The Structure and Conformational Switching of Rap1b
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Transcriptional Control of Tissue-Resident Memory T Cell Generation
Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2019 © 2019 Filip Cvetkovski All rights reserved ABSTRACT Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Tissue-resident memory T cells (TRM) are a non-circulating subset of memory that are maintained at sites of pathogen entry and mediate optimal protection against reinfection. Lung TRM can be generated in response to respiratory infection or vaccination, however, the molecular pathways involved in CD4+TRM establishment have not been defined. Here, we performed transcriptional profiling of influenza-specific lung CD4+TRM following influenza infection to identify pathways implicated in CD4+TRM generation and homeostasis. Lung CD4+TRM displayed a unique transcriptional profile distinct from spleen memory, including up-regulation of a gene network induced by the transcription factor IRF4, a known regulator of effector T cell differentiation. In addition, the gene expression profile of lung CD4+TRM was enriched in gene sets previously described in tissue-resident regulatory T cells. Up-regulation of immunomodulatory molecules such as CTLA-4, PD-1, and ICOS, suggested a potential regulatory role for CD4+TRM in tissues. Using loss-of-function genetic experiments in mice, we demonstrate that IRF4 is required for the generation of lung-localized pathogen-specific effector CD4+T cells during acute influenza infection. Influenza-specific IRF4−/− T cells failed to fully express CD44, and maintained high levels of CD62L compared to wild type, suggesting a defect in complete differentiation into lung-tropic effector T cells. -
S41467-020-18249-3.Pdf
ARTICLE https://doi.org/10.1038/s41467-020-18249-3 OPEN Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain Lei Zhao1,2,17, Zhongqi Li 1,2,17, Joaquim S. L. Vong2,3,17, Xinyi Chen1,2, Hei-Ming Lai1,2,4,5,6, Leo Y. C. Yan1,2, Junzhe Huang1,2, Samuel K. H. Sy1,2,7, Xiaoyu Tian 8, Yu Huang 8, Ho Yin Edwin Chan5,9, Hon-Cheong So6,8, ✉ ✉ Wai-Lung Ng 10, Yamei Tang11, Wei-Jye Lin12,13, Vincent C. T. Mok1,5,6,14,15 &HoKo 1,2,4,5,6,8,14,16 1234567890():,; The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovas- cular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation- dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which pro- minently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood–brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed tran- scriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible. -
Molecular Associations and Clinical Significance of Raps In
ORIGINAL RESEARCH published: 21 June 2021 doi: 10.3389/fmolb.2021.677979 Molecular Associations and Clinical Significance of RAPs in Hepatocellular Carcinoma Sarita Kumari 1†, Mohit Arora 2†, Jay Singh 1, Lokesh K. Kadian 2, Rajni Yadav 3, Shyam S. Chauhan 2* and Anita Chopra 1* 1Laboratory Oncology Unit, Dr. BRA-IRCH, All India Institute of Medical Sciences, New Delhi, India, 2Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India, 3Department of Pathology, All India Institute of Medical Sciences, New Delhi, India Hepatocellular carcinoma (HCC) is an aggressive gastrointestinal malignancy with a high rate of mortality. Multiple studies have individually recognized members of RAP gene family as critical regulators of tumor progression in several cancers, including hepatocellular carcinoma. These studies suffer numerous limitations including a small sample size and lack of analysis of various clinicopathological and molecular Edited by: Veronica Aran, features. In the current study, we utilized authoritative multi-omics databases to Instituto Estadual do Cérebro Paulo determine the association of RAP gene family expression and detailed molecular and Niemeyer (IECPN), Brazil clinicopathological features in hepatocellular carcinoma (HCC). All five RAP genes Reviewed by: were observed to harbor dysregulated expression in HCC compared to normal liver Pooja Panwalkar, Weill Cornell Medicine, United States tissues. RAP2A exhibited strongest ability to differentiate tumors from the normal Jasminka Omerovic, tissues. RAP2A expression was associated with progressive tumor grade, TP53 and University of Split, Croatia CTNNB1 mutation status. Additionally, RAP2A expression was associated with the *Correspondence: Anita Chopra alteration of its copy numbers and DNA methylation. RAP2A also emerged as an [email protected] independent marker for patient prognosis. -
Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement. -
Double Minute Chromosomes in Glioblastoma Multiforme Are Revealed by Precise Reconstruction of Oncogenic Amplicons
Published OnlineFirst August 12, 2013; DOI: 10.1158/0008-5472.CAN-13-0186 Cancer Tumor and Stem Cell Biology Research Double Minute Chromosomes in Glioblastoma Multiforme Are Revealed by Precise Reconstruction of Oncogenic Amplicons J. Zachary Sanborn1,2,Sofie R. Salama2,3, Mia Grifford2, Cameron W. Brennan4, Tom Mikkelsen6, Suresh Jhanwar5, Sol Katzman2, Lynda Chin7, and David Haussler2,3 Abstract DNA sequencing offers a powerful tool in oncology based on the precise definition of structural rearrange- ments and copy number in tumor genomes. Here, we describe the development of methods to compute copy number and detect structural variants to locally reconstruct highly rearranged regions of the tumor genome with high precision from standard, short-read, paired-end sequencing datasets. We find that circular assemblies are the most parsimonious explanation for a set of highly amplified tumor regions in a subset of glioblastoma multiforme samples sequenced by The Cancer Genome Atlas (TCGA) consortium, revealing evidence for double minute chromosomes in these tumors. Further, we find that some samples harbor multiple circular amplicons and, in some cases, further rearrangements occurred after the initial amplicon-generating event. Fluorescence in situ hybridization analysis offered an initial confirmation of the presence of double minute chromosomes. Gene content in these assemblies helps identify likely driver oncogenes for these amplicons. RNA-seq data available for one double minute chromosome offered additional support for our local tumor genome assemblies, and identified the birth of a novel exon made possible through rearranged sequences present in the double minute chromosomes. Our method was also useful for analysis of a larger set of glioblastoma multiforme tumors for which exome sequencing data are available, finding evidence for oncogenic double minute chromosomes in more than 20% of clinical specimens examined, a frequency consistent with previous estimates. -
'Hrap1b-Retro: a Novel Human Processed Rap1b Gene
Letters to the Editor 146 Figure 1 The hRap1B-retro gene is localized on chromosome 5 q13.3. Upper part: summary of differences in the sequence alignment between hRap1B-retro and hRap1B cDNAs and the corresponding genomic regions on the 5th and 12th chromosomes. In addition to the three nucleotide substitutions in the open reading frame (ORF), seven more differences between both genes are present in the untranslated regions (UTRs). The coordinates above the sequences are relative to the start codon ATG in hRap1B cDNA (GI: 58219793). hRap1B-r_Ram1-3: full-length cDNAs of hRap1B-retro from Ramos cell line (GIs: 50475494, 50474682, 50470789); hRap1B-r_Neur: full-length cDNA of hRap1B-retro from neuroblastoma (GI: 50498405); hRap1B-r_Plac: full-length cDNA of hRap1B-retro from placenta (GI: 50492447). 5chr: genomic DNA sequence from chromosome 5 (GI: 51465008: 26064529–26060269), 12chr: genomic DNA sequence from chromosome 12 (GI: 29803948: 31147958– 31197631). Lower part: exonic structure of the hRap1B-retro and hRap1B mother genes mapped onto their cDNAs. Numbering stands for exon numbers. shown to transform NIH 3T3 cells oncogenically.2 In this light, a 4Department of Physiological Chemistry and the Centre for better expression profiling of the hRap1B-retro gene identified Biomedical Genetics, University Medical Centre Utrecht, by us will help to validate whether it defines a novel drug target. CG Utrecht, The Netherlands E-mail: [email protected] Acknowledgements TZ thanks Professor Martin Vingron for the helpful discussions and References support. TZ acknowledges support received from the BioSapiens Network of Excellence, funded by the European Commission 1 Gyan E, Frew M, Bowen D, Beldjord C, Preudhomme C, Lacombe C within its FP6 Programme, under the thematic area ‘Life sciences, et al. -
Hrap1b-Retro: a Novel Human Processed Rap1b Gene Blurs the Picture?
