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https://www.readbyqxmd.com/read/28922851/%C3%AE-endosulfine-arpp-19e-expression-in-a-rat-model-of-stroke
#1
Rupal I Mehta, Natalia Tsymbalyuk, Svetlana Ivanova, Jesse A Stokum, Kyoon Woo, Volodymyr Gerzanich, J Marc Simard
In nutrient restricted environments, the yeast endosulfines Igo1/2 are activated via TORC1 inhibition and function critically to initiate and coordinate the cellular stress response that promotes survival. We examined expression of αEnsa, the mammalian homolog of yeast endosulfines, in rat stroke. Prominent neuronal upregulation of αEnsa was identified in 3 patterns within the ischemic gradient: (1) neurons in GFAP-/HSF1+ cortex showed upregulation and near-complete nuclear translocation of αEnsa protein within hours of ischemic onset; (2) neurons in GFAP+/HSF1+ cortex showed upregulation in cytoplasm and nuclei that persisted for days; (3) neurons in GFAP+/HSF1- cortex showed delayed cytosolic-only upregulation that persisted for days...
October 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28919038/covalent-ligand-discovery-against-druggable-hotspots-targeted-by-anti-cancer-natural-products
#2
Elizabeth A Grossman, Carl C Ward, Jessica N Spradlin, Leslie A Bateman, Tucker R Huffman, David K Miyamoto, Jordan I Kleinman, Daniel K Nomura
Many natural products that show therapeutic activities are often difficult to synthesize or isolate and have unknown targets, hindering their development as drugs. Identifying druggable hotspots targeted by covalently acting anti-cancer natural products can enable pharmacological interrogation of these sites with more synthetically tractable compounds. Here, we used chemoproteomic platforms to discover that the anti-cancer natural product withaferin A targets C377 on the regulatory subunit PPP2R1A of the tumor-suppressor protein phosphatase 2A (PP2A) complex leading to activation of PP2A activity, inactivation of AKT, and impaired breast cancer cell proliferation...
September 11, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28916342/pp2a-regulates-signaling-through-hormonal-receptors-in-breast-cancer-with-important-therapeutic-implications
#3
REVIEW
Ion Cristóbal, Blanca Torrejón, Javier Martínez-Useros, Juan Madoz-Gurpide, Federico Rojo, Jesús García-Foncillas
The functional inhibition of protein phosphatase 2A (PP2A) has emerged in the last years as a common alteration in breast cancer that determines poor outcome and contributes to disease progression and aggressiveness. Furthermore, expression of estrogen receptor (ER) is a high relevant molecular event with key therapeutic implications in breast cancer, and androgen receptor (AR) signaling is involved in the pathogenesis of breast cancer and represents a novel target with crescent importance in this disease. In this review, we summarize the role of the tumor suppressor PP2A in modulating ER and AR signaling in breast cancer, the molecular mechanisms involved, and its biological and therapeutic impact...
September 12, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28904398/genetic-variants-in-ppp2ca-are-associated-with-gastric-cancer-risk-in-a-chinese-population
#4
Tongtong Huang, Kexin He, Yingying Mao, Meng Zhu, Caiwang Yan, Fei Yu, Qi Qi, Tianpei Wang, Yan Wang, Jiangbo Du, Li Liu
Protein phosphatase 2A (PP2A), a tumor suppressor protein, has been implicated in cell cycle and apoptosis. Additionally, studies have illustrated its crucial roles in transformation of normal human cells to tumorigenic status. PPP2CA, which encodes the alpha isoform of the catalytic subunit of PP2A, has been recently reported to be associated with several types of cancers. Therefore, we hypothesized that genetic variants in PPP2CA might influence susceptibility of gastric cancer. To test this hypothesis, three tagging single nucleotide polymorphisms (SNPs) in PPP2CA were genotyped in a case-control study including 1,113 cases and 1,848 controls in a Chinese population...
