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Atsushi Hatano, Masaki Matsumoto, Keiichi I Nakayama
A key issue in the study of signal transduction is how multiple signaling pathways are systematically integrated into the cell. We have now performed multiple phosphoproteomics analyses focused on the dynamics of the T-cell receptor (TCR) signaling network and its subsystem mediated by the Ca(2+) signaling pathway. Integration of these phosphoproteomics data sets and extraction of components of the TCR signaling network dependent on Ca(2+) signaling showed unexpected phosphorylation kinetics for candidate substrates of the Ca(2+) -dependent phosphatase calcineurin (CN) during TCR stimulation...
October 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Evgenia Salta, Annerieke Sierksma, Elke Vanden Eynden, Bart De Strooper
microRNA-132 (miR-132) is involved in prosurvival, anti-inflammatory and memory-promoting functions in the nervous system and has been found consistently downregulated in Alzheimer's disease (AD). Whether and how miR-132 deficiency impacts AD pathology remains, however, unaddressed. We show here that miR-132 loss exacerbates both amyloid and TAU pathology via inositol 1,4,5-trisphosphate 3-kinase B (ITPKB) upregulation in an AD mouse model. This leads to increased ERK1/2 and BACE1 activity and elevated TAU phosphorylation...
2016: EMBO Molecular Medicine
Ariane Scoumanne, Patricia Molina-Ortiz, Daniel Monteyne, David Perez-Morga, Christophe Erneux, Stéphane Schurmans
Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is the last identified member of the inositol 1,4,5-trisphosphate 3-kinases family which phosphorylates inositol 1,4,5-trisphosphate into inositol 1,3,4,5-tetrakisphosphate. Although expression and function of the two other family members ITPKA and ITPKB are rather well characterized, similar information is lacking for ITPKC. Here, we first defined the expression of Itpkc mRNA and protein in mouse tissues and cells using in situ hybridization and new antibodies...
March 22, 2016: Advances in Biological Regulation
Ankmalika G Louis, Leman Yel, Jia N Cao, Sudhanshu Agrawal, Sudhir Gupta
Common variable immunodeficiency (CVID) is a heterogenous disorder characterized by hypogammaglobulinemia and impaired specific antibody response and increased susceptibility to infections, autoimmunity and malignancies. A number of gene mutations, including ICOS, TACI and BAFF-R, and CD19, CD20, CD21, CD81, MSH5 and LRBA have been described; however, they account for approximately 20-25% of total cases of CVID. In this study, we report a patient with CVID with an intrinsic microdeletion of chromosome 1q42...
January 2016: Clinical & Translational Immunology
Luise Westernberg, Claire Conche, Yina Hsing Huang, Stephanie Rigaud, Yisong Deng, Sabine Siegemund, Sayak Mukherjee, Lyn'Al Nosaka, Jayajit Das, Karsten Sauer
β-selection is the most pivotal event determining αβ T cell fate. Here, surface-expression of a pre-T cell receptor (pre-TCR) induces thymocyte metabolic activation, proliferation, survival and differentiation. Besides the pre-TCR, β-selection also requires co-stimulatory signals from Notch receptors - key cell fate determinants in eukaryotes. Here, we show that this Notch-dependence is established through antagonistic signaling by the pre-TCR/Notch effector, phosphoinositide 3-kinase (PI3K), and by inositol-trisphosphate 3-kinase B (Itpkb)...
