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Protein phosphatase 2a

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https://www.readbyqxmd.com/read/28077320/serine-threonine-phosphatases-in-atrial-fibrillation
#1
Jordi Heijman, Shokoufeh Ghezelbash, Xander H T Wehrens, Dobromir Dobrev
Serine/threonine protein phosphatases control dephosphorylation of numerous cardiac proteins, including a variety of ion channels and calcium-handling proteins, thereby providing precise post-translational regulation of cardiac electrophysiology and function. Accordingly, dysfunction of this regulation can contribute to the initiation, maintenance and progression of cardiac arrhythmias. Atrial fibrillation (AF) is the most common heart rhythm disorder and is characterized by electrical, autonomic, calcium-handling, contractile, and structural remodeling, which include, among other things, changes in the phosphorylation status of a wide range of proteins...
January 7, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28073841/activation-of-eif4e-by-aurora-kinase-a-depicts-a-novel-druggable-axis-in-everolimus-resistant-cancer-cells
#2
Ahmed Katsha, Lihong Wang, Janet Arras, Omar M Omar, Jeffrey A Ecsedy, Abbes Belkhiri, Wael El-Rifai
PURPOSE: In this study, we investigated the role of Aurora kinase A (AURKA) in regulating EIF4E, cap-dependent translation, and resistance to mTOR inhibitor, RAD001 (everolimus). EXPERIMENTAL DESIGN: Tumor xenografts and in vitro cell models of upper gastrointestinal adenocarcinomas (UGCs) were used to determine the role of AURKA in activation of EIF4E and cap-dependent translation. Overexpression, knockdown, and pharmacologic inhibition of AURKA were used in vitro and in vivo...
January 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28069811/tgf-%C3%AE-1-smad3-pathway-targets-pp2a-ampk-foxo1-to-regulate-hepatic-gluconeogenesis
#3
Hariom Yadav, Samir Devalaraja, Stephanie Chung, Sushil G Rane
Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia or diabetes. Maintenance of glucose homeostasis is achieved via functional interactions amongst various organs, liver, skeletal muscle, adipose tissue, brain and the endocrine pancreas. The liver is the primary site for endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D)...
January 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28069132/molecular-regulation-of-the-spindle-assembly-checkpoint-by-kinases-and-phosphatases
#4
G Manic, F Corradi, A Sistigu, S Siteni, I Vitale
The spindle assembly checkpoint (SAC) is a surveillance mechanism contributing to the preservation of genomic stability by monitoring the microtubule attachment to, and/or the tension status of, each kinetochore during mitosis. The SAC halts metaphase to anaphase transition in the presence of unattached and/or untensed kinetochore(s) by releasing the mitotic checkpoint complex (MCC) from these improperly-oriented kinetochores to inhibit the anaphase-promoting complex/cyclosome (APC/C). The reversible phosphorylation of a variety of substrates at the kinetochore by antagonistic kinases and phosphatases is one major signaling mechanism for promptly turning on or turning off the SAC...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28067171/molecular-cloning-and-developmental-expression-patterns-of-the-striatin-gene-encoding-a-member-of-the-regulatory-subunits-for-the-protein-serine-threonine-phosphatase-2a-in-fish
#5
S-S Xie, Z-W Luo, F-Y Liu, L Liu, Z Chen, J-W Xiang, T-H Yang, R-L Qi, Y Yang, Q Nie, L Wang, Z Huang, X-H Hu, Y-F Liu, Q Sun, Y Xiao, W-J Qing, W-B Liu, Y-Z Liu, D-Y Zhang, D W-C Li
The protein phosphatase-2A (PP-2A) is one of the most important serine/threonine phosphatases in eukaryotes. The holoenzyme of PP-2A consists of three subunits: a scaffold A subunit, a catalytic C subunit and a regulatory B subunit. While both A and C subunits are coded by two different genes, the B subunits exist in 26 or more isoforms which are encoded by at least 15 different genes. Previous studies have shown that besides regulating specific PP-2A activity, the various B subunits may have other functions...