September 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28903318/myc-dependent-recruitment-of-runx1-and-gata2-on-the-set-oncogene-promoter-enhances-pp2a-inactivation-in-acute-myeloid-leukemia
#5
Raffaella Pippa, Ana Dominguez, Raquel Malumbres, Akinori Endo, Elena Arriazu, Nerea Marcotegui, Elizabeth Guruceaga, María D Odero
The SET (I2PP2A) oncoprotein is a potent inhibitor of protein phosphatase 2A (PP2A) that regulates many cell processes and important signaling pathways. Despite the importance of SET overexpression and its prognostic impact in both hematologic and solid tumors, little is known about the mechanisms involved in its transcriptional regulation. In this report, we define the minimal promoter region of the SET gene, and identify a novel multi-protein transcription complex, composed of MYC, SP1, RUNX1 and GATA2, which activates SET expression in AML...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28893598/microcystins-synthesis-and-structure-activity-relationship-studies-toward-pp1-and-pp2a
#6
REVIEW
Miriam Fontanillo, Maja Köhn
Microcystins are highly toxic cyanotoxins responsible for plant, animal and human poisoning. Exposure to microcystins, mainly through drinkable water and contaminated food, is a current world health concern. Although it is quite challenging, the synthesis of these potent cyanotoxins, analogs and derivatives helps to evaluate their toxicological properties and to elucidate their binding mechanisms to their main targets Protein Phosphatase-1 (PP1) and -2A (PP2A). This review focuses on synthetic approaches to prepare microcystins and analogs and compiles structure-activity relationship (SAR) studies that describe the unique features of microcystins that make them so potent...
August 24, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28893580/high-intraocular-pressure-produces-learning-and-memory-impairments-in-rats
#7
Yuxiang Yuan, Zhiqi Chen, Lu Li, Xing Li, Qian Xia, Hong Zhang, Qiming Duan, Yin Zhao
Primary open angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide. Previous MRI studies have revealed that POAG can be associated with alterations in hippocampal function. Thus, the aim of this study was to investigate a relationship between chronic high intraocular pressure (IOP) and hippocampal changes in a rat model. We used behavioural tests to assess learning and memory ability, and additionally investigated the hippocampal expression of pathological amyloid beta (Aβ), phospho-tau, and related pathway proteins...
September 8, 2017: Brain Research
https://www.readbyqxmd.com/read/28893508/regulation-of-protein-phosphatase-2a-during-embryonic-diapause-process-in-the-silkworm-bombyx-mori
#8
Shi-Hong Gu, Hsiao-Yen Hsieh, Pei-Ling Lin
Regulation of protein phosphorylation requires coordinated interactions between protein kinases and protein phosphatases. In the present study, we investigated regulation of protein phosphatase 2A (PP2A) during the embryonic diapause process of B. mori. An immunobloting analysis showed that Bombyx eggs contained a catalytic C subunit, a major 55-kDa regulatory B subunit (B55/PR55 subunit), and a structural A subunit, with the A and B subunits undergoing differential changes between diapause and non-diapause eggs during embryonic process...
September 8, 2017: Journal of Insect Physiology
https://www.readbyqxmd.com/read/28884018/pp2a-b-holoenzyme-substrate-recognition-regulation-and-role-in-cytokinesis
#9
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/28878488/research-progress-on-the-autonomous-flowering-time-pathway-in-arabidopsis
#10
REVIEW
Jing-Zhi Cheng, Yu-Ping Zhou, Tian-Xiao Lv, Chu-Ping Xie, Chang-En Tian
The transition from vegetative to reproductive growth phase is a pivotal and complicated process in the life cycle of flowering plants which requires a comprehensive response to multiple environmental aspects and endogenous signals. In Arabidopsis, six regulatory flowering time pathways have been defined by their response to distinct cues, namely photoperiod, vernalization, gibberellin, temperature, autonomous and age pathways, respectively. Among these pathways, the autonomous flowering pathway accelerates flowering independently of day length by inhibiting the central flowering repressor FLC...
July 2017: Physiology and Molecular Biology of Plants: An International Journal of Functional Plant Biology
https://www.readbyqxmd.com/read/28877982/non-canonical-regulation-of-insulin-mediated-erk-activation-by-phosphoinositide-3-kinase-%C3%AE
#11
Maradumane L Mohan, Arunachal Chatterjee, Swetha Ganapathy, Sromona Mukherjee, Sowmya Srikanthan, George P Jolly, Rohit S Anand, Sathyamangla V Naga Prasad
Classically Class IB Phosphoinositide 3-kinase (PI3Kγ) plays a role in ERK activation following G-protein coupled receptor (GPCR) activation. Knock-down of PI3Kγ unsuspectingly resulted in loss of ERK activation to receptor tyrosine kinase-agonists like epidermal growth factor or insulin. Mouse embryonic fibroblasts (MEFs) or primary adult cardiac fibroblasts isolated from PI3Kγ knock-out mice (PI3KγKO) showed loss in insulin-stimulated ERK activation. However, expression of kinase-dead PI3Kγ resulted in rescue of insulin-stimulated ERK activation...
