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https://www.readbyqxmd.com/read/27930667/protein-phosphatase-6-protects-prophase-i-arrested-oocytes-by-safeguarding-genomic-integrity
#1
Meng-Wen Hu, Tie-Gang Meng, Zong-Zhe Jiang, Ming-Zhe Dong, Heide Schatten, Xingzhi Xu, Zhen-Bo Wang, Qing-Yuan Sun
Mammalian oocytes are arrested at prophase of the first meiotic division in the primordial follicle pool for months, even years, after birth depending on species, and only a limited number of oocytes resume meiosis, complete maturation, and ovulate with each reproductive cycle. We recently reported that protein phosphatase 6 (PP6), a member of the PP2A-like subfamily, which accounts for cellular serine/threonine phosphatase activity, functions in completing the second meiosis. Here, we generated mutant mice with a specific deletion of Ppp6c in oocytes from the primordial follicle stage by crossing Ppp6cF/F mice with Gdf9-Cre mice and found that Ppp6cF/F; GCre+ mice are infertile...
December 8, 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27913678/regulation-of-protein-phosphatase-2a-pp2a-tumor-suppressor-function-by-pme-1
#2
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/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/27774130/enhancing-therapeutic-efficacy-of-cisplatin-by-blocking-dna-damage-repair
#4
Yuwei Cong, Liangyan Wang, Zigui Wang, Shasha He, Dongfang Zhou, Xiabin Jing, Yubin Huang
Self-repair of nuclear DNA damage is the most known reason that leads to drug resistance of cancer tissue and limited therapeutic efficacy of anticancer drugs. Inhibition of protein phosphatase 2A (PP2A) would block DNA damage-induced defense of cancer cells to suppress DNA repair for enhanced cancer treatment. Here, we combined a PP2A inhibitor LB (4-(3-carboxy-7-oxa-bicyclo[2.2.1]heptane-2-carbonyl) piperazine-1-carboxylic acid tert-butyl ester) and the DNA damage chemotherapeutic drug cisplatin through a simple physical superposition...
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27720936/mir-17-92-represses-ptprot-and-pp2a-phosphatases-and-amplifies-tonic-bcr-signaling-in-dlbcl-cells
#5
Ewa Jablonska, Patryk Gorniak, Maciej Szydlowski, Tomasz Sewastianik, Emilia Bialopiotrowicz, Anna Polak, Krzysztof Warzocha, Przemyslaw Juszczynski
B-cell receptor (BCR) signaling plays pivotal role in the pathogenesis of diffuse large B-cell lymphomas (DLBCL), and targeting the BCR pathway is a highly promising therapeutic strategy in this malignancy. Oncogenic microRNA miR-17-92 modulates multiple cellular processes such as survival, proliferation, apoptosis, angiogenesis and BCR signaling. In the present study, we identified new targets of miR-17-92, PTPROt and PP2A phosphatases, which regulate SYK and AKT activity- critical components of BCR signal transduction in DLBCL cells...
October 6, 2016: Experimental Hematology
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/27696687/phosphatidic-acid-induces-decidualization-by-stimulating-akt-pp2a-binding-in-human-endometrial-stromal-cells
#7
So Young Lee, Yun Young Lee, Joong Sub Choi, Mee-Sup Yoon, Joong-Soo Han
Decidualization of human endometrial stromal cells (hESCs) is crucial for successful uterine implantation and maintaining pregnancy. We previously reported that phospholipase D1 (PLD1) is required for cAMP-induced decidualization of hESCs. However, the mechanism by which phosphatidic acid (PA), the product of PLD1 action, might regulate decidualization is not known. We confirmed that PA induced decidualization of hESCs by observing morphological changes and measuring increased levels of decidualization markers such as IGFBP1 and prolactin transcripts (P < 0...
