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Neurotrophin-3 Production Promotes Human Neuroblastoma Cell Survival by Inhibiting Trkc-Induced Apoptosis
Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis Jimena Bouzas-Rodriguez, … , Servane Tauszig-Delamasure, Patrick Mehlen J Clin Invest. 2010;120(3):850-858. https://doi.org/10.1172/JCI41013. Research Article Oncology Tropomyosin-related kinase receptor C (TrkC) is a neurotrophin receptor with tyrosine kinase activity that was expected to be oncogenic. However, it has several characteristics of a tumor suppressor: its expression in tumors has often been associated with good prognosis; and it was recently demonstrated to be a dependence receptor, transducing different positive signals in the presence of ligand but inducing apoptosis in the absence of ligand. Here we show that the TrkC ligand neurotrophin-3 (NT-3) is upregulated in a large fraction of aggressive human neuroblastomas (NBs) and that it blocks TrkC-induced apoptosis of human NB cell lines, consistent with the idea that TrkC is a dependence receptor. Functionally, both siRNA knockdown of NT-3 expression and incubation with a TrkC-specific blocking antibody triggered apoptosis in human NB cell lines. Importantly, disruption of the NT-3 autocrine loop in malignant human neuroblasts triggered in vitro NB cell death and inhibited tumor growth and metastasis in both a chick and a mouse xenograft model. Thus, we believe that our data suggest that NT-3/TrkC disruption is a putative alternative targeted therapeutic strategy for the treatment of NB. Find the latest version: https://jci.me/41013/pdf Research article Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis Jimena Bouzas-Rodriguez,1 Jorge Ruben Cabrera,1 Céline Delloye-Bourgeois,1 Gabriel Ichim,1 Jean-Guy Delcros,1 Marie-Anne Raquin,2 Raphaël Rousseau,3 Valérie Combaret,3 Jean Bénard,4 Servane Tauszig-Delamasure,1 and Patrick Mehlen1 1Apoptosis, Cancer and Development Laboratory–Equipe labellisée “La Ligue,” CNRS UMR5238, Université de Lyon, France. -
Ephrinb3 Is an Anti-Apoptotic Ligand That Inhibits the Dependence Receptor Functions of Epha4 Receptors During Adult Neurogenesis
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1793 (2009) 231–238 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamcr EphrinB3 is an anti-apoptotic ligand that inhibits the dependence receptor functions of EphA4 receptors during adult neurogenesis Céline Furne a,1, Jerome Ricard b,1, Jorge Ruben Cabrera a, Laurent Pays a, John R. Bethea b, Patrick Mehlen a,⁎,2, Daniel J. Liebl b,⁎,2 a Laboratory Apoptosis Cancer and Development, CNRS UMR 5238, Center Léon Bérard, University of Lyon, Lyon, France b The Miami Project to Cure Paralysis and Department of Neurosurgery, University of Miami School of Medicine, Miami, FL, USA article info abstract Article history: Eph receptors have been implicated in regulating a diverse array of cellular functions in the developing Received 18 December 2007 nervous system. Recently, Eph receptors have been shown to promote cell death in adult germinal zones; Received in revised form 2 September 2008 however, their mechanisms of action remain ill-defined. In this study, we demonstrate that EphA4 is a new Accepted 15 September 2008 member of the dependence receptors family, which can initiate cell death in the absence of its ligand Available online 7 October 2008 ephrinB3. Upon removal of its ligand, EphA4 triggers cell death that is dependent on caspase activation as caspase inhibitors prevent cell death. EphA4 itself is cleaved by caspase-3-like caspase in the intracellular Keywords: Ephrin domain at position D773/774, which is necessary for cell death initiation as mutation of the cleavage site Eph receptor abolishes apoptosis. -
Up-Regulation of Bax and Endonuclease G, and Down-Modulation of Bcl-XL Involved in Cardiotoxin III-Induced Apoptosis in K562 Cells
EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 38, No. 4, 435-444, August 2006 Up-regulation of Bax and endonuclease G, and down-modulation of Bcl-XL involved in cardiotoxin III-induced apoptosis in K562 cells Sheng-Huei Yang1, Ching-Ming Chien1, Keywords: apoptosis; bcl-2-associated X protein; car- Mei-Chin Lu2, Yi-Hsiung Lin1, diotoxin III, Naja naja atra; caspase; endonuclease G; Xiu-Wei Hu1 and Shinne-Ren Lin1,3 K562 cells 1Faculty of Medicinal and Applied Chemistry 2 Introduction Graduate Institute of Natural Products Kaohsiung Medical University Many therapeutic and chemopreventive agents Kaohsiung 807, Taiwan, ROC 3Corresponding author: Tel, 886-7-3121101#2219; eliminate cancerous cells by inducing programmed Fax, 886-7-3123443; E-mail, [email protected] cell death (apoptosis) (Kaufmann et al., 2000; Ro- bertson et al., 2000). Apoptosis is an important Accepted 24 July 2006 cellular process for destruction of undesirable cells during development or homeostasis in multi-cellular Abbreviations: CTX III, Carditoxin III; MTT, 3-(4,5-dimethylthia- organisms. This process is characterized by distinct zol-2-yl)-2,5-diphenyltetrazolium bromide; PARP, poly (ADP-ribo- morphological changes including plasma membrane se) polymerase; Z-VAD-FMK, benzyloxycarbonyl-Val-Ala-Asp- bleb, cell shrinkage, depolarization of mitochondria, fluoromethylketone chromatin condensation, and DNA fragmentation (Kaufmann et al., 2001; Reed, 2001). Caspases are essential for the execution of cell death by various Abstract apoptotic stimuli (Cohen, 1997; Shi, 2002). Caspase activation is often regulated by various cellular pro- Cardiotoxin III (CTX III), a basic polypeptide with 60 teins including members of the IAP (Deveraux and amino acid residues isolated from Naja naja atra Reed, 1999) and Bcl-2 families (Adams and Cory, venom, has been reported to have anticancer activity. -
Coumarin Induces Cell Cycle Arrest and Apoptosis in Human
in vivo 21: 1003-1010 (2007) Coumarin Induces Cell Cycle Arrest and Apoptosis in Human Cervical Cancer HeLa Cells through a Mitochondria- and Caspase-3 Dependent Mechanism and NF-κB Down-regulation JING-YUAN CHUANG1, YUNG-FENG HUANG1, HSU-FENG LU2, HENG-CHEN HO3, JAI-SING YANG4, TE-MAO LI5, NAI-WEN CHANG3 and JING-GUNG CHUNG6,7 Departments of 1Medical Laboratory Science and Biotechnology, 3Biochemistry, 4Pharmacology and 6Microbiology, 7School of Biological Science and Technology, and 5Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan; 2Department of Clinical Pathology, Cheng Hsin Rehabilitation Medical Center, Taipei, Taiwan, R.O.C. Abstract. The effects of coumarin on cell viability, cell cycle investigators have also reported on the use of coumarin (1,2- arrest and induction of apoptosis were investigated in human benzopyrone), or its metabolite 7-hydroxycoumarin, for the cervical cancer HeLa cells. Coumarin was cytotoxic with an treatment of some human carcinomas (4-7). No adverse effects of coumarin have been reported in humans using doses up to IC50 of 54.2 ÌM, induced morphological changes, and caused G0/G1 arrest and apoptosis. The decreasing number of viable 7 g daily, after two weeks of continued treatment (8, 9). In the cells appeared to be due to induction of cell cycle arrest and present study, the effect of coumarin on cell cycle arrest and apoptotic cell death, since coumarin induced morphologically induction of apoptosis in human cervical cancer HeLa cells, for apoptotic changes and internucleosomal DNA laddering which no information is currently available, was examined. fragmentation and increased the sub-G1 group. -
View Open Access Neurodegeneration in Alzheimer's Disease: Caspases and Synaptic Element Interdependence Dale E Bredesen1,2
Molecular Neurodegeneration BioMed Central Review Open Access Neurodegeneration in Alzheimer's disease: caspases and synaptic element interdependence Dale E Bredesen1,2 Address: 1Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA USA 94945 and 2Department of Neurology, University of California, San Francisco, CA USA 94143 Email: Dale E Bredesen - [email protected] Published: 26 June 2009 Received: 4 March 2009 Accepted: 26 June 2009 Molecular Neurodegeneration 2009, 4:27 doi:10.1186/1750-1326-4-27 This article is available from: http://www.molecularneurodegeneration.com/content/4/1/27 © 2009 Bredesen; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Extensive genetic, biochemical, and histological evidence has implicated the amyloid-β peptide (Aβ) in Alzheimer's disease pathogenesis, and several mechanisms have been suggested, such as metal binding, reactive oxygen species production, and membrane pore formation. However, recent evidence argues for an additional role for signaling mediated by the amyloid precursor protein, APP, in part via the caspase cleavage of APP at aspartate 664. Here we review the effects and implications of this cleavage event, and propose a model of Alzheimer's disease that focuses on the critical nature of this cleavage and its downstream effects. Review: programmed cell death, cell death revealed a more active, and more plastic, role for the cell signaling, and neurodegenerative disease in its own life/death decision than was previously appre- Many of the diseases that affect the nervous system feature ciated. -