September 6, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28875582/identification-of-signaling-pathways-targeted-by-the-food-contaminant-fb1-transcriptome-and-kinome-analysis-of-samples-from-pig-liver-and-intestine
#12
Marion Régnier, Pascal Gourbeyre, Philippe Pinton, Scott Napper, Joëlle Laffite, Anne-Marie Cossalter, Jean-Denis Bailly, Yannick Lippi, Justine Bertrand-Michel, Ana Paula F R L Bracarense, Hervé Guillou, Nicolas Loiseau, Isabelle P Oswald
SCOPE: Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium species. In mammals, this toxin causes widespread organ-specific damage; it promotes hepatotoxicity, is immunotoxic, alters intestinal functions… Despite its inhibitory effect on de novo ceramide synthesis, its molecular mechanism of action and toxicity are not totally elucidated. METHOD & RESULTS: To explore the mechanism of FB1 toxicity, we analyzed the transcriptome and kinome of two organs targeted by FB1: the liver and the jejunum...
September 5, 2017: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/28869464/oxygen-and-glucose-deprivation-alter-synaptic-distribution-of-tau-protein-the-role-of-phosphorylation
#13
Panagiota Mavroeidi, Olga Mavrofrydi, Elpiniki Pappa, Myrto Panopoulou, Panagiota Papazafiri, Sylva Haralambous, Spiros Efthimiopoulos
Alterations in tau synaptic distribution are considered to underlie synaptic dysfunction observed in Alzheimer's disease (AD). In the present study, brain blood hypoperfusion was simulated in mouse brain slices, and tau levels and phosphorylation were investigated in total extracts, as well as in postsynaptic density fractions (PSDs) and non-PSDs obtained through differential extraction and centrifugation. Oxygen deprivation (OD) resulted in tau dephosphorylation at several AD-related residues and activation of GSK3β and phosphatase PP2A...
August 30, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28840249/a-kinase-phosphatase-network-that-regulates-kinetochore-microtubule-attachments-and-the-sac
#14
Giulia Vallardi, Marilia Henriques Cordeiro, Adrian Thomas Saurin
The KMN network (for KNL1, MIS12 and NDC80 complexes) is a hub for signalling at the outer kinetochore. It integrates the activities of two kinases (MPS1 and Aurora B) and two phosphatases (PP1 and PP2A-B56) to regulate kinetochore-microtubule attachments and the spindle assembly checkpoint (SAC). We will first discuss each of these enzymes separately, to describe how they are regulated at kinetochores and why this is important for their primary function in controlling either microtubule attachments or the SAC...
2017: Progress in Molecular and Subcellular Biology
https://www.readbyqxmd.com/read/28835516/an-rna-interference-screen-identifies-druggable-regulators-of-mecp2-stability
#15
Laura M Lombardi, Manar Zaghlula, Yehezkel Sztainberg, Steven A Baker, Tiemo J Klisch, Amy A Tang, Eric J Huang, Huda Y Zoghbi
Alterations in gene dosage due to copy number variation are associated with autism spectrum disorder, intellectual disability (ID), and other psychiatric disorders. The nervous system is so acutely sensitive to the dose of methyl-CpG-binding protein 2 (MeCP2) that even a twofold change in MeCP2 protein-either increased or decreased-results in distinct disorders with overlapping features including ID, autistic behavior, and severe motor dysfunction. Rett syndrome is caused by loss-of-function mutations in MECP2, whereas duplications spanning the MECP2 locus result in MECP2 duplication syndrome (MDS), which accounts for ~1% of X-linked ID...
August 23, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28830934/op449-inhibits-breast-cancer-growth-without-adverse-metabolic-effects
#16
Gadi Shlomai, Zara Zelenko, Irini Markella Antoniou, Marilyn Stasinopoulos, Aviva Tobin-Hess, Michael P Vitek, Derek LeRoith, Emily Jane Gallagher
Hyperinsulinemia is associated with a decrease in breast cancer recurrence-free survival and overall survival. Inhibition of insulin receptor signaling is associated with glycemic dysregulation. SET is a direct modulator of PP2A, which negatively regulates the PI3K/AKT/mTOR pathway. OP449, a SET inhibitor, decreases AKT/mTOR activation. The effects of OP449 treatment on breast cancer growth in the setting of pre-diabetes, and its metabolic implications are currently unknown. We found that the volumes and weights of human MDA-MB-231 breast cancer xenografts were greater in hyperinsulinemic mice compared with controls (P < 0...
