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Hee Kyoung Chung, Shelley R Wang, Lan Xiao, Navneeta Rathor, Douglas J Turner, Peixin Yang, Myriam Gorospe, Jaladanki N Rao, Jian-Ying Wang
The mammalian intestinal epithelium is a rapidly self-renewing tissue in the body and its homeostasis depends on a dynamic balance among proliferation, migration, apoptosis, and differentiation of intestinal epithelial cells (IECs). The PP2A-associated protein α4 controls the activity and specificity of serine/threonine phosphatases and is thus implicated in many cellular processes. Here we investigated the mechanisms whereby α4 controls the homeostasis of the intestinal epithelium using a genetic approach...
March 19, 2018: Molecular and Cellular Biology
Najat Dzaki, Ghows Azzam
Members of the Aedes genus of mosquitoes are widely recognized as vectors of viral diseases. Ae.albopictus is its most invasive species, and are known to carry viruses such as Dengue, Chikugunya and Zika. Its emerging importance puts Ae.albopictus on the forefront of genetic interaction and evolution studies. However, a panel of suitable reference genes specific for this insect is as of now undescribed. Nine reference genes, namely ACT, eEF1-γ, eIF2α, PP2A, RPL32, RPS17, PGK1, ILK and STK were evaluated. Expression patterns of the candidate reference genes were observed in a total of seventeen sample types, separated by stage of development and age...
2018: PloS One
Gang Xiao, Lai N Chan, Lars Klemm, Daniel Braas, Zhengshan Chen, Huimin Geng, Qiuyi Chen Zhang, Ali Aghajanirefah, Kadriye Nehir Cosgun, Teresa Sadras, Jaewoong Lee, Tamara Mirzapoiazova, Ravi Salgia, Thomas Ernst, Andreas Hochhaus, Hassan Jumaa, Xiaoyan Jiang, David M Weinstock, Thomas G Graeber, Markus Müschen
B cell activation during normal immune responses and oncogenic transformation impose increased metabolic demands on B cells and their ability to retain redox homeostasis. While the serine/threonine-protein phosphatase 2A (PP2A) was identified as a tumor suppressor in multiple types of cancer, our genetic studies revealed an essential role of PP2A in B cell tumors. Thereby, PP2A redirects glucose carbon utilization from glycolysis to the pentose phosphate pathway (PPP) to salvage oxidative stress. This unique vulnerability reflects constitutively low PPP activity in B cells and transcriptional repression of G6PD and other key PPP enzymes by the B cell transcription factors PAX5 and IKZF1...
March 6, 2018: Cell
Lie Wang, Giri Kumar Chandaka, Robert C Foehring, Joseph C Callaway, William E Armstrong
Oxytocin (OT) neurons exhibit larger afterhyperpolarizations (AHPs) following spike trains during pregnancy and lactation, when these neurons burst and release more OT. Calcium-dependent AHPs mediated by SK channels show this plasticity, and are reduced when the channel is phosphorylated by casein kinase 2 (CK2), and increased when dephosphorylated by protein phosphatase 2A (PP2A), by altering Ca2+ sensitivity. We compared AHP currents in supraoptic OT neurons after CK2 inhibition with 4,5,6,7-tetrabromobenzotriazole (TBB), or PP1-PP2A inhibition with okadaic acid (OA) focusing on the peak current at 100 ms representing the SK-mediated, medium AHP (ImAHP )...
March 14, 2018: Journal of Neurophysiology
Jian Yin, Ran Li, Wenchao Liu, Yunchang Chen, Xin Zhang, Xifeng Li, Xuying He, Chuanzhi Duan
Early brain injury (EBI) following subarachnoid hemorrhage (SAH) can lead to inflammation and neuronal dysfunction. There is a need for effective strategies to mitigate these effects and improve the outcome of patients who experience SAH. The mRNA-destabilizing protein tristetraprolin (TTP) is an anti-inflammatory factor that induces the decay of cytokine transcripts and has been implicated in diseases such as glioma. However, the mechanism of action of TTP in EBI after SAH is unclear. The present study investigated the effects of TTP regulation via phosphorylation in a rat model of SAH by protein phosphatase (PP)2A, which is a pleiotropic enzyme complex with multiple substrate phospho-proteins...