2016: ELife
Sydney Dubois, Pierre-Julien Viailly, Sylvain Mareschal, Elodie Bohers, Philippe Bertrand, Philippe Ruminy, Catherine Maingonnat, Jean-Philippe Jais, Pauline Peyrouze, Martin Figeac, Thierry J Molina, Fabienne Desmots, Thierry Fest, Corinne Haioun, Thierry Lamy, Christiane Copie-Bergman, Josette Brière, Tony Petrella, Danielle Canioni, Bettina Fabiani, Bertrand Coiffier, Richard Delarue, Frédéric Peyrade, André Bosly, Marc André, Nicolas Ketterer, Gilles Salles, Hervé Tilly, Karen Leroy, Fabrice Jardin
PURPOSE: Next-generation sequencing (NGS) has detailed the genomic characterization of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. We set out to design a clinically feasible NGS panel focusing on genes whose mutations hold potential therapeutic impact. Furthermore, for the first time, we evaluated the prognostic value of these mutations in prospective clinical trials. EXPERIMENTAL DESIGN: A Lymphopanel was designed to identify mutations in 34 genes, selected according to literature and a whole exome sequencing study of relapsed/refractory DLBCL patients...
June 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Yi Jin, Yalan Liu, Jin Zhang, Wei Huang, Hongni Jiang, Yingyong Hou, Chen Xu, Changwen Zhai, Xue Gao, Shuyang Wang, Ying Wu, Hongguang Zhu, Shaohua Lu
Many studies demonstrated unique microRNA profiles in lung cancer. Nonetheless, the role and related signal pathways of miR-375 in lung cancer are largely unknown. Our study investigated relationships between carcinogenesis and miR-375 in adenocarcinoma, squamous cell carcinoma and small cell lung carcinoma to identify new molecular targets for treatment. We evaluated 723 microRNAs in microdissected cancerous cells and adjacent normal cells from 126 snap-frozen lung specimens using microarrays. We validated the expression profiles of miR-375 and its 22 putative target mRNAs in an independent cohort of 78 snap-frozen lung cancer tissues using quantitative reverse-transcriptase PCR...
2015: PloS One
Sylvain Mareschal, Sydney Dubois, Pierre-Julien Viailly, Philippe Bertrand, Elodie Bohers, Catherine Maingonnat, Jean-Philippe Jaïs, Bruno Tesson, Philippe Ruminy, Pauline Peyrouze, Christiane Copie-Bergman, Thierry Fest, Thierry Jo Molina, Corinne Haioun, Gilles Salles, Hervé Tilly, Thierry Lecroq, Karen Leroy, Fabrice Jardin
Despite the many efforts already spent to enumerate somatic mutations in diffuse large B-cell lymphoma (DLBCL), previous whole-genome and whole-exome studies conducted on patients of mixed outcomes failed at characterizing the 30% of patients who will relapse or resist current immunochemotherapies. To address this issue, we performed whole-exome sequencing of normal/tumoral DNA pairs in 14 relapsed/refractory (R/R) patients subclassified by full-transcriptome arrays (six activated B-cell like, three germinal center B-cell like, and five primary mediastinal B-cell lymphomas), from the LNH-03 LYSA clinical trial program...
March 2016: Genes, Chromosomes & Cancer
Christophe Erneux, Somadri Ghosh, Sandra Koenig
Inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) 3-kinases (Itpks) catalyze the phosphorylation of inositol(1,4,5)trisphosphate into inositol(1,3,4,5)tetrakisphosphate (Ins(1,3,4,5)P4). Three isoenzymes Itpka/b and c have been identified in human, rat and mouse. They share a catalytic domain relatively well conserved at the C-terminal end and a quite isoenzyme specific regulatory domain at the N-terminal end of the protein. Activity determined in cell homogenates with Ins(1,4,5)P3 and ATP as substrate is generally very low compared to Ins(1,4,5)P3 5-phosphatase, except in a few tissues such as brain, testis, thymus or intestine...
January 2016: Advances in Biological Regulation
Dustin T Rae, Jonah D Hocum, Victor Bii, H Joachim Deeg, Grant D Trobridge
Using a novel retroviral shuttle vector approach we identified genes that collaborate with a patient derived RUNX1 (AML1) mutant. RUNX1 mutations occurs in 40% of myelodysplastic syndromes (MDS). MDS are a group of hematopoietic stem cell disorders that are characterized by dysplasia that often progress to acute myeloid leukemia (AML). Our goal was to identify genes dysregulated by vector-mediated genotoxicity that may collaborate with the RUNX1 mutant (D171N). D171N expressing cells have a survival and engraftment disadvantage and require additional genetic lesions to survive and persist...
