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Protein phosphatase 2a

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https://www.readbyqxmd.com/read/28431339/novel-coumarin-and-quinolinone-based-polycycles-as-cell-division-cycle-25-a-and-c-phosphatases-inhibitors-induce-proliferation-arrest-and-apoptosis-in-cancer-cells
#1
Clemens Zwergel, Brigitte Czepukojc, Emilie Evain-Bana, Zhanjie Xu, Giulia Stazi, Mattia Mori, Alexandros Patsilinakos, Antonello Mai, Bruno Botta, Rino Ragno, Denise Bagrel, Gilbert Kirsch, Peter Meiser, Claus Jacob, Mathias Montenarh, Sergio Valente
Cell division cycle phosphatases CDC25 A, B and C are involved in modulating cell cycle processes and are found overexpressed in a large panel of cancer typology. Here, we describe the development of two novel quinone-polycycle series of CDC25A and C inhibitors on the one hand 1a-k, coumarin-based, and on the other 2a-g, quinolinone-based, which inhibit either enzymes up to a sub-micro molar level and at single-digit micro molar concentrations, respectively. When tested in six different cancer cell lines, compound 2c displayed the highest efficacy to arrest cell viability, showing in almost all cell lines sub-micro molar IC50 values, a profile even better than the reference compound NCS95397...
April 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28422052/folic-acid-reduces-tau-phosphorylation-by-regulating-pp2a-methylation-in-streptozotocin-induced-diabetic-mice
#2
Miaoyan Zheng, Chen Zou, Mengyue Li, Guowei Huang, Yuxia Gao, Huan Liu
High incidence rate of Alzheimer's disease (AD) is observed in patients with type 2 diabetes. Aggregated β-amyloid (Aβ) and hyperphosphorylated tau are the hallmarks of AD. Hyperphosphorylated tau has been detected in diabetic animals as well as in diabetic patients. Folates mediate the transfer of one carbon unit, required in various biochemical reactions. The effect of folate on tau phosphorylation in diabetic models still remains unknown. In this study, we investigated the effect and mechanism of folic acid on hyperphosphorylation of tau in streptozotocin (STZ)-induced diabetic mice...
April 19, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28404686/propofol-anesthesia-is-reduced-in-phospholipase-c-related-inactive-protein-type-1-knockout-mice
#3
Yoshikazu Nikaido, Tomonori Furukawa, Shuji Shimoyama, Junko Yamada, Keisuke Migita, Kohei Koga, Tetsuya Kushikata, Kazuyoshi Hirota, Takashi Kanematsu, Masato Hirata, Shinya Ueno
The GABA type A receptor (GABAA-R) is a major target of intravenous anesthetics. Phospholipase C-related inactive protein type-1 (PRIP-1) is important in GABAA-R phosphorylation and membrane trafficking. In this study, we investigated the role of PRIP-1 in general anesthetic action. The anesthetic effects of propofol, etomidate, and pentobarbital were evaluated in wild-type and PRIP-1 knockout (PRIP-1 KO) mice by measuring the latency and duration of loss of righting reflex (LORR) and loss of tail-pinch withdrawal response (LTWR)...
April 12, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28402338/insulin-deprivation-induces-pp2a-inhibition-and-tau-hyperphosphorylation-in-htau-mice-a-model-of-alzheimer-s-disease-like-tau-pathology
#4
Maud Gratuze, Jacinthe Julien, Franck R Petry, Françoise Morin, Emmanuel Planel
Abnormally hyperphosphorylated tau aggregated as intraneuronal neurofibrillary tangles is one of the two neuropathological hallmarks of Alzheimer's disease (AD). The majority of AD cases are sporadic with numerous environmental, biological and genetic risks factors. Interestingly, insulin dysfunction and hyperglycaemia are both risk factors for sporadic AD. However, how hyperglycaemia and insulin dysfunction affect tau pathology, is not well understood. In this study, we examined the effects of insulin deficiency on tau pathology in transgenic hTau mice by injecting different doses of streptozotocin (STZ), a toxin that destroys insulin-producing cells in the pancreas...