January 9, 2017: Current Molecular Medicine
https://www.readbyqxmd.com/read/28065690/medium-throughput-biochemical-compound-screening-identifies-novel-agents-for-pharmacotherapy-of-neurofibromatosis-type-i
#6
Galina Semenova, Dina Stepanova, Sergey M Deyev, Jonathan Chernoff
The variable manifestation of phenotypes that occur in patients with neurofibromatosis type 1 (NF1) includes benign and malignant neurocutaneous tumors for which no adequate treatment exists. Cell-based screening of known bioactive compounds library identified the protein phosphatase 2A (PP2A) inhibitor Cantharidin and the L-type calcium channel blocker Nifedipine as potential candidates for NF1 pharmacotherapy. Validation of screening results using human NF1-associated malignant peripheral nerve sheath tumor (MPNST) cells showed that Cantharidin effectively impeded MPNST cell growth, while Nifedipine treatment significantly decreased local tumor growth in an MPNST xenograft animal model...
January 5, 2017: Biochimie
https://www.readbyqxmd.com/read/28049830/characterization-of-cytopathic-factors-through-genome-wide-analysis-of-the-zika-viral-proteins-in-fission-yeast
#7
Ge Li, Melissa Poulsen, Csaba Fenyvuesvolgyi, Yoko Yashiroda, Minoru Yoshida, J Marc Simard, Robert C Gallo, Richard Y Zhao
The Zika virus (ZIKV) causes microcephaly and the Guillain-Barré syndrome. Little is known about how ZIKV causes these conditions or which ZIKV viral protein(s) is responsible for the associated ZIKV-induced cytopathic effects, including cell hypertrophy, growth restriction, cell-cycle dysregulation, and cell death. We used fission yeast for the rapid, global functional analysis of the ZIKV genome. All 14 proteins or small peptides were produced under an inducible promoter, and we measured the intracellular localization and the specific effects on ZIKV-associated cytopathic activities of each protein...
January 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28045581/overexpression-of-the-pp2a-c5-gene-confers-increased-salt-tolerance-in-arabidopsis-thaliana
#8
Rongbin Hu, Yinfeng Zhu, Guoxin Shen, Hong Zhang
Protein phosphatase 2A (PP2A) was shown to play important roles in biotic and abiotic stress signaling pathways in plants. PP2A is made of three subunits: a scaffolding subunit A, a regulatory subunit B, and a catalytic subunit C. It is believed that the B subunit recognizes specific substrates and the C subunit directly acts on the selected substrates, whereas the A subunit brings a B subunit and a C subunit together to form a specific PP2A holoenzyme. Because there are multiple isoforms for each PP2A subunit, there could be hundreds of novel PP2A holoenzymes in plants...
January 3, 2017: Plant Signaling & Behavior
https://www.readbyqxmd.com/read/28040742/a-role-for-the-twins-protein-phosphatase-pp2a-b55-in-the-maintenance-of-drosophila-genome-integrity
#9
Chiara Merigliano, Antonio Marzio, Fioranna Renda, Maria Patrizia Somma, Maurizio Gatti, Fiammetta Vernì
The protein phosphatase 2A (PP2A) is a conserved heterotrimeric enzyme that regulates several cellular processes including the DNA damage response and mitosis. Consistent with these functions, PP2A is mutated in many types of cancer and acts as a tumor suppressor. In mammalian cells, PP2A inhibition results in DNA double strand breaks (DSBs) and chromosome aberrations (CABs). However, the mechanisms through which PP2A prevents DNA damage are still unclear. Here, we focus on the role of the Drosophila twins (tws) gene in the maintenance of chromosome integrity; tws encodes the B regulatory subunit (B/B55) of PP2A...
December 30, 2016: Genetics
https://www.readbyqxmd.com/read/28039265/safety-tolerability-and-preliminary-activity-of-lb-100-an-inhibitor-of-protein-phosphatase-2a-in-patients-with-relapsed-solid-tumors
#10
John S Kovach, Vincent Chung, Aaron S Mansfield, Fadi Braiteh, Donald Richards, Henry Durivage, Richard S Ungerleider, Francis Johnson
PURPOSE: To determine the maximum tolerated dose and to assess the safety, tolerability, and potential activity of LB-100, a first-in-class small molecule inhibitor of protein phosphatase 2A (PP2A) in adult patients with progressive solid tumors. EXPERIMENTAL DESIGN: LB-100 was administered intravenously daily for 3 days in 21-day cycles in a 3+3 dose-escalation design. RESULTS: There were 29 patient entries over 7 dose escalations. One patient stopped treatment after one dose because of an acute infection and was re-enrolled after recovery; each course was analyzed as a separate patient entry...
