A Computational Assessment of ARHGEF6 Gene ⇑ Yashvant M
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Deregulated Gene Expression Pathways in Myelodysplastic Syndrome Hematopoietic Stem Cells
Leukemia (2010) 24, 756–764 & 2010 Macmillan Publishers Limited All rights reserved 0887-6924/10 $32.00 www.nature.com/leu ORIGINAL ARTICLE Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells A Pellagatti1, M Cazzola2, A Giagounidis3, J Perry1, L Malcovati2, MG Della Porta2,MJa¨dersten4, S Killick5, A Verma6, CJ Norbury7, E Hellstro¨m-Lindberg4, JS Wainscoat1 and J Boultwood1 1LRF Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, Oxford, UK; 2Department of Hematology Oncology, University of Pavia Medical School, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 3Medizinische Klinik II, St Johannes Hospital, Duisburg, Germany; 4Division of Hematology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 5Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK; 6Albert Einstein College of Medicine, Bronx, NY, USA and 7Sir William Dunn School of Pathology, University of Oxford, Oxford, UK To gain insight into the molecular pathogenesis of the the World Health Organization.6,7 Patients with refractory myelodysplastic syndromes (MDS), we performed global gene anemia (RA) with or without ringed sideroblasts, according to expression profiling and pathway analysis on the hemato- poietic stem cells (HSC) of 183 MDS patients as compared with the the French–American–British classification, were subdivided HSC of 17 healthy controls. The most significantly deregulated based on the presence or absence of multilineage dysplasia. In pathways in MDS include interferon signaling, thrombopoietin addition, patients with RA with excess blasts (RAEB) were signaling and the Wnt pathways. Among the most signifi- subdivided into two categories, RAEB1 and RAEB2, based on the cantly deregulated gene pathways in early MDS are immuno- percentage of bone marrow blasts. -
Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. -
Cdc42 and Rac1 Activity Is Reduced in Human Pheochromocytoma and Correlates with FARP1 and ARHGEF1 Expression
234 P Croisé et al. Rho-GTPase activity in human 23:4 281–293 Research pheochromocytoma Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression Pauline Croisé1, Sébastien Houy1, Mathieu Gand1, Joël Lanoix2, Valérie Calco1, Petra Tóth1, Laurent Brunaud3, Sandra Lomazzi4, Eustache Paramithiotis2, Daniel Chelsky2, Stéphane Ory1,* and Stéphane Gasman1,* Correspondence 1Institut des Neurosciences Cellulaires et Intégratives (INCI), CNRS UPR 3212, Strasbourg, France should be addressed 2Caprion Proteome, Inc., Montréal, Québec, Canada to S Ory or S Gasman 3Service de Chirurgie Digestive, Hépato-bilaire et Endocrinienne, CHRU Nancy, Hôpitaux de Brabois, Email Vandoeuvre les Nancy, France [email protected] or 4Centre de Ressources Biologiques (CRB), CHRU Nancy, Hôpitaux de Brabois, Vandoeuvres les Nancy, France [email protected] *(S Ory and S Gasman contributed equally to this work) Abstract Among small GTPases from the Rho family, Cdc42, Rac, and Rho are well known to mediate Key Words a large variety of cellular processes linked with cancer biology through their ability to cycle f Rho-GTPases between an inactive (GDP-bound) and an active (GTP-bound) state. Guanine nucleotide f pheochromocytoma exchange factors (GEFs) stimulate the exchange of GDP for GTP to generate the activated f mass spectrometry form, whereas the GTPase-activating proteins (GAPs) catalyze GTP hydrolysis, leading to f Rho-GEF Endocrine-Related Cancer Endocrine-Related the inactivated form. Modulation of Rho GTPase activity following altered expression of Rho-GEFs and/or Rho-GAPs has already been reported in various human tumors. However, nothing is known about the Rho GTPase activity or the expression of their regulators in human pheochromocytomas, a neuroendocrine tumor (NET) arising from chromaffin cells of the adrenal medulla. -
Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding Rnas
