Glioma Cell Secretion: a Driver of Tumor Progression and a Potential Therapeutic Target Damian A
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Rab3a As a Modulator of Homeostatic Synaptic Plasticity
Wright State University CORE Scholar Browse all Theses and Dissertations Theses and Dissertations 2014 Rab3A as a Modulator of Homeostatic Synaptic Plasticity Andrew G. Koesters Wright State University Follow this and additional works at: https://corescholar.libraries.wright.edu/etd_all Part of the Biomedical Engineering and Bioengineering Commons Repository Citation Koesters, Andrew G., "Rab3A as a Modulator of Homeostatic Synaptic Plasticity" (2014). Browse all Theses and Dissertations. 1246. https://corescholar.libraries.wright.edu/etd_all/1246 This Dissertation is brought to you for free and open access by the Theses and Dissertations at CORE Scholar. It has been accepted for inclusion in Browse all Theses and Dissertations by an authorized administrator of CORE Scholar. For more information, please contact [email protected]. RAB3A AS A MODULATOR OF HOMEOSTATIC SYNAPTIC PLASTICITY A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy By ANDREW G. KOESTERS B.A., Miami University, 2004 2014 Wright State University WRIGHT STATE UNIVERSITY GRADUATE SCHOOL August 22, 2014 I HEREBY RECOMMEND THAT THE DISSERTATION PREPARED UNDER MY SUPERVISION BY Andrew G. Koesters ENTITLED Rab3A as a Modulator of Homeostatic Synaptic Plasticity BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Doctor of Philosophy. Kathrin Engisch, Ph.D. Dissertation Director Mill W. Miller, Ph.D. Director, Biomedical Sciences Ph.D. Program Committee on Final Examination Robert E. W. Fyffe, Ph.D. Vice President for Research Dean of the Graduate School Mark Rich, M.D./Ph.D. David Ladle, Ph.D. F. Javier Alvarez-Leefmans, M.D./Ph.D. Lynn Hartzler, Ph.D. -
Ubiquitylome Profiling of Parkin-Null Brain Reveals Dysregulation Of
Neurobiology of Disease 127 (2019) 114–130 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi Ubiquitylome profiling of Parkin-null brain reveals dysregulation of calcium T homeostasis factors ATP1A2, Hippocalcin and GNA11, reflected by altered firing of noradrenergic neurons Key J.a,1, Mueller A.K.b,1, Gispert S.a, Matschke L.b, Wittig I.c, Corti O.d,e,f,g, Münch C.h, ⁎ ⁎ Decher N.b, , Auburger G.a, a Exp. Neurology, Goethe University Medical School, 60590 Frankfurt am Main, Germany b Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior - MCMBB; Clinic for Neurology, Philipps-University Marburg, 35037 Marburg, Germany c Functional Proteomics, SFB 815 Core Unit, Goethe University Medical School, 60590 Frankfurt am Main, Germany d Institut du Cerveau et de la Moelle épinière, ICM, Paris, F-75013, France e Inserm, U1127, Paris, F-75013, France f CNRS, UMR 7225, Paris, F-75013, France g Sorbonne Universités, Paris, F-75013, France h Institute of Biochemistry II, Goethe University Medical School, 60590 Frankfurt am Main, Germany ARTICLE INFO ABSTRACT Keywords: Parkinson's disease (PD) is the second most frequent neurodegenerative disorder in the old population. Among Parkinson's disease its monogenic variants, a frequent cause is a mutation in the Parkin gene (Prkn). Deficient function of Parkin Mitochondria triggers ubiquitous mitochondrial dysfunction and inflammation in the brain, but it remains unclear howse- Parkin lective neural circuits become vulnerable and finally undergo atrophy. Ubiquitin We attempted to go beyond previous work, mostly done in peripheral tumor cells, which identified protein Calcium targets of Parkin activity, an ubiquitin E3 ligase. -
Ras-Associated, Small GTP-Binding Protein Mouse, Recombinant, E. Coli