October 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28822962/glucose-transporter-4-glut4-deficient-hearts-develop-maladaptive-hypertrophy-in-response-to-physiologic-or-pathologic-stresses
#17
Adam Raymond Wende, Jaetaek Kim, William Holland, Benjamin E Wayment, Brian T O'Neill, Joseph Tuinei, Manoja K Brahma, Mark E Pepin, Mark A McCrory, Ivan Luptak, Ganesh V Halade, Sheldon E Litwin, E Dale Abel
Pathological cardiac hypertrophy may be associated with reduced expression of the GLUT4 glucose transporter in contrast to exercise-induced cardiac hypertrophy, where GLUT4 levels are increased. However, mice with cardiac specific deletion of GLUT4 (G4H-/-) have normal cardiac function in the unstressed state. This study tested the hypothesis that cardiac GLUT4 is required for myocardial adaptations to hemodynamic demands. G4H-/- and control littermates (Con) were subjected to either a pathological model of left ventricular pressure overload (transverse aortic constriction; TAC) or a physiological model of endurance exercise (swim training)...
August 19, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28821708/a-reversible-phospho-switch-mediated-by-ulk1-regulates-the-activity-of-autophagy-protease-atg4b
#18
N Pengo, A Agrotis, K Prak, J Jones, R Ketteler
Upon induction of autophagy, the ubiquitin-like protein LC3 is conjugated to phosphatidylethanolamine (PE) on the inner and outer membrane of autophagosomes to allow cargo selection and autophagosome formation. LC3 undergoes two processing steps, the proteolytic cleavage of pro-LC3 and the de-lipidation of LC3-PE from autophagosomes, both executed by the same cysteine protease ATG4. How ATG4 activity is regulated to co-ordinate these events is currently unknown. Here we find that ULK1, a protein kinase activated at the autophagosome formation site, phosphorylates human ATG4B on serine 316...
August 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28819544/hypoxia-downregulates-mapk-erk-but-not-stat3-signaling-in-ros-dependent-and-hif-1-independent-manners-in-mouse-embryonic-stem-cells
#19
Jan Kučera, Julie Netušilová, Stanislava Sladeček, Martina Lánová, Ondřej Vašíček, Kateřina Štefková, Jarmila Navrátilová, Lukáš Kubala, Jiří Pacherník
Hypoxia is involved in the regulation of stem cell fate, and hypoxia-inducible factor 1 (HIF-1) is the master regulator of hypoxic response. Here, we focus on the effect of hypoxia on intracellular signaling pathways responsible for mouse embryonic stem (ES) cell maintenance. We employed wild-type and HIF-1α-deficient ES cells to investigate hypoxic response in the ERK, Akt, and STAT3 pathways. Cultivation in 1% O2 for 24 h resulted in the strong dephosphorylation of ERK and its upstream kinases and to a lesser extent of Akt in an HIF-1-independent manner, while STAT3 phosphorylation remained unaffected...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28818393/the-modulation-of-the-phosphorylation-status-of-nkcc1-in-organ-cultured-bovine-lenses-implications-for-the-regulation-of-fiber-cell-and-overall-lens-volume
#20
Irene Vorontsova, Paul J Donaldson, Zhiying Kong, Chiharu Wickremesinghe, Leo Lam, Julie C Lim
In this study we have used an antibody that specifically detects the phosphorylation status of the Sodium/Potassium/2 Chloride Cotransporter (NKCC1) to study whether the activity of NKCC1 can be regulated in organ cultured bovine lenses. Western blotting was first used to confirm the expression of NKCC1, phosphorylated NKCC1 (NKCC1-P) and the regulatory kinases WNK/SPAK and phosphatases PP1/PP2A in bovine lenses at the protein level. Changes to NKCC1-P status were then assessed by organ culturing bovine lenses in either isotonic, hypertonic or hypotonic solutions in the presence or absence of the NKCC inhibitor, bumetanide, or phosphatase inhibitors okadaic acid and calyculin A...
August 14, 2017: Experimental Eye Research
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