Review Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding RNAs Yu Zhang †, Jun Li †, Xing-Ning Lai, Xue-Qiao Jiao, Jun-Ping Xiong and Li-Xia Xiong * Department of Pathophysiology, Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Medical College, Nanchang University, 461 Bayi Road, Nanchang 330006, China; [email protected] (Y.Z.); [email protected] (J.L.); [email protected] (X.-N.L.); [email protected] (X.-Q.J.); [email protected] (J.-P.X.) * Correspondence: [email protected]; Tel.: +86-791-8636-0556 † These authors contributed equally to this work. Received: 30 December 2018; Accepted: 8 February 2019; Published: 11 February 2019 Abstract: Breast cancer is the most common malignant tumors in females. Although the conventional treatment has demonstrated a certain effect, some limitations still exist. The Rho guanosine triphosphatase (GTPase) Cdc42 (Cell division control protein 42 homolog) is often upregulated by some cell surface receptors and oncogenes in breast cancer. Cdc42 switches from inactive guanosine diphosphate (GDP)-bound to active GTP-bound though guanine-nucleotide- exchange factors (GEFs), results in activation of signaling cascades that regulate various cellular processes such as cytoskeletal changes, proliferation and polarity establishment. Targeting Cdc42 also provides a strategy for precise breast cancer therapy. In addition, Cdc42 is a potential target for several types of non-coding RNAs including microRNAs and lncRNAs. These non-coding RNAs is extensively involved in Cdc42-induced tumor processes, while many of them are aberrantly expressed. Here, we focus on the role of Cdc42 in cell morphogenesis, proliferation, motility, angiogenesis and survival, introduce the Cdc42-targeted non-coding RNAs, as well as present current development of effective Cdc42-targeted inhibitors in breast cancer. -
Spatiotemporal Profiling of Cytosolic Signaling Complexes in Living Cells by Selective Proximity Proteomics
ARTICLE https://doi.org/10.1038/s41467-020-20367-x OPEN Spatiotemporal profiling of cytosolic signaling complexes in living cells by selective proximity proteomics Mi Ke1,6, Xiao Yuan1,6,AnHe1, Peiyuan Yu 1, Wendong Chen1, Yu Shi2, Tony Hunter 2, Peng Zou 3 & ✉ Ruijun Tian 1,4,5 1234567890():,; Signaling complexes are often organized in a spatiotemporal manner and on a minute timescale. Proximity labeling based on engineered ascorbate peroxidase APEX2 pioneered in situ capture of spatiotemporal membrane protein complexes in living cells, but its appli- cation to cytosolic proteins remains limited due to the high labeling background. Here, we develop proximity labeling probes with increased labeling selectivity. These probes, in combination with label-free quantitative proteomics, allow exploring cytosolic protein assemblies such as phosphotyrosine-mediated protein complexes formed in response to minute-scale EGF stimulation. As proof-of-concept, we systematically profile the spatio- temporal interactome of the EGFR signaling component STS1. For STS1 core complexes, our proximity proteomics approach shows comparable performance to affinity purification-mass spectrometry-based temporal interactome profiling, while also capturing additional— especially endosomally-located—protein complexes. In summary, we provide a generic approach for exploring the interactome of mobile cytosolic proteins in living cells at a tem- poral resolution of minutes. 1 Department of Chemistry, School of Science, Southern University of Science and Technology, Shenzhen, China. 2 Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA. 3 College of Chemistry and Molecular Engineering, Peking University, Beijing, China. 4 Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen, China. -
Title: Therapeutic Potential of HSP90 Inhibition for Neurofibromatosis Type 2
