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https://www.readbyqxmd.com/read/29028833/merkel-cell-polyomavirus-recruits-mycl-to-the-ep400-complex-to-promote-oncogenesis
#1
Jingwei Cheng, Donglim Esther Park, Christian Berrios, Elizabeth A White, Reety Arora, Rosa Yoon, Timothy Branigan, Tengfei Xiao, Thomas Westerling, Alexander Federation, Rhamy Zeid, Benjamin Strober, Selene K Swanson, Laurence Florens, James E Bradner, Myles Brown, Peter M Howley, Megha Padi, Michael P Washburn, James A DeCaprio
Merkel cell carcinoma (MCC) frequently contains integrated copies of Merkel cell polyomavirus DNA that express a truncated form of Large T antigen (LT) and an intact Small T antigen (ST). While LT binds RB and inactivates its tumor suppressor function, it is less clear how ST contributes to MCC tumorigenesis. Here we show that ST binds specifically to the MYC homolog MYCL (L-MYC) and recruits it to the 15-component EP400 histone acetyltransferase and chromatin remodeling complex. We performed a large-scale immunoprecipitation for ST and identified co-precipitating proteins by mass spectrometry...
October 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28884018/pp2a-b-holoenzyme-substrate-recognition-regulation-and-role-in-cytokinesis
#2
Cheng-Guo Wu, Hui Chen, Feng Guo, Vikash K Yadav, Sean J Mcilwain, Michael Rowse, Alka Choudhary, Ziqing Lin, Yitong Li, Tingjia Gu, Aiping Zheng, Qingge Xu, Woojong Lee, Eduard Resch, Benjamin Johnson, Jenny Day, Ying Ge, Irene M Ong, Mark E Burkard, Ylva Ivarsson, Yongna Xing
Protein phosphatase 2A (PP2A) is a major Ser/Thr phosphatase; it forms diverse heterotrimeric holoenzymes that counteract kinase actions. Using a peptidome that tiles the disordered regions of the human proteome, we identified proteins containing [LMFI]xx[ILV]xEx motifs that serve as interaction sites for B'-family PP2A regulatory subunits and holoenzymes. The B'-binding motifs have important roles in substrate recognition and in competitive inhibition of substrate binding. With more than 100 novel ligands identified, we confirmed that the recently identified LxxIxEx B'α-binding motifs serve as common binding sites for B' subunits with minor variations, and that S/T phosphorylation or D/E residues at positions 2, 7, 8 and 9 of the motifs reinforce interactions...
2017: Cell Discovery
https://www.readbyqxmd.com/read/28770955/the-regulatory-role-of-dopamine-receptor-d1-on-pp2a-via-sumo-1-modification
#3
C-Q Yu, L-Q Yin, Z-T Tu, D-W Liu, W-P Luo
OBJECTIVE: Renal dopamine receptor D1 played a critical role in the regulation of body blood pressure. Under hypertension, over-phosphorylation of D1 receptor impaired its function. G protein kinase 4 (GRK4) and protein phosphatase 2A (PP2A) exerted the effect to phosphorylate and de-phosphorylate D1 receptor. A current study revealed that the inhibition of GRK4 cannot normalize the phosphorylation level of D1 receptor. Meanwhile, the PP2A was activated under hypertension, indicating abnormal de-phosphorylation function of D1 receptor, the reason for which remains unknown...
July 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28760745/a-pp2a-mediated-feedback-mechanism-controls-ca-2-dependent-no-synthesis-under-physiological-oxygen
#4
Thomas P Keeley, Richard C M Siow, Ron Jacob, Giovanni E Mann
Intracellular O2 is a key regulator of NO signaling, yet most in vitro studies are conducted in atmospheric O2 levels, hyperoxic with respect to the physiologic milieu. We investigated NO signaling in endothelial cells cultured in physiologic (5%) O2 and stimulated with histamine or shear stress. Culture of cells in 5% O2 (>5 d) decreased histamine- but not shear stress-stimulated endothelial (e)NOS activity. Unlike cells adapted to a hypoxic environment (1% O2), those cultured in 5% O2 still mobilized sufficient Ca(2+) to activate AMPK...