Letters to the Editor 145 human and mouse P-gp efflux capacity for imatinib, it is clear 2 Rumpold H, Wolf AM, Gruenewald K, Gastl G, Gunsilius E, Wolf D. that imatinib is an in vivo substrate for mouse P-gp.7,8 RNAi-mediated knockdown of P-glycoprotein using a transposon- We believe the differences in imatinib resistance seen when based vector system durably restores imatinib sensitivity in imatinib- comparing the K562 data by Rumpold et al. with our data in resistant CML cell lines. Exp Hematol 2005; 33: 767–775. 3 Zong Y, Zhou S, Sorrentino BP. Loss of P-glycoprotein expression in P-gp null mice is best explained by the possibility that CML stem hematopoietic stem cells does not improve responses to imatinib in cells express other ABC transporters that may provide a a murine model of chronic myelogenous leukemia. Leukemia 2005; redundant efflux mechanism for imatinib. The lack of expression 19: 1590–1596. of these compensatory transporters in K562 cells could therefore 4 Ferrao PT, Frost MJ, Siah SP, Ashman LK. Overexpression of explain the sensitizing effect of decreased expression of P-gp in P-glycoprotein in K562 cells does not confer resistance to the K562 cells. For instance, we have shown that K562 cells do not growth inhibitory effects of imatinib (STI571) in vitro. Blood 2003; 102: 4499–4503. express ABCG2 (unpublished data) while primary hematopoietic 5 Lange T, Gunther C, Kohler T, Krahl R, Musiol S, Leiblein S et al. 9 stem cells express significant levels. Therefore, we stand by our High levels of BAX, low levels of MRP-1, and high platelets are conclusion that the use of selective P-gp inhibitors to sensitize independent predictors of response to imatinib in myeloid blast CML stem cells to imatinib is not likely to be clinically useful. -
The Expression of RUNDC3B Is Associated with Promoter Methylation in Lymphoid Malignancies
The expression of RUNDC3B is associated with promoter methylation in lymphoid malignancies Running Head: Epigenetic regulation of RUNDC3B Keywords: RUNDC3B, DNA methylation, lymphoma, leukemia, B-cell, gene expression Dane W. Burmeister1, Emily H. Smith1,2, Robert T. Cristel1, Stephanie D. McKay1,3, Huidong Shi4, Gerald L. Arthur1, J. Wade Davis5,6, and Kristen H. Taylor1,* 1Department of Pathology and Anatomical Sciences; University of Missouri; Columbia, MO USA; 2Department of Dermatology; University of Michigan Health System; Ann Arbor, MI USA; 3Department of Animal Science; University of Vermont; Burlington, VT USA; 4Department of Biochemistry and Molecular Biology; Georgia Regents University; Augusta, GA USA; 5Department of Health Management and Informatics; University of Missouri; Columbia, MO USA; 6Department of Statistics; University of Missouri, Columbia, MO USA *Corresponding author: Kristen H. Taylor PhD Department of Pathology and Anatomical Sciences One Hospital Drive University of Missouri-Columbia Columbia, Missouri 65212 USA E-mail: [email protected] Telephone: 573-882-5523 FAX: 573-884-4612 This work was supported by a National Institute of Health grant NCI R00 CA132784 (K.H. Taylor) No potential conflicts exist for the authors of this manuscript. Word Count: 2991 This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/HON.2238 1 This article is protected by copyright. All rights reserved. Abstract DNA methylation is an epigenetic modification that plays an important role in regulation of gene expression. -
Structural Analysis of Autoinhibition in the Ras-Specific Exchange Factor
RESEARCH ARTICLE elife.elifesciences.org Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1 Jeffrey S Iwig1,2, Yvonne Vercoulen3†, Rahul Das1,2†, Tiago Barros1,2,4, Andre Limnander3, Yan Che1,2, Jeffrey G Pelton2, David E Wemmer2,5,6, Jeroen P Roose3*, John Kuriyan1,2,4,5,6* 1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; 2California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; 3Department of Anatomy, University of California, San Francisco, San Francisco, United States; 4Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; 5Department of Chemistry, University of California, Berkeley, Berkeley, United States; 6Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, United States Abstract RasGRP1 and SOS are Ras-specific nucleotide exchange factors that have distinct roles in lymphocyte development. RasGRP1 is important in some cancers and autoimmune diseases but, in contrast to SOS, its regulatory mechanisms are