April 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28389570/bves-regulates-c-myc-stability-via-pp2a-and-suppresses-colitis-induced-tumourigenesis
#5
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/28370936/a-cascade-of-redox-reactions-generates-complexity-in-the-biosynthesis-of-the-protein-phosphatase-2-inhibitor-rubratoxin%C3%A2-a
#6
Jian Bai, Daojiang Yan, Tao Zhang, Yongzhi Guo, Yunbao Liu, Yi Zou, Mancheng Tang, Bingyu Liu, Qiong Wu, Shishan Yu, Yi Tang, Youcai Hu
Redox modifications are key complexity-generating steps in the biosynthesis of natural products. The unique structure of rubratoxin A (1), many of which arise through redox modifications, make it a nanomolar inhibitor of protein phosphatase 2A (PP2A). We identified the biosynthetic pathway of 1 and completely mapped the enzymatic sequence of redox reactions starting from the nonadride 5. Six redox enzymes are involved, including four α-ketoglutarate- and iron(II)-dependent dioxygenases that hydroxylate four sp(3) carbons; one flavin-dependent dehydrogenase that is involved in formation of the unsaturated lactone; and the ferric-reductase-like enzyme RbtH, which regioselectively reduces one of the maleic anhydride moieties in rubratoxin B to the γ-hydroxybutenolide that is critical for PP2A inhibition...
March 28, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28366783/intestinal-immune-responses-of-jian-carp-against-aeromonas-hydrophila-depressed-by-choline-deficiency-varied-change-patterns-of-mrna-levels-of-cytokines-tight-junction-proteins-and-related-signaling-molecules-among-three-intestinal-segments
#7
Pei Wu, Yang Liu, Wei-Dan Jiang, Jun Jiang, Yong-An Zhang, Xiao-Qiu Zhou, Lin Feng
This study aimed to investigate the effects of choline deficiency on intestinal inflammation of fish after Aeromonas hydrophila infection and the potential molecular mechanisms. Juvenile Jian carp (Cyprinus carpio var. Jian) were fed two diets containing choline at 165 (deficient group) and 607 mg/kg diet respectively for 65 days. Choline deficiency decreased intestinal lysozyme activity, C3 and IgM contents, increased acid phosphatase activity, downregulated mRNA levels of antimicrobial peptides [liver-expressed antimicrobial peptide (LEAP) 2A, LEAP-2B, hepcidin and defensin], cytokines [interleukin (IL) 6a, tumor necrosis factor α (TNF-α), interferon γ2b (IFN-γ2b), IL-6b and transforming growth factor β2 (TGF-β2) only in proximal intestine, IL-10 in mid and distal intestine], immune-related signaling molecules [Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor kappa B (NF-κB), inhibitor of NF-κB (IκB), Janus kinase 3 (JAK3), and signal transducers and activators of transcription 5 (STAT5)], tight junction proteins (claudin 3b, claudin 3c, claudin 11 and occludin), and mitogen-activated protein kinases p38 (p38(MAPK)) in proximal and distal intestine of juvenile Jian carp after A...
March 30, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28352544/efficient-production-of-recombinant-pp2a-at-a-low-temperature-using-a-baculovirus-expression-system
#8
Tsuyoshi Ikehara, Shihoko Nakashima, Junichi Nakashima, Tsubasa Kinoshita, Takeshi Yasumoto
Protein phosphatase 2A (PP2A) is an enzyme useful for detecting several natural toxins represented by okadaic acid and microcystins. We found that the production of the recombinant human PP2A catalytic subunit (rhPP2Ac) in High Five insect cells could markedly increase when the cells were cultured at 19 °C instead of 27 °C used under conventional conditions. The yield and purity of the enzyme increased four- and three-folds, respectively. The benefit of the altered culturing temperature was observed with the recombinant human protein phosphatase 2B but not 2Cα...