Rab3AGST-His Ras-associated, small GTP-binding protein mouse, recombinant, E. coli Cat. No. Amount Description: N-terminal tagged Rab3A is a small GTPase that belongs to the Ras PR-115 50 µg superfamily. Rab proteins play an important role in various aspects of membrane traffic, including cargo selection, vesicle budding, vesicle motility, tethering, docking, and fusion. Rab3A, a member of For in vitro use only! the Rab small G protein family, is involved in the process of Ca2+- dependent neurotransmitter release. Rab3A activity is regulated by Shipping: shipped on dry ice a GDP/GTP exchange protein (Rab3 GEP), a Rab GDP dissociation inhibitor (Rab GDI), and a GTPaseactivating protein (Rab3 GAP). Storage Conditions: store at -80 °C The Rab3A recycling is coupled with synaptic vesicle trafficking as follows: (i) GDP-Rab3A forms an inactive complex with Rab GDI and Additional Storage Conditions: avoid freeze/thaw cycles stays in the cytosol of nerve terminals. (ii) GDPRab3A released from Shelf Life: 12 months Rab GDI is converted to GTPRab3A by Rab3 GEP. (iii) GTP-Rab3A binds effector molecules, Rabphilin-3 and Rim, localized at synaptic Molecular Weight: 54 kDa vesicles and the active zone, respectively. These complexes facilitate Accession number: NM_009001 translocation and docking of the synaptic vesicles to the active zone. The GST-Tag facilitates the protein‘s application in typical GST Purity: > 90 % (SDS-PAGE) pull-down assays. Form: liquid (Supplied in 50 mM Tris-HCl pH 8.0, 100 mM NaCl, 10 mM Activity: MgCl2 and 2 mM beta-mercaptoethanol) 100 pmol of protein can bind > 80 pmol of GDP. -
Predicting Coupling Probabilities of G-Protein Coupled Receptors Gurdeep Singh1,2,†, Asuka Inoue3,*,†, J
Published online 30 May 2019 Nucleic Acids Research, 2019, Vol. 47, Web Server issue W395–W401 doi: 10.1093/nar/gkz392 PRECOG: PREdicting COupling probabilities of G-protein coupled receptors Gurdeep Singh1,2,†, Asuka Inoue3,*,†, J. Silvio Gutkind4, Robert B. Russell1,2,* and Francesco Raimondi1,2,* 1CellNetworks, Bioquant, Heidelberg University, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany, 2Biochemie Zentrum Heidelberg (BZH), Heidelberg University, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany, 3Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan and 4Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA Received February 10, 2019; Revised April 13, 2019; Editorial Decision April 24, 2019; Accepted May 01, 2019 ABSTRACT great use in tinkering with signalling pathways in living sys- tems (5). G-protein coupled receptors (GPCRs) control multi- Ligand binding to GPCRs induces conformational ple physiological states by transducing a multitude changes that lead to binding and activation of G-proteins of extracellular stimuli into the cell via coupling to situated on the inner cell membrane. Most of mammalian intra-cellular heterotrimeric G-proteins. Deciphering GPCRs couple with more than one G-protein giving each which G-proteins couple to each of the hundreds receptor a distinct coupling profile (6) and thus specific of GPCRs present in a typical eukaryotic organism downstream cellular responses. Determining these coupling is therefore critical to understand signalling. Here, profiles is critical to understand GPCR biology and phar- we present PRECOG (precog.russelllab.org): a web- macology. Despite decades of research and hundreds of ob- server for predicting GPCR coupling, which allows served interactions, coupling information is still missing for users to: (i) predict coupling probabilities for GPCRs many receptors and sequence determinants of coupling- specificity are still largely unknown. -
Recurrent GNAQ Mutation Encoding T96S in Natural Killer/T Cell Lymphoma
ARTICLE https://doi.org/10.1038/s41467-019-12032-9 OPEN Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma Zhaoming Li 1,2,9, Xudong Zhang1,2,9, Weili Xue1,3,9, Yanjie Zhang1,3,9, Chaoping Li1,3, Yue Song1,3, Mei Mei1,3, Lisha Lu1,3, Yingjun Wang1,3, Zhiyuan Zhou1,3, Mengyuan Jin1,3, Yangyang Bian4, Lei Zhang1,2, Xinhua Wang1,2, Ling Li1,2, Xin Li1,2, Xiaorui Fu1,2, Zhenchang Sun1,2, Jingjing Wu1,2, Feifei Nan1,2, Yu Chang1,2, Jiaqin Yan1,2, Hui Yu1,2, Xiaoyan Feng1,2, Guannan Wang5, Dandan Zhang5, Xuefei Fu6, Yuan Zhang7, Ken H. Young8, Wencai Li5 & Mingzhi Zhang1,2 1234567890():,; Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive malignancy with a higher prevalence in Asia and South America. However, the molecular genetic mechanisms underlying NKTCL remain unclear. Here, we