poorly understood. Activating signals lead to the membrane recruitment of RasGRP1 and Ras engagement, but it is unclear how interactions between RasGRP1 and Ras are suppressed in the absence of such signals. We present a crystal structure of a fragment of RasGRP1 in which the Ras-binding site is blocked by an interdomain linker and the membrane-interaction surface of RasGRP1 is hidden within a dimerization interface that may be stabilized by the C-terminal oligomerization domain. NMR data demonstrate that calcium binding to the regulatory module generates substantial conformational changes that are incompatible with the inactive assembly. These features allow RasGRP1 to be maintained in an inactive state that is poised for activation by calcium and membrane-localization signals. -
UC San Diego UC San Diego Electronic Theses and Dissertations
UC San Diego UC San Diego Electronic Theses and Dissertations Title Insights from reconstructing cellular networks in transcription, stress, and cancer Permalink https://escholarship.org/uc/item/6s97497m Authors Ke, Eugene Yunghung Ke, Eugene Yunghung Publication Date 2012 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, SAN DIEGO Insights from Reconstructing Cellular Networks in Transcription, Stress, and Cancer A dissertation submitted in the partial satisfaction of the requirements for the degree Doctor of Philosophy in Bioinformatics and Systems Biology by Eugene Yunghung Ke Committee in charge: Professor Shankar Subramaniam, Chair Professor Inder Verma, Co-Chair Professor Web Cavenee Professor Alexander Hoffmann Professor Bing Ren 2012 The Dissertation of Eugene Yunghung Ke is approved, and it is acceptable in quality and form for the publication on microfilm and electronically ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ Co-Chair ________________________________________________________________ Chair University of California, San Diego 2012 iii DEDICATION To my parents, Victor and Tai-Lee Ke iv EPIGRAPH [T]here are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there -
The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma
Author Manuscript Published OnlineFirst on August 3, 2016; DOI: 10.1158/0008-5472.CAN-16-0658 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. The genomic landscape of pancreatic and periampullary adenocarcinoma Vandana Sandhu1,8, David C Wedge2,11, Inger Marie Bowitz Lothe1,3, Knut Jørgen Labori4, Stefan C Dentro2,11, Trond Buanes4,5, Martina L Skrede1, Astrid M Dalsgaard1, Else Munthe6, Ola Myklebost6, Ole Christian Lingjærde7, Anne-Lise Børresen-Dale1,5, Tone Ikdahl9,10, Peter Van Loo12,13, Silje Nord1, Elin H Kure1,8* 1Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway 2Wellcome Trust Sanger Institute, Hinxton, UK 3Department of Pathology, Oslo University Hospital, Oslo, Norway 4Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway 5Institute of Clinical Medicine, University of Oslo, Oslo, Norway 6Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway 7Department of Computer Science, University of Oslo, Oslo, Norway 8Department for Environmental Health and Science, University college of Southeast Norway, Bø in Telemark, Norway 9Department of Oncology, Oslo University Hospital, Oslo, Norway 10Akershus University Hospital, Nordbyhagen, Norway 11Department of Cancer Genomics, Big Data Institute, University of Oxford, Oxford, UK 12The Francis Crick Institute, London, UK 13Department of Human Genetics, University of Leuven, Leuven, Belgium *Corresponding author: Elin H. Kure, [email protected] Running title: Copy number aberrations in periampullary adenocarcinomas Keywords 1. Pancreatic cancer 2. Copy number aberrations 3. Integrative –omics analysis 4. Driver genes 5. Prognostic subtypes 1 Downloaded from cancerres.aacrjournals.org on September 27, 2021. -
Bioanalytical and Proteomic Approaches in the Study of Pathologic Ecs Dysfunctionality, Oxidative Stress and the Effects of PFKFB3 Modulators
Bioanalytical and proteomic approaches in the study of pathologic ECs dysfunctionality, oxidative stress and the effects of PFKFB3 modulators Sarath Babu Nukala ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) i a través del Dipòsit Digital de la UB (diposit.ub.edu) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tdx.cat) y a través del Repositorio Digital de la UB (diposit.ub.edu) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR o al Repositorio Digital de la UB.