2018: Frontiers in Neuroscience
Lingdi Zhang, Hengbo Zhou, Xueni Li, Rebecca L Vartuli, Michael Rowse, Yongna Xing, Pratyaydipta Rudra, Debashis Ghosh, Rui Zhao, Heide L Ford
Eya genes encode a unique family of multifunctional proteins that serve as transcriptional co-activators and as haloacid dehalogenase-family Tyr phosphatases. Intriguingly, the N-terminal domain of Eyas, which does not share sequence similarity to any known phosphatases, contains a separable Ser/Thr phosphatase activity. Here, we demonstrate that the Ser/Thr phosphatase activity of Eya is not intrinsic, but arises from its direct interaction with the protein phosphatase 2A (PP2A)-B55α holoenzyme. Importantly, Eya3 alters the regulation of c-Myc by PP2A, increasing c-Myc stability by enabling PP2A-B55α to dephosphorylate pT58, in direct contrast to the previously described PP2A-B56α-mediated dephosphorylation of pS62 and c-Myc destabilization...
March 13, 2018: Nature Communications
Seung Un Seo, Seon Min Woo, Kyoung-Jin Min, Taeg Kyu Kwon
Inhibition of cathespsin S not only inhibits invasion and angiogenesis, but also induces apoptosis and autophagy in cancer cells. In present study, we revealed that pharmacological inhibitor [Z-FL-COCHO (ZFL)] of cathepsin S up-regulates pro-apoptotic protein Bim expression at the posttranslational levels. These effects were not associated with MAPKs and AMPK signal pathways. Interestingly, pretreatment with the chemical chaperones (TUDCA and PBA) and knockdown of protein phosphatase 2A (PP2A) markedly inhibited ZFL-induced Bim upregulation...
March 10, 2018: Biochemical and Biophysical Research Communications
Jun Jiang, Shulin Tang, Jianhong Xia, Jikai Wen, Shuang Chen, Xiaodong Shu, Michael S Y Huen, Yiqun Deng
Wnt/β-catenin signaling activity is maintained in homeostasis by an expanding list of molecular determinants. However, the molecular components and the regulatory mechanisms involved in its fine-tuning remain to be determined. Here, we identified C9orf140, a tumor-specific protein, as a novel Axin1-interacting protein by tandem-affinity purification and mass spectrometry. We further showed that C9orf140 is a negative regulator of Wnt/β-catenin signaling in cultured cells as well as in zebrafish embryos. It functions upstream of β-catenin, outcompetes PP2A for binding to Axin1, influences the balance between phosphorylation and de-phosphorylation of β-catenin, and ultimately compromises Wnt3A-induced β-catenin accumulation...
March 13, 2018: Oncogene
Yuanyuan Tang, Joshua Berlind, Nirmala Mavila
BACKGROUND: The WNT-beta-catenin pathway is known to regulate cellular homeostasis during development and tissue regeneration. Activation of WNT signaling increases the stability of cytoplasmic beta-catenin and enhances its nuclear translocation. Nuclear beta-catenin function is regulated by transcriptional co-factors such as CREB binding protein (CBP) and p300. Hyper-activated WNT-beta-catenin signaling is associated with many cancers. However, its role in inducing stemness to liver cancer cells, its autoregulation and how it regulates tumor suppressor pathways are not well understood...
March 12, 2018: Cell Communication and Signaling: CCS
Hyewon Shin, Minzhen He, Zhi Yang, Yong Heui Jeon, Jessica Pfleger, Danish Sayed, Maha Abdellatif
The mechanisms that regulate H2A.Z and its requirement for transcription in differentiated mammalian cells remains ambiguous. In this study, we identified the interaction between the C-terminus of ANP32e and N-terminus of H2A.Z in a yeast two-hybrid screen. Knockdown of ANP32e resulted in proteasomal degradation and nuclear depletion of H2A.Z or of a chimeric green florescence protein fused to its N-terminus. This effect was reversed by inhibition of protein phosphatase 2A (PP2A) and, conversely, reproduced by overexpression of its catalytic subunit...
