DOCSLIB.ORG

Differential Geminin Requirement for Proliferation of Thymocytes and Mature T Cells

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Differential Geminin Requirement for Proliferation of Thymocytes and Mature T Cells Differential Geminin Requirement for Proliferation of Thymocytes and Mature T Cells This information is current as Dimitris Karamitros, Panorea Kotantaki, Zoi Lygerou, of October 1, 2021. Henrique Veiga-Fernandes, Vassilis Pachnis, Dimitris Kioussis and Stavros Taraviras J Immunol 2010; 184:2432-2441; Prepublished online 27 January 2010; doi: 10.4049/jimmunol.0901983 http://www.jimmunol.org/content/184/5/2432 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/01/27/jimmunol.090198 Material 3.DC1 http://www.jimmunol.org/ References This article cites 54 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/184/5/2432.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 1, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Differential Geminin Requirement for Proliferation of Thymocytes and Mature T Cells Dimitris Karamitros,* Panorea Kotantaki,* Zoi Lygerou,† Henrique Veiga-Fernandes,‡,1 Vassilis Pachnis,x Dimitris Kioussis,‡ and Stavros Taraviras* Stem/progenitor cells coordinate proliferation and differentiation, giving rise to appropriate cell numbers of functionally specialized cells during organogenesis. In different experimental systems, Geminin was shown to maintain progenitor cells and participate in fate determination decisions and organogenesis. Although the exact mechanisms are unclear, Geminin has been postulated to influence proliferation versus differentiation decisions. To gain insight into the in vivo role of Geminin in progenitor cell division and differen- tiation,wehavegeneratedmicethatspecificallylackGemininincellsoflymphoidlineagethroughCre-mediatedrecombination.Tcells lacking Geminin expression upregulate early activation markers efficiently upon TCR stimulation in vitro and are able to enter the S phase of cell cycle, but show a marked defect in completing the cycle, leading to a large proportion of T cells accumulating in S/G2/M Downloaded from phases. Accordingly, T cells deficient in Geminin show a reduced ability to repopulate lymphopenic hosts in vivo. Contrary to expect- ations, Geminin deficiency does not alter development and differentiation of T cells in vivo. Our data suggest that Geminin is required fortheproliferationeventstakingplaceeitherinvitrouponTCRreceptoractivationorduringhomeostaticexpansion,butappearstobe redundantfortheproliferationanddifferentiationofthemajorityofprogenitorTcellpopulations. TheJournalofImmunology,2010, 184: 2432–2441. http://www.jimmunol.org/ regulated balance between proliferation and differentia- a multisubunit prereplicative complex that is essential for S-phase tion is fundamental for development, organogenesis, and onset (1). Geminin binds to the DNA licensing factor Cdt1 and in- A tissue homeostasis. To achieve this, cells must integrate hibits its function, ensuring that genome replication takes place only diverse extrinsic signals, remodel chromatin, and alter their tran- once per cell cycle (1), thereby maintaining genomic integrity (2). In scriptional profiles. Changes in chromatin organization and tran- addition, it has been shown that Geminin is expressed in neural scription must be coordinated with replication to establish or progenitor cells and is downregulated in fate-restricted precursor maintain the transcriptional profile of progeny cells. cells (3), although it participates in the control of cell fate specifi- Geminin has been implicated in proliferation-differentiation cation and progenitor cell maintenance during nervous system de- by guest on October 1, 2021 decisions through balanced interactions with multiple binding velopment through modulation of proliferation, transcription, and partners. Geminin participates in cell cycle control as a negative modification of chromatin structure (4). Ectopic overexpression of regulator of licensing, a process that precedes S-phase initiation Geminin in Xenopus embryos and Drosophila induces neural spe- and consists of the formation on origins of DNA replication of cific genes and hypertrophy of neural tissue, whereas Geminin has been shown to regulate the initiation of Sox2 expression during the establishment of the neural plate