/myeloid-specific-gene-deletion-of-protein-phosphatase-2a-magnifies-myd88-and-trif-dependent-inflammation-following-endotoxin-challenge
#1
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...
November 21, 2016: 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
#2
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
#3
Deborah Denis, Cecile Rouleau, Brian S Schaffhausen
: Middle T antigen (MT), the principal oncoprotein of murine polyomavirus, transforms by association with cellular proteins. PP2A, YAP, Src family tyrosine kinases, Shc, phosphoinositide-3-kinase (PI3K) and PLCγ1 have all been implicated in MT transformation. Mutant dl1015, deleting residues 338-347 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. Because the region is proline rich, the hypothesis that it targets SH3 domains was tested, but mutation of the putative SH3 binding motif did not affect transformation...
November 16, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27810903/nnmt-silencing-activates-tumor-suppressor-pp2a-inactivates-oncogenic-stks-and-inhibits-tumor-forming-ability
#4
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
#5
Sophia 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...
October 26, 2016: 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
#6
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
#7
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...
September 26, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27638902/protein-phosphatase-2a-activation-attenuates-inflammation-in-murine-models-of-acute-lung-injury
#8
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...
September 16, 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
#9
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
#10
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 14, 2016: Nature
https://www.readbyqxmd.com/read/27597652/treatment-of-inflammatory-arthritis-via-targeting-of-tristetraprolin-a-master-regulator-of-pro-inflammatory-gene-expression
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
https://www.readbyqxmd.com/read/26974206/phosphatase-pp2a-is-requisite-for-the-function-of-regulatory-t-cells
#17
Sokratis A Apostolidis, Noé Rodríguez-Rodríguez, Abel Suárez-Fueyo, Nikolina Dioufa, Esra Ozcan, José C Crispín, Maria G Tsokos, George C Tsokos
Homeostasis of the immune system depends on the proper function of regulatory T cells (T(reg) cells). Compromised suppressive activity of T(reg) cells leads to autoimmune disease and graft rejection and promotes anti-tumor immunity. Here we report a previously unrecognized requirement for the serine-threonine phosphatase PP2A in the function of T(reg) cells. T(reg) cells exhibited high PP2A activity, and T(reg) cell-specific ablation of the PP2A complex resulted in a severe, multi-organ, lymphoproliferative autoimmune disorder...
May 2016: Nature Immunology
https://www.readbyqxmd.com/read/26936918/methionine-and-kynurenine-activate-oncogenic-kinases-in-glioblastoma-and-methionine-deprivation-compromises-proliferation
#18
Kamalakannan Palanichamy, Krishnan Thirumoorthy, Suman Kanji, Nicolaus Gordon, Rajbir Singh, John R Jacob, Nikhil Sebastian, Kevin T Litzenberg, Disha Patel, Emily Bassett, Brinda Ramasubramanian, Tim Lautenschlaeger, Steven M Fischer, Abhik Ray-Chaudhury, Arnab Chakravarti
PURPOSE: We employed a metabolomics-based approach with the goal to better understand the molecular signatures of glioblastoma cells and tissues, with an aim toward identifying potential targetable biomarkers for developing more effective and novel therapies. EXPERIMENTAL DESIGN: We used liquid chromatography coupled with mass spectrometry (LC-MS/Q-TOF and LC-MS/QQQ) for the discovery and validation of metabolites from primary and established glioblastoma cells, glioblastoma tissues, and normal human astrocytes...
July 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26876205/upregulation-of-the-oncoprotein-set-determines-poor-clinical-outcomes-in-hepatocellular-carcinoma-and-shows-therapeutic-potential
#19
M-H Hung, Y-L Chen, P-Y Chu, C-T Shih, H-C Yu, W-T Tai, C-W Shiau, K-F Chen
The SET protein is a potent inhibitor of protein phosphatase 2A (PP2A). Here, we report the oncogenic role of SET in hepatocarcinogenesis, clinical aggressiveness and anti-hepatocellular carcinoma (HCC) therapeutics. By analyzing samples obtained from 147 HCC patients, we found that SET overexpression was detected specifically in 30.6% HCC tumor samples, and was significantly associated with worse clinical features and high p-Akt expression in HCC tumors. Co-expression of SET and Akt predicted shorter post-operative recurrence-free survival in this cohort (P=0...
September 15, 2016: Oncogene
https://www.readbyqxmd.com/read/26868295/haploinsufficiency-of-the-insulin-receptor-in-the-presence-of-a-splice-site-mutation-in-ppp2r2a-results-in-a-novel-digenic-mouse-model-of-type-2-diabetes
#20
Michelle Goldsworthy, Ying Bai, Chi-Ming Li, Huanying Ge, Edwin Lamas, Helen Hilton, Christopher T Esapa, Dan Baker, Will Baron, Todd Juan, Murielle M Véniant, David J Lloyd, Roger D Cox
Insulin resistance in mice typically does not manifest as diabetes due to multiple compensatory mechanisms. Here, we present a novel digenic model of type 2 diabetes in mice heterozygous for a null allele of the insulin receptor and an N-ethyl-N-nitrosourea-induced alternative splice mutation in the regulatory protein phosphatase 2A (PP2A) subunit PPP2R2A. Inheritance of either allele independently results in insulin resistance but not overt diabetes. Doubly heterozygous mice exhibit progressive hyperglycemia, hyperinsulinemia, and impaired glucose tolerance from 12 weeks of age without significant increase in body weight...
May 2016: Diabetes
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