Author Manuscript Published OnlineFirst on May 28, 2013; DOI: 10.1158/1078-0432.CCR-12-3167 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Title: Therapeutic Potential of HSP90 Inhibition for Neurofibromatosis type 2 Karo Tanaka1, Ascia Eskin3, Fabrice Chareyre1, Walter J. Jessen4, Jan Manent5, Michiko Niwa-Kawakita6, Ruihong Chen7, Cory H. White2, Jeremie Vitte1, Zahara M. Jaffer1, Stanley F. Nelson3, Allan E. Rubenstein8, Marco Giovannini1,9§. Authors’ affiliations: House Research Institute, 1Center for Neural Tumor Research and 2Section on Genetics of Hereditary Ear Disorders, Los Angeles, CA; 3Department of Human Genetics, University of California, Los Angeles, CA; 4Informatics, Covance Inc., Princeton, NJ; 5Peter MacCallum Cancer Institute, Melbourne, Australia; 6Inserm U944, CNRS U7212, Université Paris, Institut Universitaire d'Hématologie, Paris, France; 7NexGenix Pharmaceuticals, Burlingame, CA; and 8New York University Langone Medical Center, New York, NY; and Department of Cell and Neurobiology, University of Southern California, Keck School of Medicine, Los Angeles, CA Running title: HSP90 Inhibition for NF2 Keywords: NF2, HSP90 inhibitors, Transcriptome Financial support: This work was supported by a Drug Discovery Initiative Award, Children’s Tumor Foundation, to M.G., and by the House Research Institute. Corresponding author: Marco Giovannini, House Research Institute, Center for Neural Tumor Research, 2100 West 3rd street, Los Angeles, CA90057. Phone: +1-213-989-6708; Fax: +1-213-989-6778; E-mail: [email protected] 1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 28, 2013; DOI: 10.1158/1078-0432.CCR-12-3167 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. -
Dysregulation of Rho Gtpases in the Apix/Arhgef6 Mouse Model of X
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2011 Dysregulation of Rho GTPases in the Pix/Arhgef6 mouse model of X-linked intellectual disability is paralleled by impaired structural and synaptic plasticity and cognitive deficits Ramakers, G J A ; Wolfer, D ; Rosenberger, G ; Kuchenbecker, K ; Kreienkamp, H J ; Prange-Kiel, J ; Rune, G ; Richter, K ; Langnaese, K ; Masneuf, S ; Bösl, M R ; Fischer, K D ; Krugers, H J ; Lipp, H P ; van Galen, E ; Kutsche, K Abstract: Mutations in the ARHGEF6 gene, encoding the guanine nucleotide exchange factor PIX/Cool- 2 for the Rho GTPases Rac1 and Cdc42, cause X-linked intellectual disability (ID) in humans. We show here that Pix/Arhgef6 is primarily expressed in neuropil regions of the hippocampus. To study the role of Pix/Arhgef6 in neuronal development and plasticity and gain insight into the pathogenic mechanisms underlying ID, we generated Pix/Arhgef6-deficient mice. Gross brain structure in these mice appeared to be normal; however, analysis of Golgi-Cox-stained pyramidal neurons revealed an increase in both dendritic length and spine density in the hippocampus, accompanied by an overall loss in spine synapses. Early-phase long-term potentiation was reduced and long-term depression was increased in the CA1 hippocampal area of Pix/Arhgef6-deficient animals. Knockout animals exhibited impaired spatial and complex learning and less behavioral control in mildly stressful situations, suggesting that this model mimics the human ID phenotype. The structural and electrophysiological alterations in the hippocampus were accompanied by a significant reduction in active Rac1 and Cdc42, but not RhoA. -
Individual Protomers of a G Protein-Coupled Receptor Dimer Integrate Distinct Functional Modules
OPEN Citation: Cell Discovery (2015) 1, 15011; doi:10.1038/celldisc.2015.11 © 2015 SIBS, CAS All rights reserved 2056-5968/15 ARTICLE www.nature.com/celldisc Individual protomers of a G protein-coupled receptor dimer integrate distinct functional modules Nathan D Camp1, Kyung-Soon Lee2, Jennifer L Wacker-Mhyre2, Timothy S Kountz2, Ji-Min Park2, Dorathy-Ann Harris2, Marianne Estrada2, Aaron Stewart2, Alejandro Wolf-Yadlin1, Chris Hague2 1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; 2Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, USA Recent advances in proteomic technology reveal G-protein-coupled receptors (GPCRs) are organized as large, macromolecular protein complexes in cell membranes, adding a new layer of intricacy to GPCR signaling. We previously reported the α1D-adrenergic receptor (ADRA1D)—a key regulator of cardiovascular, urinary and CNS function—binds the syntrophin family of PDZ domain proteins (SNTA, SNTB1, and SNTB2) through a C-terminal PDZ ligand inter- action, ensuring receptor plasma membrane localization and G-protein coupling. To assess