September 2016: Biotechnology Reports
https://www.readbyqxmd.com/read/28340282/carfilzomib-induces-leukaemia-cell-apoptosis-via-inhibiting-elk1-kiaa1524-elk-1-cip2a-and-activating-pp2a-not-related-to-proteasome-inhibition
#9
Chun-Yu Liu, Feng-Shu Hsieh, Pei-Yi Chu, Wen-Chun Tsai, Chun-Teng Huang, Yuan-Bin Yu, Tzu-Ting Huang, Po-Shen Ko, Man-Hsin Hung, Wan-Lun Wang, Chung-Wai Shiau, Kuen-Feng Chen
Enhancing the tumour suppressive activity of protein phosphatase 2A (PP2A) has been suggested to be an anti-leukaemic strategy. KIAA1524 (also termed CIP2A), an oncoprotein inhibiting PP2A, is associated with disease progression in chronic myeloid leukaemia and may be prognostic in cytogenetically normal acute myeloid leukaemia. Here we demonstrated that the selective proteasome inhibitor, carfilzomib, induced apoptosis in sensitive primary leukaemia cells and in sensitive leukaemia cell lines, associated with KIAA1524 protein downregulation, increased PP2A activity and decreased p-Akt, but not with the proteasome inhibition effect of carfilzomib...
March 24, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28327575/analysis-of-exome-data-for-4293-trios-suggests-gpi-anchor-biogenesis-defects-are-a-rare-cause-of-developmental-disorders
#10
Alistair T Pagnamenta, Yoshiko Murakami, John M Taylor, Consuelo Anzilotti, Malcolm F Howard, Venessa Miller, Diana S Johnson, Shereen Tadros, Sahar Mansour, I Karen Temple, Rachel Firth, Elisabeth Rosser, Rachel E Harrison, Bronwen Kerr, Niko Popitsch, Taroh Kinoshita, Jenny C Taylor, Usha Kini
Over 150 different proteins attach to the plasma membrane using glycosylphosphatidylinositol (GPI) anchors. Mutations in 18 genes that encode components of GPI-anchor biogenesis result in a phenotypic spectrum that includes learning disability, epilepsy, microcephaly, congenital malformations and mild dysmorphic features. To determine the incidence of GPI-anchor defects, we analysed the exome data from 4293 parent-child trios recruited to the Deciphering Developmental Disorders (DDD) study. All probands recruited had a neurodevelopmental disorder...
March 22, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28303020/importance-of-zinc-transporter-8-autoantibody-in-the-diagnosis-of-type-1-diabetes-in-latin-americans
#11
Karla Fabiana Brasil Gomes, Cintia Semzezem, Rodolfo Batista, Rosa Tsuneshiro Fukui, Aritania Sousa Santos, Márcia Regina Correia, Maria Rita Passos-Bueno, Maria Elizabeth Rossi da Silva
There is a scarcity of data of zinc transporter-8 autoantibody (ZnT8A) on mixed populations such as Brazilian. Therefore, we evaluated the relevance of ZnT8A for type 1 diabetes (T1D) diagnosis and the role of ZnT8 coding gene (SLC30A8) in T1D predisposition. Patients with T1D (n = 629; diabetes duration = 11 (6-16) years) and 651 controls were genotyped for SLC30A8 rs16889462 and rs2466295 variants (BeadXpress platform). ZnT8 triple antibody was measured by ELISA; glutamic acid decarboxylase (GAD65A) and protein tyrosine phosphatase (IA-2A) autoantibodies by radioimmunoassay...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28300193/interplay-of-myosin-phosphatase-and-protein-phosphatase-2a-in-the-regulation-of-endothelial-nitric-oxide-synthase-phosphorylation-and-nitric-oxide-production
#12
Róbert Bátori, Bálint Bécsi, Dénes Nagy, Zoltán Kónya, Csaba Hegedűs, Zsuzsanna Bordán, Alexander Verin, Beáta Lontay, Ferenc Erdődi
The inhibitory phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) at Thr497 (eNOS(pThr497)) by protein kinase C or RhoA-activated kinase is a major regulatory determinant of eNOS activity. The signalling mechanisms involved in the dephosphorylation of eNOS(pThr497) have not yet been clarified. This study identifies myosin phosphatase (MP) holoenzyme consisting of protein phosphatase-1 catalytic subunit (PP1c) and MP target subunit-1 (MYPT1) as an eNOS(pThr497) phosphatase. In support of this finding are: (i) eNOS and MYPT1 interacts in various endothelial cells (ECs) and in in vitro binding assays (ii) MYPT1 targets and stimulates PP1c toward eNOS(pThr497) substrate (iii) phosphorylation of MYPT1 at Thr696 (MYPT1(pThr696)) controls the activity of MP on eNOS(pThr497)...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28298211/fty720-inhibits-mesothelioma-growth-in-vitro-and-in-a-syngeneic-mouse-model
