Dependent Chemokine Receptor Signal Transduction Pathway in Dendritic
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Glioma Cell Secretion: a Driver of Tumor Progression and a Potential Therapeutic Target Damian A
Published OnlineFirst October 17, 2018; DOI: 10.1158/0008-5472.CAN-18-0345 Cancer Review Research Glioma Cell Secretion: A Driver of Tumor Progression and a Potential Therapeutic Target Damian A. Almiron Bonnin1,2, Matthew C. Havrda1,2, and Mark A. Israel1,2,3 Abstract Cellular secretion is an important mediator of cancer progres- ple oncogenic pathologies. In this review, we describe tumor cell sion. Secreted molecules in glioma are key components of secretion in high-grade glioma and highlight potential novel complex autocrine and paracrine pathways that mediate multi- therapeutic opportunities. Cancer Res; 78(21); 6031–9. Ó2018 AACR. Introduction Glioma-Secreted Molecules Impact Disease Glial cells in the central nervous system (CNS) provide trophic Progression support for neurons (1). In glial tumors, this trophic support is Glioma cells modify their microenvironment by introducing dysregulated creating a pro-oncogenic microenvironment medi- diverse molecules into the extracellular space (Table 1). To exem- ated by a heterogeneous array of molecules secreted into the plify the pro-oncogenic role that secreted molecules can have on – extracellular space (2 15). The glioma secretome includes pro- glioma pathology, we review the functional impact of specific teins, nucleic acids, and metabolites that are often overexpressed cytokines, metabolites, and nucleic acids on glioma biology. By in malignant tissue and contribute to virtually every aspect of describing some of the potent antitumorigenic effects observed in – cancer pathology (Table 1; Fig. 1; refs. 2 15), providing a strong preclinical therapeutic studies targeting tumor cell secretion, we – rationale to target the cancer cell secretory mechanisms. also highlight how blocking secreted molecules might be of fi Although the speci c mechanisms regulating secretion in therapeutic impact in gliomas, as well as other tumors. -
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. -
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. -
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. -
Studio Delle Vie Di Trasduzione Del Segnale Inositide-Dipendente Nelle Sindromi Mielodisplastiche
UNIVERSITA' DEGLI STUDI DI BOLOGNA Scuola di Dottorato in Scienze Mediche e Chirurgiche Cliniche Dottorato di Ricerca in Scienze Morfologiche Umane e Molecolari Settore Disciplinare BIO/16 Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell’Apparato Locomotore STUDIO DELLE VIE DI TRASDUZIONE DEL SEGNALE INOSITIDE-DIPENDENTE NELLE SINDROMI MIELODISPLASTICHE Tesi di Dottorato Tutore: Presentata da: CHIAR.MO PROF. LUCIO COCCO DOTT.SSA MATILDE YUNG FOLLO XIX Ciclo Anno Accademico 2005/2006 INDICE Introduzione 3 1. Sindromi Mielodisplastiche (MDS) 4 1.1.Trattamento delle MDS: 5’-azacitidina 8 2. Signalling Inositide-Dipendente: Fosfolipasi cβ1 (PI-PLCβ1) 10 2.1 Struttura del Gene della PI-PLCβ1 11 2.2 Struttura Proteica della PI-PLCβ1 12 3. Asse di Attivazione Fosfoinositide-3-Chinasi (PI3K)/Akt 14 3.1 Isoforme di Akt 16 3.2. Ruolo di Akt nei Disordini Ematopoietici 18 3.3. Ruolo di Akt nei Meccanismi Apoptotici 19 3.4. Ruolo di Akt nella Progressione attraverso il Ciclo Cellulare 20 4. Target Molecolari a Valle di Akt: mTOR, 4E-BP1e p70S6K 21 Scopo della Ricerca 23 Materiali e Metodi 25 1. Colture Cellulari in vitro 26 2. Caratteristiche dei Pazienti 26 3. Separazione delle Cellule Mononucleate 26 4. Ibridazione Fluorescente in Situ (FISH) 27 5. Estrazione del DNA ed Analisi Mutazionale 28 6. Estrazione dell’RNA e Sintesi del cDNA 28 7. Real-Time PCR 28 8. Analisi Immunocitochimica 29 9. Separazione delle Cellule CD33 31 10. Analisi Citofluorimetrica per la Quantificazione dell’Apoptosi 31 11. Analisi Citofluorimetrica per l’Analisi del Fenotipo 32 12. Separazione delle Cellule CD34 33 13. -
Cephalic Sensory Cell Types Provides Insight Into Joint Photo