October 13, 2015: Oncotarget
Stanley I Rapoport, Christopher T Primiani, Chuck T Chen, Kwangmi Ahn, Veronica H Ryan
BACKGROUND: Phosphoinositides, lipid-signaling molecules, participate in diverse brain processes within a wide metabolic cascade. HYPOTHESIS: Gene transcriptional networks coordinately regulate the phosphoinositide cascade during human brain Development and Aging. METHODS: We used the public BrainCloud database for human dorsolateral prefrontal cortex to examine age-related expression levels of 49 phosphoinositide metabolic genes during Development (0 to 20+ years) and Aging (21+ years)...
2015: PloS One
Andrew T Miller, Carol Dahlberg, Mark L Sandberg, Ben G Wen, Daniel R Beisner, John A H Hoerter, Albert Parker, Christian Schmedt, Monique Stinson, Jacqueline Avis, Cynthia Cienfuegos, Mark McPate, Pamela Tranter, Martin Gosling, Paul J Groot-Kormelink, Janet Dawson, Shifeng Pan, Shin-Shay Tian, H Martin Seidel, Michael P Cooke
Emerging approaches to treat immune disorders target positive regulatory kinases downstream of antigen receptors with small molecule inhibitors. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes...
2015: PloS One
Venil N Sumantran, Pratik Mishra, N Sudhakar
A new hallmark of cancer involves acquisition of a lipogenic phenotype which promotes tumorigenesis. Little is known about lipid metabolism in melanomas. Therefore, we used BRB (Biometrics Research Branch) class comparison tool with multivariate analysis to identify differentially expressed genes in human cutaneous melanomas, compared with benign nevi and normal skin derived from the microarray dataset (GDS1375). The methods were validated by identifying known melanoma biomarkers (CITED1, FGFR2, PTPRF, LICAM, SPP1 and PHACTR1) in our results...
April 2015: Indian Journal of Biochemistry & Biophysics
Sandra Koenig, Colette Moreau, Geneviève Dupont, Ariane Scoumanne, Christophe Erneux
Four inositol phosphate kinases catalyze phosphorylation of the second messenger inositol 1,4,5-trisphosphate [Ins(1,4,5)P3 ] to inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4 ]: these enzymes comprise three isoenzymes of inositol 1,4,5-trisphosphate 3-kinase (Itpk), referred to as Itpka, Itpkb and Itpkc, and the inositol polyphosphate multikinase (IPMK). The four enzymes that act on Ins(1,4,5)P3 are all expressed in rat pheochromocytoma PC12 cells, a model that is used to study neurite outgrowth induced by nerve growth factor (NGF)...
July 2015: FEBS Journal
Sabine Siegemund, Stephanie Rigaud, Claire Conche, Blake Broaten, Lana Schaffer, Luise Westernberg, Steven Robert Head, Karsten Sauer
Tight regulation of hematopoietic stem cell (HSC) homeostasis ensures lifelong hematopoiesis and prevents blood cancers. The mechanisms balancing HSC quiescence with expansion and differentiation into hematopoietic progenitors are incompletely understood. Here, we identify Inositol-trisphosphate 3-kinase B (Itpkb) as an essential regulator of HSC homeostasis. Young Itpkb(-/-) mice accumulated phenotypic HSC, which were less quiescent and proliferated more than wild-type (WT) controls. Itpkb(-/-) HSC downregulated quiescence and stemness associated, but upregulated activation, oxidative metabolism, protein synthesis, and lineage associated messenger RNAs...