March 7, 2018: Biochimica et Biophysica Acta
Alphonse Garcia
Small viral proteins with cationic domains can be involved in multiple biological processes including cell penetration or interaction with intracellular targets. Within the last two decades several reports indicated that the C-terminus of HIV-1 Vpr is a cell penetrating sequence, a PP2A-dependent death domain and also displays toxicity against Gram-negative E. coli. Interestingly, HIV-1 Vpr, as well as some cationic proteins encoded by different viruses, share similar physical properties with the unique anti-microbial human cathelicidin LL37 peptide...
April 2018: Medical Hypotheses
Shiqing Zhou, Yanghai Yu, Weiqiu Zhang, Xiaoyang Meng, Jinming Luo, Lin Deng, Zhou Shi, John C Crittenden
Advanced oxidation processes (AOPs) have been widely used for the destruction of organic contaminants in the aqueous phase. In this study, we introduce an AOP on activated peroxymonosulfate (PMS) by using ascorbic acid (H2A) to generate sulfate radicals (SO4•-). Sulfate radicals, hydroxyl radicals (HO•) and ascorbyl radicals (A•-) were found using electron spin resonance (ESR). But we found A•- is negligible in the degradation of microcystin-LR (MCLR) due to its low reactivity. We developed a first-principles kinetic model to simulate the MCLR degradation and predict the radical concentrations...
March 7, 2018: Environmental Science & Technology
Wenji He, Xinyu Yan, Sanqiang Pan
Amphetamine (AMPH) abuse can influence neuropsychiatric disorders and cell apoptosis by interfering with the protein kinase B/ glycogen synthase kinase 3 beta (AKT/GSK3β) pathway. However, the mechanisms underlying this regulation are poorly understood. Using PC12 cells, we found that AMPH inhibited AKT and GSK-3β phosphorylation levels and increased total GSK-3β levels. Furthermore, AMPH caused an increase in the activity of protein phosphatase 2 (PP2A), a signaling protein upstream of AKT, which in turn inhibited phosphorylated AKT levels...
March 6, 2018: Neurotoxicity Research
Zienab Etwebi, Gavin Landesberg, Kyle Preston, Satoru Eguchi, Rosario Scalia
MPO (myeloperoxidase) is a peroxidase enzyme secreted by activated leukocytes that plays a pathogenic role in cardiovascular disease, mainly by initiating endothelial dysfunction. The molecular mechanisms of the endothelial damaging action of MPO remain though largely elusive. Calpain is a calcium-dependent protease expressed in the vascular wall. Activation of calpains has been implicated in inflammatory disorders of the vasculature. Using endothelial cells and genetically modified mice, this study identifies the µ-calpain isoform as novel downstream signaling target of MPO in endothelial dysfunction...
April 2018: Hypertension
Zoltán Kónya, Bálint Bécsi, Andrea Kiss, István Tamás, Beáta Lontay, László Szilágyi, Katalin E Kövér, Ferenc Erdődi
Aralkyl and aryl selenoglycosides as well as glycosyl selenocarboxylate derivatives were assayed on the activity of protein phosphatase-1 (PP1) and -2A (PP2A) catalytic subunits (PP1c and PP2Ac) in search of compounds for PP1c and PP2Ac effectors. The majority of tested selenoglycosides activated both PP1c and PP2Ac by ∼2-4-fold in a phosphatase assay with phosphorylated myosin light chain substrate when the hydroxyl groups of the glycosyl moiety were acetylated, but they were without any effects in the non-acetylated forms...