RESEARCH ARTICLE Characterization of cephalic and non- cephalic sensory cell types provides insight into joint photo- and mechanoreceptor evolution Roger Revilla-i-Domingo1,2,3, Vinoth Babu Veedin Rajan1,2, Monika Waldherr1,2, Gu¨ nther Prohaczka1,2, Hugo Musset1,2, Lukas Orel1,2, Elliot Gerrard4, Moritz Smolka1,2,5, Alexander Stockinger1,2,3, Matthias Farlik6,7, Robert J Lucas4, Florian Raible1,2,3*, Kristin Tessmar-Raible1,2* 1Max Perutz Labs, University of Vienna, Vienna BioCenter, Vienna, Austria; 2Research Platform “Rhythms of Life”, University of Vienna, Vienna BioCenter, Vienna, Austria; 3Research Platform "Single-Cell Regulation of Stem Cells", University of Vienna, Vienna BioCenter, Vienna, Austria; 4Division of Neuroscience & Experimental Psychology, University of Manchester, Manchester, United Kingdom; 5Center for Integrative Bioinformatics Vienna, Max Perutz Labs, University of Vienna and Medical University of Vienna, Vienna, Austria; 6CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; 7Department of Dermatology, Medical University of Vienna, Vienna, Austria Abstract Rhabdomeric opsins (r-opsins) are light sensors in cephalic eye photoreceptors, but also function in additional sensory organs. This has prompted questions on the evolutionary relationship of these cell types, and if ancient r-opsins were non-photosensory. A molecular profiling approach in the marine bristleworm Platynereis dumerilii revealed shared and distinct *For correspondence: features of cephalic and non-cephalic r-opsin1-expressing cells. Non-cephalic cells possess a full set [email protected] (FR); of phototransduction components, but also a mechanosensory signature. Prompted by the latter, [email protected] (KT-R) we investigated Platynereis putative mechanotransducer and found that nompc and pkd2.1 co- Competing interest: See expressed with r-opsin1 in TRE cells by HCR RNA-FISH. -
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. -
Role of Endothelin-1 in the Gastrointestinal Tract of Horses In
Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 2003 Role of endothelin-1 in the gastrointestinal tract of horses in health and disease Ramaswamy Monickarasi Chidambaram Louisiana State University and Agricultural and Mechanical College Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_dissertations Part of the Veterinary Medicine Commons Recommended Citation Chidambaram, Ramaswamy Monickarasi, "Role of endothelin-1 in the gastrointestinal tract of horses in health and disease" (2003). LSU Doctoral Dissertations. 1717. https://digitalcommons.lsu.edu/gradschool_dissertations/1717 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Doctoral Dissertations by an authorized graduate school editor of LSU Digital Commons. For more information, please [email protected]. ROLE OF ENDOTHELIN-1 IN THE GASTROINTESTINAL TRACT OF HORSES IN HEALTH AND DISEASE A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy The Interdepartmental Program in Veterinary Medical Sciences through the Department of Comparative Biomedical Sciences By Ramaswamy M. Chidambaram BVSc, Madras Veterinary College, India, 1996 MSc, Atlantic Veterinary College, Canada, 2000 May, 2003 Dedicated to my parents, Dr. S. Chidambaram Pillai and Mrs. R. Monickarasi, and my siblings for their inspiration and support toward my pursuit of higher knowledge ii ACKNOWLEDGEMENTS I express my sincere thanks and heartfelt gratitude to my mentor Dr. Rustin Moore and Dr. Changaram Venugopal, for their involvement and personal help offered toward the completion of my dissertation. -
GNAQ and Uveal Melanoma. Karen Sisley, Rachel Doherty, Neil Cross