December 30, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28034953/atypical-pp2a-protein-phosphatase-gene-families-do-not-expand-via-paleopolyploidization
#11
Matthew A Booker, Alison DeLong
Protein Phosphatase 2A (PP2A) presents unique opportunities for analyzing molecular mechanisms of functional divergence between gene family members. The canonical PP2A holoenzyme regulates multiple eukaryotic signaling pathways by dephosphorylating target proteins and contains a catalytic (C) subunit, a structural/scaffolding (A) subunit, and a regulatory (B) subunit. Genes encoding PP2A subunits have expanded into multi-gene families in both flowering plants and mammals, and the extent to which different isoform functions may overlap is not clearly understood...
December 29, 2016: Plant Physiology
https://www.readbyqxmd.com/read/28027514/egfr-independent-elk1-cip2a-signalling-mediates-apoptotic-effect-of-an-erlotinib-derivative-td52-in-triple-negative-breast-cancer-cells
#12
Chun-Yu Liu, Tzu-Ting Huang, Chun-Teng Huang, Ming-Hung Hu, Duen-Shian Wang, Wan-Lun Wang, Wen-Chun Tsai, Chia-Han Lee, Ka-Yi Lau, Hsiu-Ping Yang, Ming-Huang Chen, Chung-Wai Shiau, Ling-Ming Tseng, Kuen-Feng Chen
OBJECTIVES: Cancerous inhibitor of protein phosphatase 2A (CIP2A) has emerged as a therapeutic determinant mediating the anti-cancer effects of several new agents. We investigated the efficacy and mechanism of TD52, an erlotinib derivative with minimal p-EGFR inhibition but significant CIP2A downregulation, in triple-negative breast cancer (TNBC) cells. METHODS: TNBC lines were used for in vitro studies. Cell apoptosis was examined by flow cytometry and Western blot...
December 24, 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/28025327/fmrp-dependent-mdm2-dephosphorylation-is-required-for-mef2-induced-synapse-elimination
#13
Nien-Pei Tsai, Julia R Wilkerson, Weirui Guo, Kimberly M Huber
The Myocyte Enhancer Factor 2 (MEF2) transcription factors suppress an excitatory synapse number by promoting degradation of the synaptic scaffold protein, postsynaptic density protein 95 (PSD-95), a process that is deficient in the mouse model of Fragile X Syndrome, Fmr1 KO. How MEF2 activation results in PSD-95 degradation and why this is defective in Fmr1 KO neurons is unknown. Here we report that MEF2 induces a Protein phosphatase 2A (PP2A)-mediated dephosphorylation of murine double minute-2 (Mdm2), the ubiquitin E3 ligase for PSD-95, which results in nuclear export and synaptic accumulation of Mdm2 as well as PSD-95 degradation and synapse elimination...
December 26, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28004338/network-analysis-identifies-disease-specific-pathways-for-parkinson-s-disease
#14
Chiara Monti, Ilaria Colugnat, Leonardo Lopiano, Adriano Chiò, Tiziana Alberio
Neurodegenerative diseases are characterized by the progressive loss of specific neurons in selected regions of the central nervous system. The main clinical manifestation (movement disorders, cognitive impairment, and/or psychiatric disturbances) depends on the neuron population being primarily affected. Parkinson's disease is a common movement disorder, whose etiology remains mostly unknown. Progressive loss of dopaminergic neurons in the substantia nigra causes an impairment of the motor control. Some of the pathogenetic mechanisms causing the progressive deterioration of these neurons are not specific for Parkinson's disease but are shared by other neurodegenerative diseases, like Alzheimer's disease and amyotrophic lateral sclerosis...
December 21, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27995573/forskolin-induces-hyperphosphorylation-of-tau-accompanied-by-cell-cycle-reactivation-in-primary-hippocampal-neurons
#15
Hai-Hong Wang, Yan Li, Ang Li, Fang Yan, Zhen-Lin Li, Zhong-Ying Liu, Lei Zhang, Jian Zhang, Wei-Ren Dong, Lin Zhang
Abnormally hyperphosphorylated tau is the major protein constituent of neurofibrillary tangles (NFTs) in the brain of Alzheimer disease (AD) patients. Cell cycle reactivation is considered an important neuropathological feature of AD, and re-expression and activation of cell cycle regulators are known to occur in neurons containing NFTs. The aim of the present study was to investigate cell cycle reactivation during tau hyperphosphorylation in primary hippocampal neurons. We used forskolin, a specific activator of PKA, to induce tau hyperphosphorylation in cultured primary hippocampal neurons, and then measured levels of cyclin D1 and cyclin B1...