Book of Abstract 2008
Co-chairs of the conference: Janko Kos, Faculty of Pharmacy, University of Ljubljana, Slovenia Gregor Serša, Institute of Oncology, Ljubljana, Slovenia Tamara Lah Turnšek, National Institute of Biology, Ljubljana, Slovenia Scientific committee: Janko Kos, Rolf Bjerkvig, Maria Grazia Daidone, Dylan Edwards, Tamara Lah Turnšek, Eberhard Neumann, Christoph Peteres, Gregor Serša, Bonnie Sloan, Gillian M. Toz e r Sponsored by: AstraZeneca UK Limited, Branch Office in Ljubljana Amgen Drugs d.o.o., Ljubljana Carl Zeiss d.o.o., Ljubljana CSC Pharma d.o.o., Ljubljana Educell d.o.o., Ljubljana Elex Unitrade, Ljubljana IGEA S.r.l., Carpi Janssen-Cilag Slovenia, Division of Johnson & Johnson d.o.o., Ljubljana Kemomed, d.o.o., Kranj Krka, d.d., Novo mesto Labormed d.o.o., Ljubljana Lek a Sandoz Company, Ljubljana LKB Vertriebs Ges.m.b. H., Wien Medias International d.o.o., Ljubljana Mediline d.o.o., Kamnik Merck d.o.o., Slovenija Mikro+Polo d.o.o., Maribor Olympus Slovenija d.o.o., Ljubljana Pivovarna Laško d.d., Laško Roche Pharmaceutical Division d.o.o., Ljubljana Sanolabor d.d., Ljubljana Santomas, Šmarje Schering-Plough CE EG, Branch Office in Ljubljana Slovenian Research Agency, Ljubljana BOOK OF ABSTRACTS Editors: Gregor Serša, Janko Kos, Tamara Lah Turnšek, Simona Kranjc, Zala Jevnikar, Nataša Obermajer Issued by: Association of Radiology and Oncology Design: Maja Licul, Simona Kranjc Printed by: Solas d.o.o CIP - Kataložni zapis o publikaciji Narodna in univerzitetna knjižnica, Ljubljana 616-006(063) CONFERENCE on Experimental and Translational Oncology (5; 2008; Kranjska gora) Book of Abstracts - 5th Conference on Experimental and Translational Oncology, Kranjska gora, Slovenia, March 26-30, 2008; [editors: Gregor Serša, Janko Kos, Tamara Lah Turnšek, ISBN 978-961-91302-2-3 Simona Kranjc, Zala Jevnikar, Nataša Obermajer] -Ljubljana: 1. -
Control of Cell Death/Survival Balance by the MET Dependence Receptor
RESEARCH ARTICLE Control of cell death/survival balance by the MET dependence receptor Leslie Duplaquet1, Catherine Leroy1†, Audrey Vinchent1†, Sonia Paget1, Jonathan Lefebvre1, Fabien Vanden Abeele2, Steve Lancel3, Florence Giffard4, Re´ jane Paumelle3, Gabriel Bidaux5, Laurent Heliot5, Laurent Poulain4, Alessandro Furlan1,5*, David Tulasne1* 1Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, Lille, France; 2Univ. Lille, Inserm, U1003 - PHYCEL - Physiologie Cellulaire, Lille, France; 3Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, Lille, France; 4Normandie Universite´, UNICAEN, INSERM U1086 ANTICIPE, UNICANCER, Cancer Centre F. Baclesse, Caen, France; 5Univ. Lille, CNRS, UMR8523 - PhLAM – laboratoire de Physique des Lasers, Atomes et Mole´cules, Lille, France Abstract Control of cell death/survival balance is an important feature to maintain tissue homeostasis. Dependence receptors are able to induce either survival or cell death in presence or absence of their ligand, respectively. However, their precise mechanism of action and their physiological importance are still elusive for most of them including the MET receptor. We evidence that pro-apoptotic fragment generated by caspase cleavage of MET localizes to the mitochondria-associated membrane region. This fragment triggers a calcium transfer from endoplasmic reticulum to mitochondria, which is instrumental for the apoptotic action of the *For correspondence: receptor. Knock-in mice bearing a mutation of MET caspase cleavage site highlighted that p40MET [email protected] (AF); production is important for FAS-driven hepatocyte apoptosis, and demonstrate that MET acts as a [email protected] (DT) dependence receptor in vivo. Our data shed light on new signaling mechanisms for dependence †These authors contributed receptors’ control of cell survival/death balance, which may offer new clues for the pathophysiology equally to this work of epithelial structures. -
Thirty Years of Research on Met Receptor to Move a Biomarker from Bench to Bedside