November 2016: FEBS Journal
https://www.readbyqxmd.com/read/27694903/cip2a-promotes-cell-cycle-progression-in-triple-negative-breast-cancer-cells-by-regulating-the-expression-and-nuclear-export-of-p27kip1
#8
H Liu, H Qiu, Y Song, Y Liu, H Wang, M Lu, M Deng, Y Gu, J Yin, K Luo, Z Zhang, X Jia, G Zheng, Z He
Triple-negative breast cancer (TNBC) is very aggressive and currently has no specific therapeutic targets; as a consequence, TNBC exhibits poor clinical outcome. In this study, we showed that cancerous inhibitor of protein phosphatase 2A (Cip2a) represents a promising target in TNBC because Cip2a was highly expressed in TNBC cells and tumor tissues, and its expression showed an inverse correlation with overall survival in patients with TNBC. We found that inhibition of Cip2a in TNBC cells induced cell cycle arrest at the G2/M phase, inhibited cell proliferation and delayed tumor growth in the xenograft model...
October 3, 2016: Oncogene
https://www.readbyqxmd.com/read/27626673/an-integrative-analysis-of-the-inr-pi3k-akt-network-identifies-the-dynamic-response-to-insulin-signaling
#9
Arunachalam Vinayagam, Meghana M Kulkarni, Richelle Sopko, Xiaoyun Sun, Yanhui Hu, Ankita Nand, Christians Villalta, Ahmadali Moghimi, Xuemei Yang, Stephanie E Mohr, Pengyu Hong, John M Asara, Norbert Perrimon
Insulin regulates an essential conserved signaling pathway affecting growth, proliferation, and metabolism. To expand our understanding of the insulin pathway, we combine biochemical, genetic, and computational approaches to build a comprehensive Drosophila InR/PI3K/Akt network. First, we map the dynamic protein-protein interaction network surrounding the insulin core pathway using bait-prey interactions connecting 566 proteins. Combining RNAi screening and phospho-specific antibodies, we find that 47% of interacting proteins affect pathway activity, and, using quantitative phosphoproteomics, we demonstrate that ∼10% of interacting proteins are regulated by insulin stimulation at the level of phosphorylation...
September 13, 2016: Cell Reports
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/27620488/%C3%AE-arrestin1-promotes-epithelial-mesenchymal-transition-via-modulating-gsk-3%C3%AE-%C3%AE-catenin-pathway-in-prostate-cancer-cells
#11
Xiaolu Duan, Tao Zhang, Zhenzhen Kong, Xin Mai, Chuangxin Lan, Dong Chen, Yang Liu, Zhiwen Zeng, Chao Cai, Tuo Deng, Wenqi Wu, Guohua Zeng
Recently, β-arrestin1 was indicated as a tumor promoter in prostate cancer, but its exact role in cancer metastasis still have not been well clarified. Here, our data revealed that β-arrestin1 could promote the migration and invasion of prostate cancer cells via initiating epithelial-mesenchymal transition (EMT). Mechanically, β-arrestin1 could increase the transcriptional activity and expression of β-catenin, together with Akt activity, whereas decrease the activities of GSK-3β and PP2A. In addition, β-arrestin1 could function as a scaffold protein in modulating the interactions between PP2A, Akt, GSK-3β and β-catenin...
October 14, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27556014/the-broken-off-switch-in-cancer-signaling-pp2a-as-a-regulator-of-tumorigenesis-drug-resistance-and-immune-surveillance
#12
REVIEW
Peter P Ruvolo
Aberrant activation of signal transduction pathways can transform a normal cell to a malignant one and can impart survival properties that render cancer cells resistant to therapy. A diverse set of cascades have been implicated in various cancers including those mediated by serine/threonine kinases such RAS, PI3K/AKT, and PKC. Signal transduction is a dynamic process involving both "On" and "Off" switches. Activating mutations of RAS or PI3K can be viewed as the switch being stuck in the "On" position resulting in continued signaling by a survival and/or proliferation pathway...