identify somatic mutations of GNAQ (encoding the T96S alteration of Gαq protein) in 8.7% (11/127) of NKTCL patients, through whole- exome/targeted deep sequencing. Using conditional knockout mice (Ncr1-Cre-Gnaqfl/fl), we demonstrate that Gαqdeficiency leads to enhanced NK cell survival. We also find that Gαq suppresses tumor growth of NKTCL via inhibition of the AKT and MAPK signaling pathways. Moreover, the Gαq T96S mutant may act in a dominant negative manner to promote tumor growth in NKTCL. Clinically, patients with GNAQ T96S mutations have inferior survival. Taken together, we identify recurrent somatic GNAQ T96S mutations that may contribute to the pathogenesis of NKTCL. Our work thus has implications for refining our understanding of the genetic mechanisms of NKTCL and for the development of therapies. -
140503 IPF Signatures Supplement Withfigs Thorax
Supplementary material for Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis Daryle J. DePianto1*, Sanjay Chandriani1⌘*, Alexander R. Abbas1, Guiquan Jia1, Elsa N. N’Diaye1, Patrick Caplazi1, Steven E. Kauder1, Sabyasachi Biswas1, Satyajit K. Karnik1#, Connie Ha1, Zora Modrusan1, Michael A. Matthay2, Jasleen Kukreja3, Harold R. Collard2, Jackson G. Egen1, Paul J. Wolters2§, and Joseph R. Arron1§ 1Genentech Research and Early Development, South San Francisco, CA 2Department of Medicine, University of California, San Francisco, CA 3Department of Surgery, University of California, San Francisco, CA ⌘Current address: Novartis Institutes for Biomedical Research, Emeryville, CA. #Current address: Gilead Sciences, Foster City, CA. *DJD and SC contributed equally to this manuscript §PJW and JRA co-directed this project Address correspondence to Paul J. Wolters, MD University of California, San Francisco Department of Medicine Box 0111 San Francisco, CA 94143-0111 [email protected] or Joseph R. Arron, MD, PhD Genentech, Inc. MS 231C 1 DNA Way South San Francisco, CA 94080 [email protected] 1 METHODS Human lung tissue samples Tissues were obtained at UCSF from clinical samples from IPF patients at the time of biopsy or lung transplantation. All patients were seen at UCSF and the diagnosis of IPF was established through multidisciplinary review of clinical, radiological, and pathological data according to criteria established by the consensus classification of the American Thoracic Society (ATS) and European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and the Latin American Thoracic Association (ALAT) (ref. 5 in main text). Non-diseased normal lung tissues were procured from lungs not used by the Northern California Transplant Donor Network. -
Novel Driver Strength Index Highlights Important Cancer Genes in TCGA Pancanatlas Patients
medRxiv preprint doi: https://doi.org/10.1101/2021.08.01.21261447; this version posted August 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients Aleksey V. Belikov*, Danila V. Otnyukov, Alexey D. Vyatkin and Sergey V. Leonov Laboratory of Innovative Medicine, School of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Moscow Region, Russia *Corresponding author: [email protected] NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 1 medRxiv preprint doi: https://doi.org/10.1101/2021.08.01.21261447; this version posted August 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Abstract Elucidating crucial driver genes is paramount for understanding the cancer origins and mechanisms of progression, as well as selecting targets for molecular therapy. Cancer genes are usually ranked by the frequency of mutation, which, however, does not necessarily reflect their driver strength. Here we hypothesize that driver strength is higher for genes that are preferentially mutated in patients with few driver mutations overall, because these few mutations should be strong enough to initiate cancer. -
APP Anterograde Transport Requires Rab3a Gtpase Activity for Assembly of the Transport Vesicle