in vertebrate embryos (5–7). *Department of Pharmacology and †Department of Biology, Medical School, Uni- During eye development in Medaka, Geminin acts antagonistically versity of Patras, Rio, Patras, Greece; and ‡Division of Molecular Immunology and xDivision of Molecular Neurobiology, Medical Research Council/National Institute to Six3 homeobox-containing transcription factor, regulating the for Medical Research, The Ridgeway, London, United Kingdom balance between proliferation and differentiation. Thus, Geminin 1Current address: Immunobiology Unit, Instituto de Medicina Molecular, Faculdade overexpression leads to the reduction in eye size, exhibiting reduced de Medicina de Lisboa, Lisboa, Portugal. numbers of proliferating cells and premature induction of neuronal Received for publication June 24, 2009. Accepted for publication December 23, marker expression (8). Furthermore, it inhibits Hox transcription 2009. factor function through direct and polycomb-mediated interactions, This work was supported by research funding from the Association for International determining axial patterning during chicken embryogenesis (9). Cancer Research, United Kingdom (to S.T.) and Leukemia Research Foundation (to D. Kioussis). D. Karamitros was supported by a European Molecular Biology Orga- Interestingly, Geminin directly binds to Brg1, the catalytic subunit nization short-term fellowship (ASTF 26.00-2007) and Lady Tata Memorial Trust of the SWI/SNF complex, and reduces the ability of helix-loop- studentship. P.K. was supported by a European Molecular Biology Organization helix–type transcription factors to activate downstream target genes, short-term fellowship (ASTF 60.00-04) and a Federation of European Biochemical Societies summer fellowship. suggesting a role of Geminin in the maintenance of neuronal pro- Address correspondence and reprint requests to Dr. Dimitris Kioussis, Division of genitor cells in an undifferentiated state (10). Recently, Geminin has Molecular Immunology, Medical Research Council/National Institute for Medical Re- been shown to be involved in sustaining hematopoietic stem cells, search, The Ridgeway, London NW7 1AA, United Kingdom or Dr. Stavros Taraviras, expanding its potential role in other systems (11). Consistent with an Department of Pharmacology, Medical School, University of Patras, 26504 Rio, Patras, Greece. E-mail addresses: [email protected] and [email protected] essential role in proliferation and differentiation, mice lacking The online version of this article contains supplemental material. Geminin expression are dying during the first days of embryogen- Abbreviations used in this paper: 7-AAD, 7-aminoactinomycin D; CFSE, carboxy- esis, revealing no formation of inner cell mass (12, 13). fluorescein diacetate succinimidyl ester; DN, double-negative; DP, double-positive; We have used T cell differentiation as a model to address the role of ES, embryonic stem; Foxp3, forkhead box p3; LCR, locus control region; LN, lymph Geminin in developmental processes that require a regulated balance node; PDBU, phorbol 12,13-dibutyrate; SP, single-positive; WT, wild-type. between proliferation and differentiation. During immune system de- Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 velopment and maturation, undifferentiated hematopoietic precursor www.jimmunol.org/cgi/doi/10.4049/jimmunol.0901983 The Journal of Immunology 2433 cells originating in the bone marrow enter the thymus and give rise to allele, and DNA was amplified under the following conditions: 94˚C for 45 s, lineage-committed cells destined to become T cells (14, 15). De- 62.7˚C for 45 s, and 72˚C for 1 min (primer location is indicated in the Gem veloping thymocytes are classified into four major populations based Dex3-4 allele, Fig. 1A). Verification of the pGKNeo/tk cassette removal was established via a PCR that uses primers that anchor the neo gene (59- on the expression of two coreceptor molecules, CD4 and CD8. Double- cctgcgtgcaatccatcttgttca-39) and exon 3 of the mouse geminin gene (59-gca- negative (DN) thymocytes, lacking both CD4 and CD8 expression, are gaaggctggatcatcttcagcg-39), and DNA was amplified for 30 cycles (95˚C for the earlier progenitors and can be further subdivided into four sub- 45 s, 65˚C for 45 s, and 72˚C for 120 s). CD2Cre and PC3Cre transgenes were populations, DN1–4, based on the expression of CD44 and CD25 also detected by PCR as previously described (24, 25). To analyze excision efficiency in GemDex3-4 mice, genomic DNAwas prepared from tail, thymus, markers (16),