Published OnlineFirst November 19, 2014; DOI: 10.1158/0008-5472.CAN-14-1932 Cancer Review Research Thirty Years of Research on Met Receptor to Move a Biomarker from Bench to Bedside Alessandro Furlan1, Zoulika Kherrouche1,Remi Montagne1, Marie-Christine Copin1,2, and David Tulasne1 Abstract Met receptor tyrosine kinase was discovered in 1984 as an oncogene. Thirty years later, Met and its ligand hepatocyte growth factor/scatter factor are promising targets for the novel therapies developed to fight against cancers, with more than 240 clinical trials currently conducted. In this review, we offer to trace and highlight the most recent findings of the exemplary track record of research on Met receptor, which allowed moving this biomarker from bench to bedside. Indeed, three decades of basic research unravelled the structural basis of the ligand/receptor interaction and their complex downstream signaling network. During this period, animal models highlighted their crucial role in the development and homeostasis of epithelial organs. In parallel, involvement of Met in tumorigenesis was confirmed by the direct association of its deregulation to poor prognosis in numerous cancers. On the basis of these data, pharmaceutical companies developed many Met inhibitors, some of which are in phase III clinical trials. These impressive achievements should not detract from many questions that still remain, such as the precise Met signaling involvement in development or homeostasis of specific epithelial structures. In addition, the processes involving Met in resistance to current therapies or the appearance of resistances to Met-targeted therapies are far from being fully understood. Cancer Res; 74(23); 6737–44. -
Death Pathways Activated in the Neurotrophic Factror-Deprived Neurons
Death pathways activated in the neurotrophic factor-deprived neurons Li-ying Yu The Finnish Graduate School of Neuroscience Institute of Biotechnology and Department of Biological and Environmental Sciences Faculty of Biosciences University of Helsinki Academic dissertation To be presented for public criticism, with the permission of the Faculty of Biosciences of the University of Helsinki, in the auditorium 2402 at Viikki Biocenter 3 on the 13th of February 2009, at 12 o’clock noon. Helsinki 2009 Supervised by: Docent Urmas Arumäe Institute of Biotechnology University of Helsinki Finland Reviewed by: Docent Matti Airaksinen Neuroscience Center University of Helsinki Finland And Docent Esa Kuismanen Department of Biosciences Division of Biochemistry University of Helsinki Finland Opponent: Professor Dale E. Bredesen Buck Institute for Age Research Novato, California United States of America ISBN 978-952-10-5272-9 (pbk) ISBN 978-952-10-5273-6 (PDF) ISSN 1795-7079 Yliopistopaino, Helsinki, 2009 咃㒠䤓㦏䓀 㪝䚞 㹔 TABLE OF CONTENTS ABBREVIATIONS LIST OF ORIGINAL PUBLICATIONS ABSTRACT 1. REVIEW OF THE LITERATURE ..........................................................................1 1.1. Programed cell death ............................................................................................1 1.1.1. Programed cell death in the development of nervous system.....................1 1.2. Neurotrophic factors .............................................................................................2 1.2.1. Neurotrophin family ...................................................................................3 -
The Trkc Receptor Induces Apoptosis When the Dependence Receptor Notion Meets the Neurotrophin Paradigm
The TrkC receptor induces apoptosis when the dependence receptor notion meets the neurotrophin paradigm Servane Tauszig-Delamasure*, Li-Ying Yu†, Jorge Ruben Cabrera*, Jimena Bouzas-Rodriguez*, Catherine Mermet- Bouvier*, Catherine Guix*, Marie-Claire Bordeaux*, Urmas Aruma¨ e†, and Patrick Mehlen*‡ *Apoptosis, Cancer and Development Laboratory, Equipe Labellise´e La Ligue, Centre National de la Recherche Scientifique, Unite´Mixte de Recherche 5238, Universite´de Lyon, Centre Le´onBe´ rard, 69008 Lyon, France; and †Research Program in Molecular Neurobiology, University of Helsinki, P.O. Box 56, Viikki Biocenter, FIN-00014, Helsinki, Finland Edited by Hans Thoenen, Max Planck Institute of Neurobiology, Martinsried, Germany, and approved June 21, 2007 (received for review February 9, 2007) The TrkC/NT-3 receptor/ligand pair is believed to be part of the neuron migration or localization during the development of the classic neurotrophic theory claiming that neuronal death occurs by nervous system and to inhibit tumor growth in adult. This activity default when neurotrophic factors become limited, through loss of has been