14534 • The Journal of Neuroscience, November 18, 2009 • 29(46):14534–14544 Neurobiology of Disease APP Anterograde Transport Requires Rab3A GTPase Activity for Assembly of the Transport Vesicle Anita Szodorai,2 Yung-Hui Kuan,2,9 Silke Hunzelmann,1,2 Ulrike Engel,4 Ayuko Sakane,6 Takuya Sasaki,6 Yoshimi Takai,7 Joachim Kirsch,3 Ulrike Mu¨ller,5 Konrad Beyreuther,2,10 Scott Brady,8 Gerardo Morfini,8 and Stefan Kins1,2 1Technical University of Kaiserslautern, Department of Human Biology and Human Genetics, D-67663 Kaiserslautern, Germany, 2Centre for Molecular Biology, 3Department of Anatomy and Cell Biology, 4Nikon Imaging Center, Bioquant, and 5Institute for Pharmacia and Molecular Biotechnology, University of Heidelberg, D-69120 Heidelberg, Germany, 6Department of Biochemistry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan, 7Division of Molecular and Cellular Biology and Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine/Faculty of Medicine, Kobe 650-0017, Japan, 8Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612, 9Max Planck Institute for Brain Research, D-60528 Frankfurt, Germany, and 10Network Aging Research, D-69115 Heidelberg, Germany The amyloid precursor protein (APP) is anterogradely transported by conventional kinesin in a distinct transport vesicle, but both the biochem- ical composition of such a vesicle and the specific kinesin-1 motor responsible for transport are poorly defined. APP may be sequentially cleaved by - and ␥-secretases leading to accumulation of -amyloid (A) peptides in brains of Alzheimer’s disease patients, whereas cleavage of APP by ␣-secretases prevents A generation. -
Inhibition of Mutant GNAQ Signaling in Uveal Melanoma Induces AMPK-Dependent Autophagic Cell Death
Published OnlineFirst February 26, 2013; DOI: 10.1158/1535-7163.MCT-12-1020 Molecular Cancer Cancer Therapeutics Insights Therapeutics Inhibition of Mutant GNAQ Signaling in Uveal Melanoma Induces AMPK-Dependent Autophagic Cell Death Grazia Ambrosini1, Elgilda Musi1, Alan L. Ho1, Elisa de Stanchina2, and Gary K. Schwartz1 Abstract Oncogenic mutations in GNAQ and GNA11 genes are found in 80% of uveal melanoma. These mutations result in the activation of the RAF/MEK signaling pathway culminating in the stimulation of ERK1/2 mitogen- activated protein kinases. In this study, using a siRNA strategy, we show that mutant GNAQ signals to both MEK and AKT, and that combined inhibition of these pathways with the MEK inhibitor selumetinib (AZD6244) and the AKT inhibitor MK2206 induced a synergistic decrease in cell viability. This effect was genotype dependent as autophagic markers like beclin1 and LC3 were induced in GNAQ-mutant cells, whereas apoptosis was the mechanism of cell death of BRAF-mutant cells, and cells without either mutation underwent cell-cycle arrest. The inhibition of MEK/ATK pathways induced activation of AMP-activated protein kinase (AMPK) in the GNAQ-mutant cells. The downregulation of AMPK by siRNA or its inhibition with compound C did not rescue the cells from autophagy, rather they died by apoptosis, defining AMPK as a key regulator of mutant GNAQ signaling and a switch between autophagy and apoptosis. Furthermore, this combination treatment was effective in inhibiting tumor growth in xenograft mouse models. These findings suggest that inhibition of MEK and AKT may represent a promising approach for targeted therapy of patients with uveal melanoma. -
Identification of Key Genes and Pathways for Alzheimer's Disease
Biophys Rep 2019, 5(2):98–109 https://doi.org/10.1007/s41048-019-0086-2 Biophysics Reports RESEARCH ARTICLE Identification of key genes and pathways for Alzheimer’s disease via combined analysis of genome-wide expression profiling in the hippocampus Mengsi Wu1,2, Kechi Fang1, Weixiao Wang1,2, Wei Lin1,2, Liyuan Guo1,2&, Jing Wang1,2& 1 CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China 2 Department of Psychology, University of Chinese Academy of Sciences, Beijing 10049, China Received: 8 August 2018 / Accepted: 17 January 2019 / Published online: 20 April 2019 Abstract In this study, combined analysis of expression profiling in the hippocampus of 76 patients with Alz- heimer’s disease (AD) and 40 healthy controls was performed. The effects of covariates (including