Load more

Recommended publications
  • Present Post: Previous Positions Held: Honors/Awards Membership In
    CURRICULUM VITAE Name: Vassilis Pachnis, M.D., Ph.D., FMedSci Date of Birth: 24 January 1953 Place of Birth: Athens, Greece Contact details: National Institute for Medical Research Institute of Molecular Biology and Biotechnology The Ridgeway, Mill Hill, Foundation for Research and Technology‐Hellas London NW7 1AA, UK. N. Plastira 100, GR‐70013, Heraklion, Greece tel. (+44) 02088162113 Tel. (+30) 2810391100 email: [email protected] Email: [email protected] Education: July 1980 University of Athens Medical School (Athens, Greece) M.D. magna cum laude June 1986 University of Pennsylvania, Philadelphia, PA (USA) Degree: Ph.D., Genetics Supervisor: Prof. Shirley Tilghman Nov 1986 – Mar 1988 Howard Hughes Medical Institute Center for Neurobiology and Behavior Columbia University, New York, NY (USA) Postdoctoral Fellow in Prof. Richard Axel's laboratory Apr 1988 – May 1991 Department of Genetics and Development Columbia University, New York, NY (USA) Postdoctoral fellow in Dr. Frank Costantini's laboratory Present Post: ‐ Head of Division of Molecular Neurobiology, National Institute for Medical Research, Medical Research Council (London, UK) ‐ Director of the Institute of Molecular Biology and Biotechnology of the Foundation for Research and Technology‐Hellas (Heraklion, Greece) Previous positions held: May 1991 – Feb 1997 Senior Scientific Staff, Group Leader, MRC National Institute for Medical Research, London (5/91‐2/97) Feb 1997 – Aug 2000 Tenured Senior Scientist, MRC National Institute for Medical Research, London Honors/Awards ‐ Scholarship from the National Scholarship Foundation of Greece for Academic excellence in Medical School ‐ Special Fellowship Award from the Leukemia Society of America (Jul 1989‐May 1991) ‐ Janssen Award for Life Time Achievement in Gastroenterology (2002) Membership in Academies ‐ Elected Fellow of the Academy of Medical Sciences, UK (2000).
    [Show full text]
  • Geminin Prevents DNA Damage in Vagal Neural Crest Cells to Ensure Normal Enteric Neurogenesis Chrysoula Konstantinidou1,3, Stavros Taraviras2* and Vassilis Pachnis1*
    Konstantinidou et al. BMC Biology (2016) 14:94 DOI 10.1186/s12915-016-0314-x RESEARCH ARTICLE Open Access Geminin prevents DNA damage in vagal neural crest cells to ensure normal enteric neurogenesis Chrysoula Konstantinidou1,3, Stavros Taraviras2* and Vassilis Pachnis1* Abstract Background: In vertebrate organisms, the neural crest (NC) gives rise to multipotential and highly migratory progenitors which are distributed throughout the embryo and generate, among other structures, the peripheral nervous system, including the intrinsic neuroglial networks of the gut, i.e. the enteric nervous system (ENS). The majority of enteric neurons and glia originate from vagal NC-derived progenitors which invade the foregut mesenchyme and migrate rostro-caudally to colonise the entire length of the gut. Although the migratory behaviour of NC cells has been studied extensively, it remains unclear how their properties and response to microenvironment change as they navigate through complex cellular terrains to reach their target embryonic sites. Results: Using conditional gene inactivation in mice we demonstrate here that the cell cycle-dependent protein Geminin (Gem) is critical for the survival of ENS progenitors in a stage-dependent manner. Gem deletion in early ENS progenitors (prior to foregut invasion) resulted in cell-autonomous activation of DNA damage response and p53-dependent apoptosis, leading to severe intestinal aganglionosis. In contrast, ablation of Gem shortly after ENS progenitors had invaded the embryonic gut did not result in discernible survival or migratory deficits. In contrast to other developmental systems, we obtained no evidence for a role of Gem in commitment or differentiation of ENS lineages. The stage-dependent resistance of ENS progenitors to mutation-induced genotoxic stress was further supported by the enhanced survival of post gut invasion ENS lineages to γ-irradiation relative to their predecessors.
