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https://www.readbyqxmd.com/read/28100785/protein-kinase-c-controls-binding-of-igo-ensa-proteins-to-protein-phosphatase-2a-in-budding-yeast
#1
Vu Thai, Noah Dephoure, Amit Weiss, Jacqueline Ferguson, Ricardo Leitao, Steven P Gygi, Douglas R Kellogg
Protein phosphatase 2A (PP2A) plays important roles in controlling mitosis in all eukaryotic cells. The form of PP2A that controls mitosis is associated with a conserved regulatory subunit that is called B55 in vertebrates and Cdc55 in budding yeast. The activity of this form of PP2A can be inhibited by binding of conserved Igo/ENSA proteins. Although the mechanisms that activate Igo/ENSA to bind to PP2A are well understood, little is known about how they are inactivated. Here, we have analyzed regulation of Igo/ENSA in the context of a checkpoint pathway that links mitotic entry to membrane growth in budding yeast...
January 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28100687/a-stripak-complex-mediates-axonal-transport-of-autophagosomes-and-dense-core-vesicles-through-pp2a-regulation
#2
Amanda L Neisch, Thomas P Neufeld, Thomas S Hays
Autophagy plays an essential role in the cellular homeostasis of neurons, facilitating the clearance of cellular debris. This clearance process is orchestrated through the assembly, transport, and fusion of autophagosomes with lysosomes for degradation. The motor protein dynein drives autophagosome motility from distal sites of assembly to sites of lysosomal fusion. In this study, we identify the scaffold protein CKA (connector of kinase to AP-1) as essential for autophagosome transport in neurons. Together with other core components of the striatin-interacting phosphatase and kinase (STRIPAK) complex, we show that CKA associates with dynein and directly binds Atg8a, an autophagosomal protein...
January 18, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28093285/the-depletion-of-atm-inhibits-colon-cancer-proliferation-and-migration-via-b56%C3%AE-2-mediated-chk1-p53-cd44-cascades
#3
Rui Liu, Jiajia Tang, Chaodong Ding, Weicheng Liang, Li Zhang, Tianke Chen, Yan Xiong, Xiaowei Dai, Wenfeng Li, Yunsheng Xu, Jin Hu, Liting Lu, Wanqin Liao, Xincheng Lu
Ataxia-telangiectasia mutated (ATM) protein kinase is a major guardian of genomic stability, and its well-established function in cancer is tumor suppression. Here, we report an oncogenic role of ATM. Using two isogenic sets of human colon cancer cell lines that differed only in their ATM status, we demonstrated that ATM deficiency significantly inhibits cancer cell proliferation, migration, and invasion. The tumor-suppressive function of ATM depletion is not modulated by the compensatory activation of ATR, but it is associated with B56γ2-mediated Chk1/p53/CD44 signaling pathways...
January 13, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28090813/effects-of-fostriecin-on-%C3%AE-2-adrenoceptor-driven-responses-in-human-mast-cells
#4
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...
January 16, 2017: Journal of Immunotoxicology
https://www.readbyqxmd.com/read/28089567/adipose-tissue-clk2-promotes-energy-expenditure-during-high-fat-diet-intermittent-fasting
#5
Maximilian Hatting, Amy K Rines, Chi Luo, Mitsuhisa Tabata, Kfir Sharabi, Jessica A Hall, Francisco Verdeguer, Christian Trautwein, Pere Puigserver
A promising approach to treating obesity is to increase diet-induced thermogenesis in brown adipose tissue (BAT), but the regulation of this process remains unclear. Here we find that CDC-like kinase 2 (CLK2) is expressed in BAT and upregulated upon refeeding. Mice lacking CLK2 in adipose tissue exhibit exacerbated obesity and decreased energy expenditure during high-fat diet intermittent fasting. Additionally, tissue oxygen consumption and protein levels of UCP1 are reduced in CLK2-deficient BAT. Phosphorylation of CREB, a transcriptional activator of UCP1, is markedly decreased in BAT cells lacking CLK2 due to enhanced CREB dephosphorylation...
January 11, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28087715/sf3b1-hsh155-heat-motif-mutations-affect-interaction-with-the-spliceosomal-atpase-prp5-resulting-in-altered-branch-site-selectivity-in-pre-mrna-splicing
#6
Qing Tang, Susana Rodriguez-Santiago, Jing Wang, Jia Pu, Andrea Yuste, Varun Gupta, Alberto Moldón, Yong-Zhen Xu, Charles C Query
Mutations in the U2 snRNP component SF3B1 are prominent in myelodysplastic syndromes (MDSs) and other cancers and have been shown recently to alter branch site (BS) or 3' splice site selection in splicing. However, the molecular mechanism of altered splicing is not known. We show here that hsh155 mutant alleles in Saccharomyces cerevisiae, counterparts of SF3B1 mutations frequently found in cancers, specifically change splicing of suboptimal BS pre-mRNA substrates. We found that Hsh155p interacts directly with Prp5p, the first ATPase that acts during spliceosome assembly, and localized the interacting regions to HEAT (Huntingtin, EF3, PP2A, and TOR1) motifs in SF3B1 associated with disease mutations...