What hope for the future? GNAQ and Uveal Melanoma. Karen Sisley, Rachel Doherty, Neil Cross To cite this version: Karen Sisley, Rachel Doherty, Neil Cross. What hope for the future? GNAQ and Uveal Melanoma.. British Journal of Ophthalmology, BMJ Publishing Group, 2011, 95 (5), pp.620. 10.1136/bjo.2010.182097. hal-00618791 HAL Id: hal-00618791 https://hal.archives-ouvertes.fr/hal-00618791 Submitted on 3 Sep 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. What hope for the future? GNAQ and Uveal Melanoma. Karen Sisley1, Rachel Doherty2 and Neil A Cross2 Academic Unit of Ophthalmology and Orthoptics, University of Sheffield1 and Department of Biosciences, Sheffield Hallam University2, Sheffield, United Kingdom. Address for correspondence: K.Sisley, Academic Unit of Ophthalmology and Orthoptics, Department of Oncology, K Floor, School of Medicine & Biomedical Sciences, Faculty of Medicine Dentistry & Health, University of Sheffield Beech Hill Road S10 2RX. Telephone: +44 (0114) 271 13199 Fax: +44 (0114) 271 3344 Email:[email protected] Keywords: -
S41598-019-44584-7.Pdf
www.nature.com/scientificreports OPEN Functional characterisation of a novel class of in-frame insertion variants of KRAS and HRAS Received: 1 February 2019 Astrid Eijkelenboom1, Frederik M. A. van Schaik2, Robert M. van Es2, Roel W. Ten Broek1, Accepted: 17 May 2019 Tuula Rinne 3, Carine van der Vleuten4, Uta Flucke1, Marjolijn J. L. Ligtenberg1,3 & Published: xx xx xxxx Holger Rehmann2,5 Mutations in the RAS genes are identifed in a variety of clinical settings, ranging from somatic mutations in oncology to germline mutations in developmental disorders, also known as ‘RASopathies’, and vascular malformations/overgrowth syndromes. Generally single amino acid substitutions are identifed, that result in an increase of the GTP bound fraction of the RAS proteins causing constitutive signalling. Here, a series of 7 in-frame insertions and duplications in HRAS (n = 5) and KRAS (n = 2) is presented, resulting in the insertion of 7–10 amino acids residues in the switch II region. These variants were identifed in routine diagnostic screening of 299 samples for somatic mutations in vascular malformations/overgrowth syndromes (n = 6) and in germline analyses for RASopathies (n = 1). Biophysical characterization shows the inability of Guanine Nucleotide Exchange Factors to induce GTP loading and reduced intrinsic and GAP-stimulated GTP hydrolysis. As a consequence of these opposing efects, increased RAS signalling is detected in a cellular model system. Therefore these in-frame insertions represent a new class of weakly activating clinically relevant RAS variants. Overgrowth syndromes, including vascular malformations represent a spectrum of conditions with congenital, aberrant vascular structures combined with overgrowth of surrounding tissue1–4. -
On the Mechanism of Task Channel Inhibition by G-Protein Coupled Receptors
Aus dem Institut für Physiologie und Pathophysiologie (Geschäftsführender Direktor: Prof. Dr. Dr. Jürgen Daut) des Fachbereichs Medizin der Philipps-Universität Marburg ON THE MECHANISM OF TASK CHANNEL INHIBITION BY G-PROTEIN COUPLED RECEPTORS Inaugural-Dissertation zur Erlangung des Doktorgrades der gesamten Humanmedizin, dem Fachbereich Medizin der Philipps-Universität Marburg vorgelegt von Moritz Lindner aus Witten Marburg, 2012 Angenommen vom Fachbereich Medizin der Philipps-Universität Marburg am: 13. Dezember 2012 Gedruckt mit Genehmigung des Fachbereichs. Dekan: Prof. Dr. Matthias Rothmund Referent: Prof. Dr. Dominik Oliver 1. Korreferent: Prof. Dr. Timothy David Plant To my dear parents Abbreviations AMP-PCP β,γ-Methyleneadenosine-5′-triphosphate ATP Adenosine-tri-phosphate BAPTA 2,2′-(Ethylenedioxy)dianiline-N,N,N′,N′-tetraacetic acid CF-Inp54 Fusion construct of a CFP with the FKBP domain from the FK506 binding protein and the yeast Inp54p Phosphatase CFP Cyan fluorescent protein CHO Chinese Hamster Ovary Ci-VSP Ciona intestinalis voltage-sensitive phosphatase DAG Diacylglycerol DNA Deoxyribonucleic acid EGTA Ethylenglycol-bis(aminoethylether)-N,N,N′N′-tetraacetic acid Et-1 Endothelin-1 Ex-0 Standard extracellular solution GFP Green-fluorescent protein GPCR G-protein coupled receptor GqPCR Gq-protein coupled receptor Gqα Q-type alpha-subunit of the G-protein GTP Guanosine-tri-phosphate HEPES 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid ICS Intracellular solution Ins(1,4,5)P3 Inositol-1,4,5-tris-phosphate K2P Two-pore-domain