    [Show full text]
  • Linking Neurons to Immunity: Lessons from Hydra COMMENTARY Yuuki Obataa and Vassilis Pachnisa,1
    COMMENTARY Linking neurons to immunity: Lessons from Hydra COMMENTARY Yuuki Obataa and Vassilis Pachnisa,1 According to the Greek mythology (1), Heracles’ sec- Hydra offers unique advantages to neuroscience re- ond labor was the destruction of the Lernaean Hydra, search as well. Its nervous system is an anatomically a fearsome fire-breathing monster with a dog-like simple network of sensory and ganglion neurons body and nine snake heads. Many had tried to slay that control a range of behaviors, including sponta- the Lernaean Hydra but in vain: Any head that was neous body contractions (5, 6). Remarkably, the an- cut off regrew and multiplied. It is remarkable how atomical organization and functional output of consistent the narrative of this myth is with our recent Hydra’s nervous system are reminiscent of the intrin- understanding of tissue and organ regeneration. Her- sic neural networks of the gastrointestinal tract in acles was successful not only because of his divine vertebrates, known as the enteric nervous system origin (he was the son of Zeus after all) and the help (ENS). The ENS is an assembly of nerve cells within of Athena, but particularly because of the assistance the gut wall, which are organized into the ganglia he received from his nephew Iolaus, who was assigned of the myenteric and submucosal plexus (7) and regu- the job of cauterizing the exposed stumps of the Hy- late most intestinal functions, including coordination of dra’s severed heads. Of course, we now understand smooth muscle contractions, the basis of intestinal why Iolaus’ contribution was so critical: His flame con- peristalsis (8).
    [Show full text]
  • EMBC Annual Report 2007
    EMBO | EMBC annual report 2007 EUROPEAN MOLECULAR BIOLOGY ORGANIZATION | EUROPEAN MOLECULAR BIOLOGY CONFERENCE EMBO | EMBC table of contents introduction preface by Hermann Bujard, EMBO 4 preface by Tim Hunt and Christiane Nüsslein-Volhard, EMBO Council 6 preface by Marja Makarow and Isabella Beretta, EMBC 7 past & present timeline 10 brief history 11 EMBO | EMBC | EMBL aims 12 EMBO actions 2007 15 EMBC actions 2007 17 EMBO & EMBC programmes and activities fellowship programme 20 courses & workshops programme 21 young investigator programme 22 installation grants 23 science & society programme 24 electronic information programme 25 EMBO activities The EMBO Journal 28 EMBO reports 29 Molecular Systems Biology 30 journal subject categories 31 national science reviews 32 women in science 33 gold medal 34 award for communication in the life sciences 35 plenary lectures 36 communications 37 European Life Sciences Forum (ELSF) 38 ➔ 2 table of contents appendix EMBC delegates and advisers 42 EMBC scale of contributions 49 EMBO council members 2007 50 EMBO committee members & auditors 2007 51 EMBO council members 2008 52 EMBO committee members & auditors 2008 53 EMBO members elected in 2007 54 advisory editorial boards & senior editors 2007 64 long-term fellowship awards 2007 66 long-term fellowships: statistics 82 long-term fellowships 2007: geographical distribution 84 short-term fellowship awards 2007 86 short-term fellowships: statistics 104 short-term fellowships 2007: geographical distribution 106 young investigators 2007 108 installation
    [Show full text]
  • Investigation of the Interplay Between SKP2, CDT1 and Geminin in Cancer Cells
    1 Investigation of the interplay between SKP2, CDT1 and Geminin in cancer cells 2 3 Andrea Ballabeni¶*, Raffaella Zamponi§ 4 5 ¶Department of Systems Biology, Harvard Medical School, Boston, MA, USA 6 (Current affiliation: Harvard School of Public Health, Boston, MA, USA) s 7 t n i 8 §Department of Experimental Oncology, European Institute of Oncology, Milan, Italy r P 9 (Current affiliation: Novartis Institutes of Biomedical research, Cambridge, MA, USA) e r 10 P 11 *Corresponding author E-mail: [email protected], [email protected] 12 13 Abstract 14 Geminin has a dual role in the regulation of DNA replication: it inhibits replication factor CDT1 15 activity during the G2 phase of the cell cycle and promotes its accumulation at the G2/M 16 transition. In this way Geminin prevents DNA re-replication during G2 phase and ensures that 17 DNA replication is efficiently executed in the next S phase. CDT1 was shown to associate with 18 SKP2, the substrate recognition factor of the SCF ubiquitin ligase complex. We investigated the 19 interplay between these three proteins in cancer cell lines. We show that Geminin, CDT1 and 20 SKP2 could possibly form a complex and propose the putative regions of CDT1 and Geminin 21 involved in the binding. We also show that, despite the physical interaction, SKP2 depletion does 22 not substantially affect CDT1 and Geminin protein levels. Moreover, we show that while 1 PeerJ PrePrints | http://dx.doi.org/10.7287/peerj.preprints.794v1 | CC-BY 4.0 Open Access | rec: 16 Jan 2015, publ: 16 Jan 2015 1 Geminin and CDT1 levels fluctuate, SKP2 levels, differently than in normal cells, are almost 2 steady during the cell cycle of the tested cancer cells.