exemplified in vivo with the dependence receptor survival signals. Here, we show that TrkC is a dependence receptor Patched and the survival of neuroepithelial cells in the devel- and, as such, induces caspase-dependent apoptotic death in the oping spinal cord (4) as well as for the netrin-1 receptors DCC absence of NT-3 in immortalized cells, a proapoptotic activity and/or UNC5H in colorectal tumorigenesis (5). Here, we pro- inhibited by the presence of NT-3. This proapoptotic activity of TrkC vide evidence that the protein tyrosine kinase receptor TrkC, a relies on the caspase-mediated cleavage of the intracellular domain main cognate receptor for NT-3, is also a dependence receptor. -
Serial Profiling of Cell-Free DNA and Nucleosome Histone Modifications
www.nature.com/scientificreports OPEN Serial profling of cell‑free DNA and nucleosome histone modifcations in cell cultures Vida Ungerer1,3, Abel J. Bronkhorst1,3, Priscilla Van den Ackerveken2, Marielle Herzog2 & Stefan Holdenrieder1* Recent advances in basic research have unveiled several strategies for improving the sensitivity and specifcity of cell‑free DNA (cfDNA) based assays, which is a prerequisite for broadening its clinical use. Included among these strategies is leveraging knowledge of both the biogenesis and physico‑chemical properties of cfDNA towards the identifcation of better disease‑defning features and optimization of methods. While good progress has been made on this front, much of cfDNA biology remains uncharted. Here, we correlated serial measurements of cfDNA size, concentration and nucleosome histone modifcations with various cellular parameters, including cell growth rate, viability, apoptosis, necrosis, and cell cycle phase in three diferent cell lines. Collectively, the picture emerged that temporal changes in cfDNA levels are rather irregular and not the result of constitutive release from live cells. Instead, changes in cfDNA levels correlated with intermittent cell death events, wherein apoptosis contributed more to cfDNA release in non‑cancer cells and necrosis more in cancer cells. Interestingly, the presence of a ~ 3 kbp cfDNA population, which is often deemed to originate from accidental cell lysis or active release, was found to originate from necrosis. High‑resolution analysis of this cfDNA population revealed an underlying DNA laddering pattern consisting of several oligo‑ nucleosomes, identical to those generated by apoptosis. This suggests that necrosis may contribute signifcantly to the pool of mono‑nucleosomal cfDNA fragments that are generally interrogated for cancer mutational profling. -
Curriculum Vitae
CURRICULUM VITAE Name : Prof. Devrim GOZUACIK, MD PhD Address : Koç University, School of Medicine, KUTTAM Research Center for Translational Medicine, Topkapi 34010, Istanbul, TURKEY. Phone : +90 212 467 87 00 E-mail : [email protected] Orcid ID : https://orcid.org/0000-0001-7739-2346 EDUCATION 2001, Ph.D. of Molecular Cell Biology, Paris Pasteur Institute and Paris-Sud (XI) University. 1997, M.Sc. (French D.E.A. degree) of Biochemistry, Ecole Polytechnique and Paris-Sud University. 1995, Medical doctor (MD) degree, Hacettepe University, Faculty of Medicine (in English). 1994, Research fellow, Dept. of Tumor Biology, Rotterdam Erasmus Medical Center. 1989-1995, Student researcher, Hacettepe Children’s Hospital Medical Biology Dept. and Hacettepe Oncology Institute. EMPLOYMENT June 2020-today, Professor, School of Medicine, KUTTAM Research Center for Translational Medicine, Koç University. 2018-today, Affiliate Member, Autophagy, Inflammation and Metabolism (AIM) Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, USA. 2018-today, Part-Time Senior Researcher, SUNUM Nanotechnology Research and Application Center. 2016-2020, Co-Founder and Board Member, EFSUN Nanodiagnostics Center of Excellence. 2018-2020, Professor, Molecular Biology Genetics and Bioengineering Program, Sabanci University. 2011-2018, Associate Professor, Molecular Biology Genetics and Bioengineering Program, Sabanci University. Sept. 2006-2011, Assistant Professor, Biological Sciences and Bioengineering Program, Sabanci University. 2001-2006, Postdoctoral fellow, Weizmann Institute of Science (Adi Kimchi Lab). CITATIONS AND H-INDEX 8338 citations in the Science Citation Index (SCI, Thomson-Reuters), h-index: 25. 8710 citations in Scopus, h-index: 25 13670 citations in Google Scholar, h-index: 28. 11 publications with >100 citations.