December 19, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27993520/overexpression-of-%C3%AE-camkii-impairs-behavioral-flexibility-and-nmdar-dependent-long-term-depression-in-the-dentate-gyrus
#16
Pengcheng Yin, Hao Xu, Qi Wang, Jiayue Wang, Liang Yin, Meichen Xu, Zhenyang Xie, Wenzhao Liu, Xiaohua Cao
Behavioral flexibility is in close proximity to dentate gyrus (DG) function and long-term depression (LTD), but the role of DG LTD in behavioral flexibility has hitherto been unexplored. Although the functions of alpha-Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) have been studied extensively, the role of βCaMKII, a constituent of the CaMKII holoenzyme, in LTD and behavioral flexibility has not been investigated in vivo. Here using the βCaMKII-F90G transgenic (TG) mice, in which the inducible and reversible overexpression of βCaMKII is restricted to dentate gyrus (DG), we found that TG mice exhibited defective behavioral flexibility in two reversal tasks and seriously impaired N-methyl-d-aspartic acid receptor (NMDAR)-dependent LTD in DG medial perforant path (MPP)...
December 16, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27992562/two-subclasses-of-differentially-expressed-tps1-genes-and-biochemically-active-tps1-proteins-may-contribute-to-sugar-signalling-in-kiwifruit-actinidia-chinensis
#17
Charlotte Voogd, Lara A Brian, Erika Varkonyi-Gasic
Trehalose metabolism and its intermediate trehalose-6-phosphate (T6P) are implicated in sensing and signalling sucrose availability. Four class I TREHALOSE-6-PHOSPHATE SYNTHASE (TPS1) genes were identified in kiwifruit, three of which have both the TPS and trehalose-6-phosphate phosphatase (TPP) domain, while the fourth gene gives rise to a truncated transcript. The transcript with highest sequence homology to Arabidopsis TPS1, designated TPS1.1a was the most highly abundant TPS1 transcript in all examined kiwifruit tissues...
2016: PloS One
https://www.readbyqxmd.com/read/27987522/-interleukin-2-signaling-pathway-regulating-molecules-in-systemic-lupus-erythematosus
#18
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/27982046/comprehensive-phenotypic-analysis-of-knockout-mice-deficient-in-cyclin-g1-and-cyclin-g2
#19
Shouichi Ohno, Jun-Ichiro Ikeda, Yoko Naito, Daisuke Okuzaki, Towa Sasakura, Kohshiro Fukushima, Yukihiro Nishikawa, Kaori Ota, Yorika Kato, Mian Wang, Kosuke Torigata, Takashi Kasama, Toshihiro Uchihashi, Daisaku Miura, Norikazu Yabuta, Eiichi Morii, Hiroshi Nojima
Cyclin G1 (CycG1) and Cyclin G2 (CycG2) play similar roles during the DNA damage response (DDR), but their detailed roles remain elusive. To investigate their distinct roles, we generated knockout mice deficient in CycG1 (G1KO) or CycG2 (G2KO), as well as double knockout mice (DKO) deficient in both proteins. All knockouts developed normally and were fertile. Generation of mouse embryonic fibroblasts (MEFs) from these mice revealed that G2KO MEFs, but not G1KO or DKO MEFs, were resistant to DNA damage insults caused by camptothecin and ionizing radiation (IR) and underwent cell cycle arrest...
December 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27974665/the-protein-phosphatase-2a-regulatory-subunit-pr70-is-a-gonosomal-melanoma-tumor-suppressor-gene
#20
Léon C L van Kempen, Margaret Redpath, Mounib Elchebly, Kathleen Oros Klein, Andreas I Papadakis, James S Wilmott, Richard A Scolyer, Per-Henrik Edqvist, Fredrik Pontén, Dirk Schadendorf, Anke F van Rijk, Stefan Michiels, Anne Dumay, Anne Helbling-Leclerc, Philippe Dessen, Jasper Wouters, Marguerite Stass, Celia M T Greenwood, Ghanem E Ghanem, Joost van den Oord, Jean Feunteun, Alan Spatz
Male gender is independently and significantly associated with poor prognosis in melanoma of all clinical stages. The biological underpinnings of this sex difference remain largely unknown, but we hypothesized that gene expression from gonosomes (sex chromosomes) might play an important role. We demonstrate that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis-free survival, suggesting a dosage benefit from two X chromosomes. The gonosomal protein phosphatase 2 regulatory subunit B, beta (PPP2R3B) gene is located on the pseudoautosomal region (PAR) of the X chromosome in females and the Y chromosome in males...
December 14, 2016: Science Translational Medicine
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