December 2016: BBA Clinical
https://www.readbyqxmd.com/read/27531894/novel-b55%C3%AE-pp2a-mutations-in-aml-promote-akt-t308-phosphorylation-and-sensitivity-to-akt-inhibitor-induced-growth-arrest
#13
Geoffrey Shouse, Rosalia de Necochea-Campion, Saied Mirshahidi, Xuan Liu, Chien-Shing Chen
Activation of the Protein Kinase B (PKB), or AKT pathway has been shown to correlate with acute myeloid leukemia (AML) prognosis. B55α-Protein Phosphatase 2A (PP2A) has been shown to dephosphorylate AKT at Thr-308 rendering it inactive. In fact, low expression of the PP2A regulatory subunit B55α was associated with activated phospho-AKT and correlated with inferior outcomes in AML. Despite this fact, no studies have specifically demonstrated a mechanism whereby B55α expression is regulated in AML. In this study, we demonstrate novel loss of function mutations in the PPP2R2A gene identified in leukemic blasts from three AML patients...
August 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27521959/ppp2r5b-a-regulatory-subunit-of-pp2a-contributes-to-adipocyte-insulin-resistance
#14
Muheeb Beg, Ankita Srivastava, Kripa Shankar, Salil Varshney, Sujith Rajan, Abhishek Gupta, Durgesh Kumar, Anil N Gaikwad
Insulin resistance is associated with deregulation of insulin signaling owing to the chronic exposure of insulin (hyperinsulinemia) to the tissues. Phosphorylation and dephosphorylation events in insulin signaling pathway play an essential role in signal transduction and glucose uptake. Amongst all, Akt protein is considered to be central to the overall insulin signaling proteins. In glucose responsive tissues like adipose and muscles, activation of Akt is responsible for triggering GLUT4 translocation and glucose transport...
December 5, 2016: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/27517128/microcystin-lr-promotes-cell-proliferation-in-the-mice-liver-by-activating-akt-and-p38-erk-jnk-cascades
#15
Jinghui Liu, Beilei Wang, Pu Huang, Hanying Wang, Kailun Xu, Xiaofeng Wang, Lihong Xu, Zonglou Guo
Microcystin-LR (MC-LR), a heptapeptide produced by blue-green algae, is shown to induce cytotoxicity by inhibiting protein phosphatase 2A (PP2A) activity. Our previous study revealed that MC-LR promoted cell proliferation in vitro by activating the Akt/mTORC1/S6K1 pathway. This study aims to further investigate the effects of MC-LR on cell proliferation and the correlated mechanisms in vivo. Mice were injected intraperitoneally with 20-80 μg/kg/d MC-LR from 2 h (hours) to 4 d (days). The results showed that the associations of MC-LR with PP2A/C (PP2A C subunit) were concentration-dependent but not time-dependent in the liver, whereas the total PP2A activity was inhibited in both concentration and time dependent manners...
November 2016: Chemosphere
https://www.readbyqxmd.com/read/27485451/recurrent-ppp2r1a-mutations-in-uterine-cancer-act-through-a-dominant-negative-mechanism-to-promote-malignant-cell-growth
#16
Dorien Haesen, Layka Abbasi Asbagh, Rita Derua, Antoine Hubert, Stefanie Schrauwen, Yana Hoorne, Frédéric Amant, Etienne Waelkens, Anna Sablina, Veerle Janssens
Somatic missense mutations in the Ser/Thr protein phosphatase 2A (PP2A) Aα scaffold subunit gene PPP2R1A are among the few genomic alterations that occur frequently in serous endometrial carcinoma (EC) and carcinosarcoma, two clinically aggressive subtypes of uterine cancer with few therapeutic options. Previous studies reported that cancer-associated Aα mutants exhibit defects in binding to other PP2A subunits and contribute to cancer development by a mechanism of haploinsufficiency. Here we report on the functional significance of the most recurrent PPP2R1A mutations in human EC, which cluster in Aα HEAT repeats 5 and 7...