February 22, 2018: Bioorganic & Medicinal Chemistry
Anastasia Sacharidou, Ken L Chambliss, Victoria Ulrich, Jane E Salmon, Yu-Min Shen, Joachim Herz, David Y Hui, Lance S Terada, Philip W Shaul, Chieko Mineo
In the antiphospholipid syndrome (APS), antiphospholipid antibody (aPL) recognition of β2 glycoprotein (β2GPI) promotes thrombosis, and preclinical studies indicate that this is due to endothelial NO synthase (eNOS) antagonism via apoER2-dependent processes. How apoER2 molecularly links these events is unknown. Here we show that in endothelial cells the apoER2 cytoplasmic tail serves as a scaffold for aPL-induced assembly and activation of the heterotrimeric protein phosphatase PP2A. Dab2 recruitment to the apoER2 NPXY motif promotes the activating L309 methylation of the PP2A catalytic subunit by leucine methyl transferase-1...
March 2, 2018: Blood
Orsolya Kapuy, P K Vinod, Gábor Bánhegyi, Béla Novák
Ostreococcus tauri is the smallest free-living unicellular organism with one copy of each core cell cycle genes in its genome. There is a growing interest in this green algae due to its evolutionary origin. Since O. tauri is diverged early in the green lineage, relatively close to the ancestral eukaryotic cell, it might hold a key phylogenetic position in the eukaryotic tree of life. In this study, we focus on the regulatory network of its cell division cycle. We propose a mathematical modelling framework to integrate the existing knowledge of cell cycle network of O...
February 19, 2018: Plant Physiology and Biochemistry: PPB
Olivia Monteiro, Changwei Chen, Ryan Bingham, Argyrides Argyrou, Rachel Buxton, Christina Pancevac Jönsson, Emma Jones, Angela Bridges, Kelly Gatfield, Sybille Krauß, Jeremy Lambert, Rosamund Langston, Susann Schweiger, Iain Uings
Expression of mutant Huntingtin (HTT) protein is central to the pathophysiology of Huntington's Disease (HD). The E3 ubiquitin ligase MID1 appears to have a key role in facilitating translation of the mutant HTT mRNA suggesting that interference with the function of this complex could be an attractive therapeutic approach. Here we describe a peptide that is able to disrupt the interaction between MID1 and the α4 protein, a regulatory subunit of protein phosphatase 2A (PP2A). By fusing this peptide to a sequence from the HIV-TAT protein we demonstrate that the peptide can disrupt the interaction within cells and show that this results in a decrease in levels of ribosomal S6 phosphorylation and HTT expression in cultures of cerebellar granule neurones derived from HdhQ111/Q7 mice...
February 27, 2018: Neuroscience Letters
Joshua J Thompson, Christopher S Williams
Protein phosphorylation is a ubiquitous cellular process that allows for the nuanced and reversible regulation of protein activity. Protein phosphatase 2A (PP2A) is a heterotrimeric serine-threonine phosphatase-composed of a structural, regulatory, and catalytic subunit-that controls a variety of cellular events via protein dephosphorylation. While much is known about PP2A and its basic biochemistry, the diversity of its components-especially the multitude of regulatory subunits-has impeded the determination of PP2A function...
February 26, 2018: Genes
Qiang Niu, Wei Zhao, Jin Wang, Chunming Li, Tao Yan, Wei Lv, Guojing Wang, Weihong Duan, Tao Zhang, Kunnan Wang, Dinghua Zhou
Chemotherapy is the best choice for the vast majority of hepatocellular carcinoma patients at late stage, but few effective chemotherapy drugs are available in clinic. Licochalcone A (LicA) is a new chemotherapy drug inducing apoptosis as Bcl-2 inhibitor, but few studies report on LicA‑induced autophagy. This study investigated the phenomenon and mechanisms of LicA-induced autophagy looking for a targeted combination drug. Human hepatocellular carcinoma cells (HCCs) were treated with LicA, to detect markers of autophagy and to investigate the mechanisms...
February 16, 2018: International Journal of Molecular Medicine
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