    [Show full text]
  • EMBO Facts & Figures
    excellence in life sciences Reykjavik Helsinki Oslo Stockholm Tallinn EMBO facts & figures & EMBO facts Copenhagen Dublin Amsterdam Berlin Warsaw London Brussels Prague Luxembourg Paris Vienna Bratislava Budapest Bern Ljubljana Zagreb Rome Madrid Ankara Lisbon Athens Jerusalem EMBO facts & figures HIGHLIGHTS CONTACT EMBO & EMBC EMBO Long-Term Fellowships Five Advanced Fellows are selected (page ). Long-Term and Short-Term Fellowships are awarded. The Fellows’ EMBO Young Investigators Meeting is held in Heidelberg in June . EMBO Installation Grants New EMBO Members & EMBO elects new members (page ), selects Young EMBO Women in Science Young Investigators Investigators (page ) and eight Installation Grantees Gerlind Wallon EMBO Scientific Publications (page ). Programme Manager Bernd Pulverer S Maria Leptin Deputy Director Head A EMBO Science Policy Issues report on quotas in academia to assure gender balance. R EMBO Director + + A Conducts workshops on emerging biotechnologies and on H T cognitive genomics. Gives invited talks at US National Academy E IC of Sciences, International Summit on Human Genome Editing, I H 5 D MAN 201 O N Washington, DC.; World Congress on Research Integrity, Rio de A M Janeiro; International Scienti c Advisory Board for the Centre for Eilish Craddock IT 2 015 Mammalian Synthetic Biology, Edinburgh. Personal Assistant to EMBO Fellowships EMBO Scientific Publications EMBO Gold Medal Sarah Teichmann and Ido Amit receive the EMBO Gold the EMBO Director David del Álamo Thomas Lemberger Medal (page ). + Programme Manager Deputy Head EMBO Global Activities India and Singapore sign agreements to become EMBC Associate + + Member States. EMBO Courses & Workshops More than , participants from countries attend 6th scienti c events (page ); participants attend EMBO Laboratory Management Courses (page ); rst online course EMBO Courses & Workshops recorded in collaboration with iBiology.
    [Show full text]
  • Geminin-Deficient Neural Stem Cells Exhibit Normal Cell Division and Normal Neurogenesis
    Geminin-Deficient Neural Stem Cells Exhibit Normal Cell Division and Normal Neurogenesis Kathryn M. Schultz1,2, Ghazal Banisadr4., Ruben O. Lastra1,2., Tammy McGuire5, John A. Kessler5, Richard J. Miller4, Thomas J. McGarry1,2,3* 1 Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America, 2 Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America, 3 Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America, 4 Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America, 5 Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America Abstract Neural stem cells (NSCs) are the progenitors of neurons and glial cells during both embryonic development and adult life. The unstable regulatory protein Geminin (Gmnn) is thought to maintain neural stem cells in an undifferentiated state while they proliferate. Geminin inhibits neuronal differentiation in cultured cells by antagonizing interactions between the chromatin remodeling protein Brg1 and the neural-specific transcription factors Neurogenin and NeuroD. Geminin is widely expressed in the CNS during throughout embryonic development, and Geminin expression is down-regulated when neuronal precursor cells undergo terminal differentiation. Over-expression of Geminin in gastrula-stage Xenopus embryos can expand the size of the neural plate. The role of Geminin in regulating vertebrate neurogenesis in vivo has not been rigorously examined. To address this question, we created a strain of Nestin-Cre/Gmnnfl/fl mice in which the Geminin gene was specifically deleted from NSCs.