October 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27478065/appl1-promotes-glucose-uptake-in-response-to-mechanical-stretch-via-the-pkc%C3%AE-non-muscle-myosin-iia-pathway-in-c2c12-myotubes
#17
Tsugumichi Saito, Shuichi Okada, Yoko Shimoda, Yuko Tagaya, Aya Osaki, Eijiro Yamada, Ryo Shibusawa, Yasuyo Nakajima, Atsushi Ozawa, Tetsurou Satoh, Masatomo Mori, Masanobu Yamada
Expression of adaptor protein, phosphotyrosine interaction, pleckstrin homology domain, and leucine zipper containing 1 (APPL1) promoted glucose transporter 4 (GLUT4) translocation and glucose uptake in adipose and muscle tissues in response to stimulation with insulin, adiponectin, or exercise. In response to mechanical stretch, knockdown of APPL1 in C2C12 myotubes suppressed glucose uptake. APPL1-induced increased glucose uptake was mediated by protein kinase C (PKC) ζ but not AKT, AMPK, or calmodulin-dependent protein kinase...
November 2016: Cellular Signalling
https://www.readbyqxmd.com/read/27352821/microcystin-lr-induces-a-wide-variety-of-biochemical-changes-in-the-a549-human-non-small-cell-lung-cancer-cell-line-roles-for-protein-phosphatase-2a-and-its-substrates
#18
Hanying Wang, Kailun Xu, Beilei Wang, Jinghui Liu, Xiaofeng Wang, Mingluan Xing, Pu Huang, Zonglou Guo, Lihong Xu
Our previous studies have described the toxic effects of microcystin-LR (MC-LR) in various normal cell lines and human hepatoma SMMC-7721 cells, but the specific effects of MC-LR in other types of cancer cells with respect to protein phosphatase 2A (PP2A) have not been fully elaborated. A549 human lung adenocarcinoma cells have been identified to express organic anion-transporting polypeptides (OATP) involved in cellular uptake of MC-LR, and thus probably make an appropriate in vitro model to assess MC-LR's cytotoxicity...
June 29, 2016: Environmental Toxicology
https://www.readbyqxmd.com/read/27350399/cucurbitacin-b-reverses-multidrug-resistance-by-targeting-cip2a-to-reactivate-protein-phosphatase-2a-in-mcf-7-adriamycin-cells
#19
Fen Cai, Liang Zhang, Xiangling Xiao, Chao Duan, Qiuyue Huang, Chunsheng Fan, Jian Li, Xuewen Liu, Shan Li, Ying Liu
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that is overexpressed in various tumors. A previous study found that CIP2A expression is associated with doxorubicin (Dox) resistance. In the present study, we investigated whether cucurbitacin B (CuB), a natural anticancer compound found in Cucurbitaceae, reversed multidrug resistance (MDR) and downregulated CIP2A expression in MCF-7/Adriamycin (MCF-7/Adr) cells, a human breast multidrug-resistant cancer cell line. CuB treatment significantly suppressed MCF-7/Adr cell proliferation, and reversed Dox resistance...
August 2016: Oncology Reports
https://www.readbyqxmd.com/read/27329844/activation-of-protein-phosphatase-2a-in-flt3-acute-myeloid-leukemia-cells-enhances-the-cytotoxicity-of-flt3-tyrosine-kinase-inhibitors
#20
Amanda M Smith, Matthew D Dun, Erwin M Lee, Celeste Harrison, Richard Kahl, Hayley Flanagan, Nikita Panicker, Baratali Mashkani, Anthony S Don, Jonathan Morris, Hamish Toop, Richard B Lock, Jason A Powell, Daniel Thomas, Mark A Guthridge, Andrew Moore, Leonie K Ashman, Kathryn A Skelding, Anoop Enjeti, Nicole M Verrills
Constitutive activation of the receptor tyrosine kinase Fms-like tyrosine kinase 3 (FLT3), via co-expression of its ligand or by genetic mutation, is common in acute myeloid leukemia (AML). In this study we show that FLT3 activation inhibits the activity of the tumor suppressor, protein phosphatase 2A (PP2A). Using BaF3 cells transduced with wildtype or mutant FLT3, we show that FLT3-induced PP2A inhibition sensitizes cells to the pharmacological PP2A activators, FTY720 and AAL(S). FTY720 and AAL(S) induced cell death and inhibited colony formation of FLT3 activated cells...
June 18, 2016: Oncotarget
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