April 30, 2015: Blood
Agnieszka Jeda, Andrzej Witek, Grazyna Janikowska, Grzegorz Cwynar, Tomasz Janikowski, Małgorzata Ciałon, Joanna Orchel, Urszula Mazurek
INTRODUCTION: Influence of histamine on tumor development remains obscure. The exact mechanism of this action is not known. Different data indicate high concentrations of histamine in tumor tissues, such as malignant melanoma, breast cancer, colon carcinoma, lymphomas and leukemia. To the best of our knowledge, the literature offers no reports about the role of histamine and of differences between expression patterns of histamine-related genes in endometrial cancer AIM: The aim of the study was a comparative analysis of the gene expression profile involved with histaminergic system in endometrioid endometrial cancer in relation to histologically normal endometrium, and identification of differentiation genes whose transcriptional activity significantly differs in pathomorphological grades G1,G2, G3 of endometrial cancer as compared to the control group...
March 2014: Ginekologia Polska
Virginie Stygelbout, Karelle Leroy, Valérie Pouillon, Kunie Ando, Eva D'Amico, Yonghui Jia, H Robert Luo, Charles Duyckaerts, Christophe Erneux, Stéphane Schurmans, Jean-Pierre Brion
ITPKB phosphorylates inositol 1,4,5-trisphosphate into inositol 1,3,4,5-tetrakisphosphate and controls signal transduction in various hematopoietic cells. Surprisingly, it has been reported that the ITPKB messenger RNA level is significantly increased in the cerebral cortex of patients with Alzheimer's disease, compared with control subjects. As extracellular signal-regulated kinases 1/2 activation is increased in the Alzheimer brain and as ITPKB is a regulator of extracellular signal-regulated kinases 1/2 activation in some hematopoietic cells, we tested whether this increased activation in Alzheimer's disease might be related to an increased activity of ITPKB...
February 2014: Brain: a Journal of Neurology
Frank Stein, Manuel Kress, Sabine Reither, Alen Piljić, Carsten Schultz
The number of fluorescent sensors and their use in living cells has significantly increased in the past years. Yet, the analysis of data from single cells or cell populations usually remains a very time-consuming enterprise. Here, we introduce FluoQ, a new macro for the image analysis software ImageJ, which enables fast analysis of multiparameter time-lapse fluorescence microscopy data with minimal manual input. FluoQ provides statistical analysis of all measured parameters and delivers the results in multiple graphic and numeric displays...
September 20, 2013: ACS Chemical Biology
Abhijeet Bakre, Lauren E Andersen, Victoria Meliopoulos, Keegan Coleman, Xiuzhen Yan, Paula Brooks, Jackelyn Crabtree, S Mark Tompkins, Ralph A Tripp
Human protein kinases (HPKs) have profound effects on cellular responses. To better understand the role of HPKs and the signaling networks that influence influenza virus replication, a small interfering RNA (siRNA) screen of 720 HPKs was performed. From the screen, 17 HPKs (NPR2, MAP3K1, DYRK3, EPHA6, TPK1, PDK2, EXOSC10, NEK8, PLK4, SGK3, NEK3, PANK4, ITPKB, CDC2L5 (CDK13), CALM2, PKN3, and HK2) were validated as essential for A/WSN/33 influenza virus replication, and 6 HPKs (CDK13, HK2, NEK8, PANK4, PLK4 and SGK3) were identified as vital for both A/WSN/33 and A/New Caledonia/20/99 influenza virus replication...
2013: PloS One
Ximena Soto, Jingjing Li, Robert Lea, Eamon Dubaissi, Nancy Papalopulu, Enrique Amaya
Wound healing is essential for survival. We took advantage of the Xenopus embryo, which exhibits remarkable capacities to repair wounds quickly and efficiently, to investigate the mechanisms responsible for wound healing. Previous work has shown that injury triggers a rapid calcium response, followed by the activation of Ras homolog (Rho) family guanosine triphosphatases (GTPases), which regulate the formation and contraction of an F-actin purse string around the wound margin. How these processes are coordinated following wounding remained unclear...
July 2, 2013: Proceedings of the National Academy of Sciences of the United States of America
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