    [Show full text]
  • Geminin Deploys Multiple Mechanisms to Regulate Cdt1 Before Cell Division Thus Ensuring the Proper Execution of DNA Replication
    Geminin deploys multiple mechanisms to regulate Cdt1 before cell division thus ensuring the proper execution of DNA replication Andrea Ballabenia, Raffaella Zamponib, Jodene K. Moorea, Kristian Helinc,d, and Marc W. Kirschnera,1 aDepartment of Systems Biology, Harvard Medical School, Boston, MA 02115; bNovartis Institutes for Biomedical Research, Cambridge, MA 02139; cBiotech Research and Innovation Centre and dCentre for Epigenetics, University of Copenhagen, 2200 Copenhagen, Denmark Contributed by Marc W. Kirschner, June 7, 2013 (sent for review March 4, 2013) Cdc10-dependent transcript 1 (Cdt1) is an essential DNA replication the initiation of S phase and its duration. We show that although protein whose accumulation at the end of the cell cycle promotes Cdt1 protein accumulates in G2 phase, it still turns over very the formation of pre-replicative complexes and replication in the quickly and that to produce high Cdt1 levels when cells exit next cell cycle. Geminin is thought to be involved in licensing rep- mitosis into G1, the accumulation in G2 must overcome degra- lication by promoting the accumulation of Cdt1 in mitosis, because dation. This regulation is a product of Geminin’s positive regu- decreasing the Geminin levels prevents Cdt1 accumulation and lation of Cdt1 protein and RNA in the preceding G2 phase. impairs DNA replication. Geminin is known to inhibit Cdt1 func- Degradation of Cdt1 is not a consequence of DNA damage, be- tion; its depletion during G2 leads to DNA rereplication and check- cause Cdt1 levels decrease upon Geminin depletion even in point activation. Here we show that, despite rapid Cdt1 protein presence of inhibitors of DNA synthesis.
    [Show full text]
  • Quaternary Structure of the Human Cdt1-Geminin Complex Regulates DNA Replication Licensing
    Quaternary structure of the human Cdt1-Geminin complex regulates DNA replication licensing V. De Marcoa,1, P. J. Gillespieb,2,A.Lib,2,3, N. Karantzelisc, E. Christodouloua,1, R. Klompmakerd, S. van Gerwena, A. Fisha, M. V. Petoukhove, M. S. Iliouf,4, Z. Lygerouf, R. H. Medemad, J. J. Blowb,5, D. I. Svergune, S. Taravirasc, and A. Perrakisa,5 aDepartment of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands; bWellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom; Departments of cPharmacology and fBiology, Medical School, University of Patras, 26500 Rio, Patras, Greece; dDepartment of Medical Oncology and Cancer Genomics Center, Laboratory of Experimental Oncology, University Medical Center Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands; and eEuropean Molecular Biology Laboratory, Hamburg Outstation, Notkestrasse 85, D-22603 Hamburg, Germany Edited by John Kuriyan, University of California, Berkeley, CA, and approved October 2, 2009 (received for review May 14, 2009) All organisms need to ensure that no DNA segments are rerepli- the remainder becomes inactivated and incapable of inhibiting Cdt1 cated in a single cell cycle. Eukaryotes achieve this through a (16–18). The remaining Geminin gets reactivated in the next cell process called origin licensing, which involves tight spatiotemporal cycle, through a mechanism that is not well understood, but is control of the assembly of prereplicative complexes (pre-RCs) onto dependent on the nuclear import of Geminin, which restores its chromatin. Cdt1 is a key component and crucial regulator of pre-RC ability to block Cdt1 (16, 19, 20).