the uniqueness of this novel GPCR complex, 23 human GPCRs containing Type I PDZ ligands were subjected to TAP/MS proteomic analysis. Syntrophins did not interact with any other GPCRs. Unexpectedly, a second PDZ domain protein, scribble (SCRIB), was detected in ADRA1D complexes. Biochemical, proteomic, and dynamic mass redistribution analyses indicate syntrophins and SCRIB compete for the PDZ ligand, simultaneously exist within an ADRA1D multimer, and impart divergent pharmacological properties to the complex. Our results reveal an unprecedented modular dimeric architecture for the ADRA1D in the cell membrane, providing unexpected opportunities for fine-tuning receptor function through novel protein interactions in vivo, and for intervening in signal transduction with small molecules that can stabilize or disrupt unique GPCR:PDZ protein interfaces. -
The Mental Retardation Protein PAK3 Contributes to Synapse Formation and Plasticity in Hippocampus
10816 • The Journal of Neuroscience, December 1, 2004 • 24(48):10816–10825 Development/Plasticity/Repair The Mental Retardation Protein PAK3 Contributes to Synapse Formation and Plasticity in Hippocampus Bernadett Boda, Stefano Alberi, Irina Nikonenko, Roxanne Node-Langlois, Pascal Jourdain, Marlyse Moosmayer, Lorena Parisi-Jourdain, and Dominique Muller Department of Basic Neuroscience, Centre Medical Universitaire, 1211 Geneva 4, Switzerland Mutations of the gene coding for PAK3 (p21-activated kinase 3) are associated with X-linked, nonsyndromic forms of mental retardation (MRX) in which the only distinctive clinical feature is the cognitive deficit. The mechanisms through which PAK3 mutation produces the mental handicap remain unclear, although an involvement in the mechanisms that regulate the formation or plasticity of synaptic networks has been proposed. Here we show, using a transient transfection approach, that antisense and small interfering RNA-mediated suppression of PAK3 or expression of a dominant-negative PAK3 carrying the human MRX30 mutation in rat hippocampal organotypic slice cultures results in the formation of abnormally elongated dendritic spines and filopodia-like protrusions and a decrease in mature spine synapses. Ultrastructural analysis of the changes induced by expression of PAK3 carrying the MRX30 mutation reveals that many elongated spines fail to express postsynaptic densities or contact presynaptic terminals. These defects are associated with a reduced spontaneous activity, altered expression of AMPA-type glutamate receptors, and defective long-term potentiation. Together, these data identify PAK3 as a key regulator of synapse formation and plasticity in the hippocampus and support interpretations that these defects might contribute to the cognitive deficits underlying this form of mental retardation. -
A De Novo Mutation in the X-Linked PAK3 Gene Is the Underlying Cause of Intellectual Disability and Macrocephaly in Monozygotic Twins
European Journal of Medical Genetics xxx (2017) 1e5 Contents lists available at ScienceDirect European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg A de novo mutation in the X-linked PAK3 gene is the underlying cause of intellectual disability and macrocephaly in monozygotic twins Jozef Hertecant a, b, Makanko Komara c, Aslam Nagi a, Olfat Al-Zaabi d, Waseem Fathallah e, Hong Cui f, Yaping Yang f, Christine M. Eng f, Mohammad Al Sorkhy g, * Mohammad A. Ghattas g, Lihadh Al-Gazali b, Bassam R. Ali c, a Department of Paediatrics, Tawam Hospital, Al-Ain, United Arab Emirates b Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates c Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates d Fujairah Hospital, Fujairah, United Arab Emirates e Mafraq Hospital, Abu Dhabi, United Arab Emirates f Department of Molecular and Human Genetics, Baylor College of Medicine, Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA g College of Pharmacy, Al Ain University of Science and Technology, Al-Ain, United Arab Emirates article info abstract Article history: Pathogenic variants in theP21 protein (Cdc42/Rac)-activated kinase 3gene (PAK3) lead to a rare non Received 29 May 2016 syndromic X-linked intellectual disability. The protein encoded by this gene forms an activated complex Received in revised form with GTP-bound RAS-like (P21), CDC2 and RAC1 proteins which then mediates a variety of cellular 17 January 2017 processes. So far, mutations in PAK3 gene have been reported in few families affected with intellectual Accepted 18 January 2017 disability associated with neurological manifestations such as speech defect, behavioral problem, brain Available online xxx structural abnormalities, microcephaly and cerebral palsy. -