July 31, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28736280/the-serine-threonine-protein-phosphatase-2a-controls-autoimmunity
#5
Amir Sharabi, Isaac R Kasper, George C Tsokos
Protein phosphatase 2A (PP2A) is the first serine/threonine phosphatase recognized to contribute to human and murine lupus immunopathology. PP2A expression in SLE is controlled both epigenetically and genetically, and it is increased in patients with SLE, which contributes to decreased IL-2 production, decreased CD3ζ and increased FcRγ expression on the surface of T cells, increased CREMα expression, hypomethylation of genes associated with SLE pathogenesis, and increased IL-17 production. β regulatory subunit of PP2A regulates IL-2 deprivation-induced T cell death and is decreased in SLE patients...
July 21, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28678890/platinum-sensitive-2-like-impacts-growth-root-morphology-seed-set-and-stress-responses
#6
Amr R A Kataya, Maria T Creighton, Toga P Napitupulu, Christine Sætre, Behzad Heidari, Peter Ruoff, Cathrine Lillo
Eukaryotic protein phosphatase 4 (PP4) is a PP2A-type protein phosphatase that is part of a conserved complex with regulatory factors PSY2 and PP4R2. Various lines of Arabidopsis thaliana with mutated PP4 subunit genes were constructed to study the so far completely unknown functions of PP4 in plants. Mutants with knocked out putative functional homolog of the PSY2 LIKE (PSY2L) gene were dwarf and bushy, while plants with knocked out PP4R2 LIKE (PP4R2L) looked very similar to WT. The psy2l seedlings had short roots with disorganized morphology and impaired meristem...
2017: PloS One
https://www.readbyqxmd.com/read/28655554/t-type-ca-2-channels-elicit-pro-proliferative-and-anti-apoptotic-responses-through-impaired-pp2a-akt1-signaling-in-pasmcs-from-patients-with-pulmonary-arterial-hypertension
#7
Safietou Sankhe, Sevasti Manousakidi, Fabrice Antigny, Jennifer Arthur Ataam, Sana Bentebbal, Yann Ruchon, Florence Lecerf, Jessica Sabourin, Laura Price, Elie Fadel, Peter Dorfmüller, Saadia Eddahibi, Marc Humbert, Frédéric Perros, Véronique Capuano
Idiopathic pulmonary arterial hypertension (iPAH) is characterized by obstructive hyperproliferation and apoptosis resistance of distal pulmonary artery smooth muscle cells (PASMCs). T-type Ca(2+) channel blockers have been shown to reduce experimental pulmonary hypertension, although the impact of T-type channel inhibition remains unexplored in PASMCs from iPAH patients. Here we show that T-type channels Cav3.1 and Cav3.2 are present in the lung and PASMCs from iPAH patients and control subjects. The blockade of T-type channels by the specific blocker, TTA-A2, prevents cell cycle progression and PASMCs growth...
June 24, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28612433/musculin-inhibits-human-t-helper-17-cell-response-to-interleukin-2-by-controlling-stat5b-activity
#8
Veronica Santarlasci, Alessio Mazzoni, Manuela Capone, Maria Caterina Rossi, Laura Maggi, Gianni Montaini, Beatrice Rossettini, Rolando Cimaz, Matteo Ramazzotti, Giusi Barra, Raffaele De Palma, Enrico Maggi, Francesco Liotta, Lorenzo Cosmi, Sergio Romagnani, Francesco Annunziato
We recently demonstrated that human T-helper (Th) 17 cells, unlike Th1 cells, do not proliferate in response to T-cell receptor stimulation, mainly because of their reduced capacity to produce and respond to IL-2. In this study, we show that their lower responsiveness to IL-2 is due to the selective expression of Musculin (MSC), a member of the basic helix-loop-helix transcription factors. We show that MSC expression in human Th17 cells is retinoic acid orphan receptor (ROR)γt-dependent, and allows the upregulation of PPP2R2B, a regulatory member of the protein phosphatase 2A (PP2A) enzyme...