December 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/28077320/serine-threonine-phosphatases-in-atrial-fibrillation
#7
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
#8
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
#9
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
#10
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/28065690/medium-throughput-biochemical-compound-screening-identifies-novel-agents-for-pharmacotherapy-of-neurofibromatosis-type-i
#11
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/28059583/mir7-3hg-a-myc-dependent-modulator-of-cell-proliferation-inhibits-autophagy-by-a-regulatory-loop-involving-ambra1
#12
Mariacristina Capizzi, Flavie Strappazzon, Valentina Cianfanelli, Elena Papaleo, Francesco Cecconi
Macroautophagy/autophagy is a tightly regulated intracellular catabolic pathway involving the lysosomal degradation of cytoplasmic organelles and proteins to be recycled into metabolic precursors. AMBRA1 (autophagy and beclin 1 regulator 1) has a central role in the autophagy signaling network; it acts upstream of MTORC1-dependent autophagy by stabilizing the kinase ULK1 (unc-51 like autophagy activating kinase 1) and by favoring autophagosome core complex formation. AMBRA1 also regulates the cell cycle by modulating the activity of the phosphatase PPP2/PP2A (protein phosphatase 2) and degradation of MYC...
January 6, 2017: Autophagy
https://www.readbyqxmd.com/read/28057023/xiap-bir-domain-suppresses-mir-200a-expression-and-subsequently-promotes-egfr-protein-translation-and-anchorage-independent-growth-of-bladder-cancer-cell
#13
Chao Huang, Xingruo Zeng, Guosong Jiang, Xin Liao, Claire Liu, Jingxia Li, Honglei Jin, Junlan Zhu, Hong Sun, Xue-Ru Wu, Chuanshu Huang
BACKGROUND: The X-linked inhibitor of apoptosis protein (XIAP) is a well-known potent apoptosis suppressor and also participates in cancer cell biological behaviors, therefore attracting great attentions as a potential antineoplastic therapeutic target for past years. Anti-IAP therapy is reported to be closely related to epidermal growth factor receptor (EGFR) expression level. However, whether and how XIAP modulates EGFR expression remains largely unknown. METHODS: Human XIAP was knockdown with short-hairpin RNA in two different bladder cancer cell lines, T24T and UMUC3...
January 5, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28056422/propofol-inhibits-lps-induced-apoptosis-in-lung-epithelial-cell-line-beas-2b
#14
Xiang Lv, Xuhui Zhou, Jia Yan, Jue Jiang, Hong Jiang
Lipopolysaccharide (LPS) plays an important role in lung endothelial apoptosis which is crucial for lung fibrogenesis in ARDS progression. Reactive oxygen species (ROS) has been reported to be involved in LPS-induced lung epithelial cell apoptosis. Propofol is a commonly used intravenous anesthetic agent in clinic and it could attenuate LPS-induced epithelial cells oxidation and apoptosis. However, the mechanisms are still obscure. In this study, we examined whether and how propofol attenuates LPS-induced oxidation and apoptosis in BEAS-2B cells...
January 2, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28045581/overexpression-of-the-pp2a-c5-gene-confers-increased-salt-tolerance-in-arabidopsis-thaliana
#15
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/28041796/a-pp2a-b55-mediated-crosstalk-between-torc1-and-torc2-regulates-the-differentiation-response-in-fission-yeast
#16
Ruth Martín, Marina Portantier, Nathalia Chica, Mari Nyquist-Andersen, Juan Mata, Sandra Lopez-Aviles
Extracellular cues regulate cell fate, and this is mainly achieved through the engagement of specific transcriptional programs. The TORC1 and TORC2 complexes mediate the integration of nutritional cues to cellular behavior, but their interplay is poorly understood. Here, we use fission yeast to investigate how phosphatase activity participates in this interplay during the switch from proliferation to sexual differentiation. We find that loss of PP2A-B55(Pab1) enhances the expression of differentiation-specific genes and leads to premature conjugation...
December 24, 2016: Current Biology: CB
https://www.readbyqxmd.com/read/28040742/a-role-for-the-twins-protein-phosphatase-pp2a-b55-in-the-maintenance-of-drosophila-genome-integrity
#17
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/28040741/premature-silencing-of-the-spindle-assembly-checkpoint-is-prevented-by-the-bub1-h2a-sgo1-pp2a-axis-in-saccharomyces-cerevisiae
#18
Fengzhi Jin, Michael Bokros, Yanchang Wang
The spindle assembly checkpoint (SAC) monitors mistakes in kinetochore-microtubule interaction and its activation prevents anaphase entry. The SAC remains active until all chromosomes have achieved bipolar attachment that applies tension on kinetochores. Our previous data in budding yeast Saccharomyces cerevisiae show that Ipl1/Aurora B kinase and a centromere-associated protein Sgo1 are required to prevent SAC silencing prior to tension generation, but we believe that this regulatory network is incomplete...
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
#19
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
#20
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
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