    [Show full text]
  • PROGRAMME & Book of Abstracts
    PROGRAMME & book of abstracts “. MOVING FORWARD TOGETHER” www.EDBC2019Alicante.com ORGANISED BY CONTENTS SPONSORS & COLLABORATORS ORGANIZATION .......................................................................... 4 GENERAL INFORMATION ......................................................... 5 INSTRUCTIONS FOR SPEAKERS AND AUTHORS ................ 8 CONGRESS TIMETABLE ............................................................ 9 SCIENTIFIC PROGRAMME WEDNESDAY 23 .................................................................... 12 THURSDAY 24 ........................................................................ 13 FRIDAY 25 ............................................................................... 16 SATURDAY 26 ........................................................................ 19 POSTER SESSIONS ................................................................... 21 EXHIBITORS AND SPONSORS ................................................ 48 ABSTRACTS ................................................................................ 51 AUTHORS’ INDEX ...................................................................... 263 4 EDBC2019 EDBC2019 5 ORGANIZATION GENERAL INFORMATION ORGANIZING COMMITTEE INVITED SPEAKERS VENUE Ángela Nieto. Alicante Enrique Amaya. Manchester Auditorio de la Diputación de Alicante - ADDA Víctor Borrell. Alicante Detlev Arendt. Heidelberg Paseo Campoamor, s/n Sergio Casas-Tintó. Madrid Laure Bally Cuif. Paris 03010 Alicante, Spain Pilar Cubas. Madrid Fernando Casares. Sevilla www.addaalicante.es
    [Show full text]
  • Geminin Deficiency Enhances Survival in a Murine Medulloblastoma Model by Inducing Apoptosis of Preneoplastic Granule Neuron Precursors
    www.impactjournals.com/Genes&Cancer Genes & Cancer, Vol. 8 (9-10), September 2017 Geminin deficiency enhances survival in a murine medulloblastoma model by inducing apoptosis of preneoplastic granule neuron precursors Savita Sankar1, Ethan Patterson1, Emily M. Lewis1, Laura E. Waller1, Caili Tong1, Joshua Dearborn2, David Wozniak2, Joshua B. Rubin3, Kristen L. Kroll1 1 Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO, USA 2 Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA 3 Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA Correspondence to: Kristen L. Kroll, email: [email protected] Keywords: neural, medulloblastoma, cerebellum, DNA replication, apoptosis Received: September 15, 2017 Accepted: November 03, 2017 Published: November 12, 2017 Copyright: Sankar et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Abstract ABSTRACT Medulloblastoma is the most common malignant brain cancer of childhood. Further understanding of tumorigenic mechanisms may define new therapeutic targets. Geminin maintains genome fidelity by controlling re-initiation of DNA replication within a cell cycle. In some contexts, Geminin inhibition induces cancer-selective cell cycle arrest and apoptosis and/or sensitizes cancer cells to Topoisomerase IIα inhibitors such as etoposide, which is used in combination chemotherapies for medulloblastoma. However, Geminin’s potential role in medulloblastoma tumorigenesis remained undefined. Here, we found that Geminin is highly expressed in human and mouse medulloblastomas and in murine granule neuron precursor (GNP) cells during cerebellar development.
    [Show full text]
  • Control of Eukaryotic DNA Replication Initiation—Mechanisms to Ensure Smooth Transitions
    G C A T T A C G G C A T genes Review Control of Eukaryotic DNA Replication Initiation—Mechanisms to Ensure Smooth Transitions Karl-Uwe Reusswig and Boris Pfander * Max Planck Institute of Biochemistry, DNA Replication and Genome Integrity, 82152 Martinsried, Germany; [email protected] * Correspondence: [email protected] Received: 31 December 2018; Accepted: 25 January 2019; Published: 29 January 2019 Abstract: DNA replication differs from most other processes in biology in that any error will irreversibly change the nature of the cellular progeny. DNA replication initiation, therefore, is exquisitely controlled. Deregulation of this control can result in over-replication characterized by repeated initiation events at the same replication origin. Over-replication induces DNA damage and causes genomic instability. The principal mechanism counteracting over-replication in eukaryotes is a division of replication initiation into two steps—licensing and firing—which are temporally separated and occur at distinct cell cycle phases. Here, we review this temporal replication control with a specific focus on mechanisms ensuring the faultless transition between licensing and firing phases. Keywords: DNA replication; DNA replication initiation; cell cycle; post-translational protein modification; protein degradation; cell cycle transitions 1. Introduction DNA replication control occurs with exceptional accuracy to keep genetic information stable over as many as 1016 cell divisions (estimations based on [1]) during, for example, an average human lifespan. A fundamental part of the DNA replication control system is dedicated to ensure that the genome is replicated exactly once per cell cycle. If this control falters, deregulated replication initiation occurs, which leads to parts of the genome becoming replicated more than once per cell cycle (reviewed in [2–4]).
    [Show full text]