Whole Exome Sequencing of Thymic Neuroendocrine Tumor With
176:2 Y Li, Y Peng and others Sequencing thymic 176:2 187–194 Clinical Study neuroendocrine tumor Whole exome sequencing of thymic neuroendocrine tumor with ectopic ACTH syndrome Yanli Li1,*, Ying Peng1,*, Xiuli Jiang1, Yulong Cheng3, Weiwei Zhou1, Tingwei Su1, Jing Xie2, Xu Zhong1, Dalong Song1, Luming Wu1, Liwen Fan1, Min Li1, Jie Hong1, Weiqing Wang1, Guang Ning1,3 and Yanan Cao1 1Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors and 2Department of Pathology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China, and 3Laboratory of Endocrinology and Metabolism, Institute of Health Correspondence Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & should be addressed Shanghai Jiao-Tong University School of Medicine (SJTUSM), Shanghai, China to Y Cao *(Y Li and Y Peng contributed equally to this work) Email [email protected] Abstract Objective: Thymic neuroendocrine tumor is the second-most prevalent cause of ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), which is a rare disease characterized by ectopic ACTH oversecretion from nonpituitary tumors. However, the genetic abnormalities of thymic neuroendocrine tumors with EAS remain largely unknown. We aim to elucidate the genetic abnormalities and identify the somatic mutations of potential tumor-related genes of thymic neuroendocrine tumors with EAS by whole exome sequencing. Design and methods: Nine patients with thymic neuroendocrine tumors with EAS who were diagnosed at Shanghai Clinical Center for Endocrine and Metabolic Diseases in Ruijin Hospital between 2002 and 2014 were enrolled. We performed whole exome sequencing on the DNA obtained from thymic neuroendocrine tumors and matched peripheral blood using the Hiseq2000 platform. -
1 Genome-Wide Comparisons of Variation in Linkage Disequilibrium
Downloaded from genome.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Genome-wide comparisons of variation in linkage disequilibrium Yik Y. Teo1,*, Andrew E. Fry1, Kanishka Bhattacharya1, Kerrin S. Small1, Dominic P. Kwiatkowski1,2, Taane G. Clark1,2 1 Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom 2 Wellcome Trust Sanger Institute, Hinxton, United Kingdom Running title: Genome-wide comparisons of LD Keywords: linkage disequilibrium, imputation, positive selection, meta-analysis, genome-wide association study * Corresponding author: Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, United Kingdom. Email: [email protected], phone: +44 1865 287712, fax: +44 1865 287 501. ABSTRACT Current genome-wide surveys of common diseases and complex traits fundamentally aim to detect indirect associations where the SNPs carrying the association signals are not biologically active but are in linkage disequilibrium (LD) with some unknown functional polymorphisms. Reproducing any novel discoveries from these genome-wide scans in independent studies is now a prerequisite for the putative findings to be accepted. Significant differences in patterns of LD between populations can affect the portability of phenotypic associations when the replication effort or meta-analyses are attempted in populations that are distinct from the original population which the genome-wide study is performed in. Here we introduce a novel method for genome-wide analyses of LD variations between populations that allow the identification of candidate regions with different patterns of LD. The evidence of LD variation provided by the introduced method correlated with the degree of differences in the frequencies of the most common haplotype across the populations.