September 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28512245/merkel-cell-polyomavirus-small-t-antigen-initiates-merkel-cell-carcinoma-like-tumor-development-in-mice
#9
Monique E Verhaegen, Doris Mangelberger, Paul W Harms, Markus Eberl, Dawn M Wilbert, Julia Meireles, Christopher K Bichakjian, Thomas L Saunders, Sunny Y Wong, Andrzej A Dlugosz
Merkel cell carcinoma (MCC) tumor cells express several markers detected in normal Merkel cells, a nonproliferative population of neuroendocrine cells that arise from epidermis. MCCs frequently contain Merkel cell polyomavirus (MCPyV) DNA and express viral transforming antigens, sT and tLT, but the role of these putative oncogenes in MCC development, and this tumor's cell of origin, are unknown. Using a panel of preterm transgenic mice, we show that epidermis-targeted coexpression of sT and the cell fate-determinant atonal bHLH transcription factor 1 (ATOH1) leads to development of widespread cellular aggregates, with histology and marker expression mimicking that of human intraepidermal MCC...
June 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28500640/dysregulation-of-the-mek-erk-mnk1-signalling-cascade-by-middle-t-antigen-of-the-trichoydsplasia-spinulosa-polyomavirus
#10
J H Wu, D Narayanan, R A Simonette, P L Rady, S K Tyring
BACKGROUND: Trichodysplasia spinulosa (TS) is a disfiguring folliculocentric cutaneous disease caused by infection with the trichodysplasia spinulosa polyomavirus (TSPyV). The TSPyV genome contains splice variants encoding the middle tumour (mT) antigen, although the potential role for TSPyV mT antigen in disease development remains unknown. OBJECTIVE: The current study was designed to investigate the mechanistic properties of TSPyV mT antigen, which may further our understanding of TS pathogenesis and provide insight into potential therapies...
May 13, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28389570/bves-regulates-c-myc-stability-via-pp2a-and-suppresses-colitis-induced-tumourigenesis
#11
Bobak Parang, Andrew M Kaz, Caitlyn W Barrett, Sarah P Short, Wei Ning, Cody E Keating, Mukul K Mittal, Rishi D Naik, Mary K Washington, Frank L Revetta, J Joshua Smith, Xi Chen, Keith T Wilson, Thomas Brand, David M Bader, William P Tansey, Ru Chen, Teresa A Brentnall, William M Grady, Christopher S Williams
OBJECTIVE: Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD. DESIGN: We determined BVES promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC...
May 2017: Gut
https://www.readbyqxmd.com/read/28267764/ex-vivo-modulation-of-the-foxo1-phosphorylation-state-does-not-lead-to-dysfunction-of-t-regulatory-cells
#12
Kristen Kelley Penberthy, Monica Weaver Buckley, Sanja Arandjelovic, Kodi Ravichandran
Peripheral regulatory CD4+ T cells (Treg cells) prevent maladaptive inflammatory responses to innocuous foreign antigens. Treg cell dysfunction has been linked to many inflammatory diseases, including allergic airway inflammation. Glucocorticoids that are used to treat allergic airway inflammation and asthma are thought to work in part by promoting Treg cell differentiation; patients who are refractory to these drugs have defective induction of anti-inflammatory Treg cells. Previous observations suggest that Treg cells deficient in the transcription factor FoxO1 are pro-inflammatory, and that FoxO1 activity is regulated by its phosphorylation status and nuclear localization...
2017: PloS One
https://www.readbyqxmd.com/read/28137908/the-pp2a-b56-phosphatase-opposes-cyclin-e-autocatalytic-degradation-via-site-specific-dephosphorylation
#13
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...
April 15, 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
#14
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
#15
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
#16
REVIEW
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
#17
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
#18
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
#19
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
#20
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 patients.Experimental Design: Data mining of The Cancer Genome Atlas datasets identified nicotinamide-N-methyl transferase (NNMT) as a prognostic marker for glioblastoma, 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...
May 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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