#13
Agata Szymiczek, Sandra Pastorino, David Larson, Mika Tanji, Laura Pellegrini, Jiaming Xue, Shuangjing Li, Carlotta Giorgi, Paolo Pinton, Yasutaka Takinishi, Harvey I Pass, Hideki Furuya, Giovanni Gaudino, Andrea Napolitano, Michele Carbone, Haining Yang
BACKGROUND: Malignant mesothelioma (MM) is a very aggressive type of cancer, with a dismal prognosis and inherent resistance to chemotherapeutics. Development and evaluation of new therapeutic approaches is highly needed. Immunosuppressant FTY720, approved for multiple sclerosis treatment, has recently raised attention for its anti-tumor activity in a variety of cancers. However, its therapeutic potential in MM has not been evaluated yet. METHODS: Cell viability and anchorage-independent growth were evaluated in a panel of MM cell lines and human mesothelial cells (HM) upon FTY720 treatment to assess in vitro anti-tumor efficacy...
March 15, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28274314/-inhibitory-effect-of-magnesium-cantharidate-on-human-hepatoma-smmc-7721-cell-proliferation-by-blocking-mapk-signaling-pathway
#14
Yun Liu, Xiaofei Li, Qianqian Zou, Liu Liu, Xinting Zhu, Qi Jia, Lingjun Wang, Rong Yan
Objective To investigate the anticancer mechanism of magnesium cantharidate by observing its effect on the mitogen-activated protein kinase (MAPK) signaling pathway in human hepatoma SMMC-7721 cells. Methods The protein phosphatase 2A (PP2A) activity detection kit was used to detect the effects of magnesium cantharidate and okadaic acid (OA) on PP2A activity. After the treatment of SMMC-7721 cells with magnesium cantharidate and/or OA, mRNA levels of extracellular signal-regulated kinase 1 (ERK1), ERK2, p38MAPK, c-Jun N-terminal kinase 1 (JNK1) and JNK2 were detected by real-time quantitative PCR, and the protein expression levels and protein phosphorylation of ERK1, ERK2, p38 MAPK and JNK were determined by Western blotting...
March 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/28265764/germline-specific-labeling-of-the-somatic-chromosomes-by-protein-phosphatase-2a-and-histone-h3s28-phosphorylation-in-acricotopus-lucidus
#15
Wolfgang Staiber
Additional chromosomes limited to the germline (=Ks) were established as a special form of germline-soma differentiation in the Orthocladiinae, a subfamily of the Chironomidae (Bauer and Beermann in Z Naturforsch 7b: 557-563, 1952). The Ks together with the somatic chromosomes (=Ss) pass through a complex chromosome cycle with elimination at mitosis and a monopolar migration of all Ks. The dissimilar behavior of Ks and Ss in these exceptional mitoses initiated the search for differential chromosome marks in the orthocladiid Acricotopus lucidus...
March 6, 2017: Protoplasma
https://www.readbyqxmd.com/read/28256936/proteomic-analysis-of-the-neurotrophic-effect-of-gelidium-amansii-in-primary-cultured-neurons
#16
Md Abdul Hannan, Md Mohibbullah, Yong-Ki Hong, Il Soo Moon
Gelidium amansii is an edible and economically important red alga consumed in South Eastern Asia. In previous studies, we reported that the ethanol extracts of G. amansii (GAE) has promising modulatory activity with respect to the morphological and functional maturation of hippocampal neurons in culture. In this study, we show that the chloroform (CHCl3) subfraction of GAE and the ethyl acetate (EtOAc) fraction dose-dependently promoted neurite outgrowth, and their effects were comparable with that of GAE. We further assessed in cultured cortical neurons, proteins differentially expressed in the presence/absence of the GAE, CHCl3 subfraction, and the EtOAc fraction by 2D-PAGE and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry...