age, gender, postmortem interval, and batch effect) were controlled, and differentially expressed genes (DEGs) were identified using a linear mixed-effects model. To explore the biological processes, func- tional pathway enrichment and protein–protein interaction (PPI) network analyses were performed on the DEGs. The extended genes with PPI to the DEGs were obtained. Finally, the DEGs and the extended genes were ranked using the convergent functional genomics method. Eighty DEGs with q \ 0.1, including 67 downregulated and 13 upregulated genes, were identified. In the pathway enrichment analysis, the 80 DEGs were significantly enriched in one Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, GABAergic synapses, and 22 Gene Ontology terms. These genes were mainly involved in neuron, synaptic signaling and transmission, and vesicle metabolism. These processes are all linked to the pathological features of AD, demonstrating that the GABAergic system, neurons, and synaptic function might be affected in AD. -
A Novel Rab11-Rab3a Cascade Required for Lysosome Exocytosis
bioRxiv preprint doi: https://doi.org/10.1101/2021.03.06.434066; this version posted March 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. A novel Rab11-Rab3a cascade required for lysosome exocytosis Cristina Escrevente1,*, Liliana Bento-Lopes1*, José S Ramalho1, Duarte C Barral1,† 1 iNOVA4Health, CDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal. * These authors contributed equally to this work. † Correspondence should be sent to: Duarte C Barral, CEDOC, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria 130, 1169-056, Lisboa, Portugal, Tel: +351 218 803 102, Fax: +351 218 803 006, [email protected]. (ORCID 0000-0001-8867-2407). Abbreviations used in this paper: FIP, Rab11-family of interacting protein; GEF, guanine nucleotide exchange factor; LE, late endosomes; LRO, lysosome-related organelle; NMIIA, non-muscle myosin heavy chain IIA; Slp-4a, synaptotagmin-like protein 4a. 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.06.434066; this version posted March 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Lysosomes are dynamic organelles, capable of undergoing exocytosis. This process is crucial for several cellular functions, namely plasma membrane repair. -
Uveal Melanoma: GNAQ and GNA11 Mutations in a Greek Population
ANTICANCER RESEARCH 37 : 5719-5726 (2017) doi:10.21873/anticanres.12010 Uveal Melanoma: GNAQ and GNA11 Mutations in a Greek Population FILIPPOS PSINAKIS 1, ANASTASIA KATSELI 2, CHRYSSANTHY KOUTSANDREA 1, KONSTANTINA FRANGIA 3, LINA FLORENTIN 2, DESPINA APOSTOLOPOULOU 2, KONSTANTINA DIMAKOPOULOU 4, DIMITRIOS PAPAKONSTANTINOU 5, ELENI GEORGOPOULOU 6 and DIMITRIOS BROUZAS 1 11st Department of Ophthalmology, National and Kapodistrian University of Athens, Athens, Greece; 2ALFA LAB, Molecular Biology and Cytogenetics Center, Leto Maternity Hospital, Athens, Greece; 3HistoBio Diagnosis Pathology Center, Athens, Greece; 4Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 5Department of Opthalmology, University of Athens, Georgios Gennimatas General Hospital, Athens, Greece; 6Private Practice, Athens, Greece Abstract. Background/Aim: Uveal melanoma is the most Uveal melanoma (UM) is the most common primary common primary adult intraocular malignancy. It is known malignancy of the eye, arising from melanocytes of the to have a strong metastatic potential, fatal for the vast choroid, ciliary body and iris. The disruption of specific majority of patients. In recent years, meticulous cytogenetic signaling pathways is considered to be involved in its and molecular profiling has led to precise prognostication, tumorigenesis. One of the main known pathways is mitogen- that unfortunately is not matched by advancements in activated protein kinase (MAPK)/ERK, known to be adjuvant therapies. G Protein subunits alpha Q (GNAQ) and disturbed as a result of G protein subunit alpha Q ( GNAQ ) alpha 11 (GNA11) are two of the major driver genes that or subunit alpha 11 ( GNA11 ) mutations (1). These mutations contribute to the development of uveal melanoma.