March 2017: Journal of Medicinal Food
https://www.readbyqxmd.com/read/28251149/fibrillar-type-i-collagen-enhances-the-differentiation-and-proliferation-of-myofibroblasts-by-lowering-%C3%AE-2%C3%AE-1-integrin-expression-in-cardiac-fibrosis
#17
Jian Hong, Ming Chu, Lijun Qian, Junhong Wang, Yan Guo, Di Xu
Many studies have shown that α2β1 integrin plays an important role in the development of cardiac fibrosis. However, the mechanism of how α2β1 integrin regulates the differentiation and proliferation of myofibroblasts in cardiac fibrosis through fibrillar collagen (FC) remains uncertain. We established that FC mimicked the 3-dimensional extracellular matrix (ECM) of fibroblasts from post-myocardial infarction (MI) patients in vivo. This allowed us to explore the differentiation and proliferation of cardiac fibroblasts on FC...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28241467/role-of-protein-phosphatase-2a-in-osteoblast-differentiation-and-function
#18
REVIEW
Hirohiko Okamura, Kaya Yoshida, Hiroyuki Morimoto, Jumpei Teramachi, Kazuhiko Ochiai, Tatsuji Haneji, Akihito Yamamoto
The reversible phosphorylation of proteins plays hugely important roles in a variety of cellular processes, such as differentiation, proliferation, and apoptosis. These processes are strictly controlled by protein kinases (phosphorylation) and phosphatases (de-phosphorylation). Here we provide a brief history of the study of protein phosphorylation, including a summary of different types of protein kinases and phosphatases. One of the most physiologically important serine/threonine phosphatases is PP2A. This review provides a description of the phenotypes of various PP2A transgenic mice and further focuses on the known functions of PP2A in bone formation, including its role in osteoblast differentiation and function...
February 23, 2017: Journal of Clinical Medicine
https://www.readbyqxmd.com/read/28239848/protein-phosphatase-2a-regulation-of-markers-of-extracellular-matrix-remodelling-in-hepatocellular-carcinoma-cells-functional-consequences-for-tumour-invasion
#19
M P Ward, J P Spiers
BACKGROUND AND PURPOSE: A hallmark of tumour invasion is breakdown of the extracellular matrix due to dysregulation of the matrix metalloproteinase (MMP) system. While our understanding of how this is regulated by kinase signalling pathways is well established, its counter-regulation by protein phosphatases (PP) is poorly understood. Therefore, we investigated the effect of PP inhibition on markers of extracellular remodelling and how PP2A activity modulated MMP-9 abundance and function of Hep3B cells...
February 27, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28224476/protein-phosphatase-2a-a-double-faced-phosphatase-of-cellular-system-and-its-role-in-neurodegenerative-disorders
#20
REVIEW
Md Nematullah, M N Hoda, Farah Khan
Protein phosphatase 2A (PP2A), a ubiquitously expressed serine/threonine phosphatase, is a vitally important phosphatase for the cellular system. Structurally, it is constituted of three different subunits, namely catalytic subunit (PP2Ac), structural scaffold subunit (PP2A-A), and regulatory subunit (PP2A-B). All subunits have various isoforms, and catalytic and scaffold subunits are ubiquitously expressed, whereas regulatory subunits are more specific to tissue and cell type. It is the numerous possibilities of PP2A holoenzyme assembly with varying isoform components that make it possess a dual nature of activator or the inhibitory character in different signaling pathways, namely neural developmental pathways, Akt/protein kinase B pathway, NF-kB pathway, MAPK pathway, apoptosis pathway, and cell cycle progression to name a few...
February 21, 2017: Molecular Neurobiology
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