DOCSLIB.ORG

FGFR1 Regulated Gene-Expression, Cell Proliferation and Differentiation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
FGFR1 Regulated Gene-Expression, Cell Proliferation and Differentiation Recent Publications in this Series: andHindbrain Midbrain intheDeveloping andDifferentiation CellProliferation FGFR1RegulatedGene-Expression, JUKKOLA TOMI 32/2006 Monica Yabal Membrane Insertion of C-tail Anchored Proteins 33/2006 Raimo Mikkola Food and Indoor Air Isolated Bacillus Non-Protein and Mechanisms of Effects on Eukaryotic Cells 34/2006 Mikael Niku Fates of Blood. Studies on Stem Cell Differentiation Potential and B Lymphocyte Generation in Chimeric Cattle 35/2006 Minni Koivunen Molecular Details of Phage φ6 RNA-Dependent RNA Synthesis 36/2006 Kai Fredriksson Structure and Dynamics of Coil-like Molecules by Residual Dipolar Couplings 1/2007 Irina Tsitko Characterization of Actinobacteria Degrading and Tolerating Organic Pollutants 2/2007 Pekka Östman Microchip Atmospheric Pressure Ionization-Mass Spectrometry FGFR1 Regulated Gene-Expression, 3/2007 Anni Hienola N-Syndecan And HB-GAM in Neural Migration and Differentiation: Modulation of Growth Factor Cell Proliferation and Differentiation in the Activity in Brain 4/2007 Ville O. Paavilainen Developing Midbrain and Hindbrain Structural Basis of Cytoskeletal Regulation by Twinfi lin 5/2007 Harri Jäälinoja Electron Cryo-Microscopy Studies of Bacteriophage φ8 and Archaeal Virus SH1 6/2007 Eini Poussu Mu in vitro DNA Transposition Applications in Protein Engineering 7/2007 Chun-Mei Li Type III Secretion System of Phytopathogenic Bacterium Pseudomonas syringae: From Gene to Function 8/2007 Saara Nuutinen The Effects of Nicotine on the Regulation of Neuronal alpha7 Nicotinic Acetylcholine Receptors and Intracellular Signalling Pathways 9/2007 Jaakko Aaltonen From Polymorph Screening to Dissolution Testing: Solid Phase Analysis during Pharmaceutical Development and Manufacturing TOMI JUKKOLA 10/2007 Jenni Antikainen Surface Proteins of Lactobacillus crispatus: Adhesive Properties and Cell Wall Anchoring 11/2007 Jing Li Institute of Biotechnology and Novel Molecular Mechanisms of Arabidopsis Disease Resistance 12/2007 Piia Salo Department of Biological and Environmental Sciences Thin-Layer Chromatography with Ultraviolet and Mass Spectrometric Detection: From Preparative-Layer to Division of Genetics Miniaturized Ultra-Thin-Layer Technique 13/2007 Mikko Sairanen Faculty of Biosciences Neurotrophins and Neuronal Plasticity in the Action of Antidepressants and Morphine 14/2007 Camilla Ribacka and Redox-linked Proton Transfer by Cytochrome C Oxidase Helsinki Graduate School of Biotechnology and Molecular Biology 15/2007 Päivi Ramu Outer Membrane Protease/adhesin PgtE of S. enterica: Role in Salmonella-Host Interaction University of Helsinki 16/2007 Joni Alvesalo Drug Discovery Screening and the Application of Genomics and Proteomics in the Drug Development Process for Chlamydia pneumoniae Helsinki 2007 ISSN 1795-7079 ISBN 978-952-10-4034-4 Dissertationes bioscientiarum molecularium Universitatis Helsingiensis in Viikki 17/2007 17/2007 Dissertationes bioscientiarum molecularium Universitatis Helsingiensis in Viikki 17/2007 FGFR1 regulated gene-expression, cell proliferation and differentiation in the developing midbrain and hindbrain Tomi Jukkola Institute of Biotechnology and Department of Biological and Environmental Sciences Division of Genetics Faculty of Biosciences and Helsinki Graduate School of Biotechnology and Molecular Biology University of Helsinki Finland Academic dissertation To be presented, with the permission of the Faculty of Biosciences of the University of Helsinki, for public criticism, in the auditorium 1041 at the Viikki Biocenter 2, Viikinkaari 5, on August 17th 2007, at 12 o’clock noon. Supervised by Docent Juha Partanen Institute of Biotechnology University of Helsinki Finland Reviewed by Professor Eero Castrén Neuroscience Center University of Helsinki Finland Professor Seppo Vainio Oulu Biocenter University of Oulu Finland Opponent Ph.D. Mark Lewandoski National Cancer Institute Frederick Cancer Research & Development Center U.S. Custos Professor Jim Schröder Department of Biological and Environmental Sciences University of Helsinki Finland ISSN 1795-7079 ISBN 978-952-10-4034-4 (paperback) ISBN 978-952-10-4035-1 (PDF, http://ethesis.helsinki.fi ) Edita, Helsinki 2007 If we knew what we were doing we wouldn’t call it science. Albert Einstein TABLE OF CONTENTS ABBREVIATIONS List of original publications I. Jukkola T*, Lahti L* Naserke T, Wurst W, Partanen J. FGF regulated gene- expression and neuronal differentiation in the developing midbrain-hindbrain region. Developmental Biology. 2006 Sep 1; 297(1): 141-57. II. Jukkola T*, Sinjushina N*, Partanen J. Drapc1 expression during mouse embryonic development. Gene Expression Patterns. 2004 Oct; 4(6): 755-62. III. Trokovic R*, Jukkola T*, Saarimäki J, Peltopuro P, Naserke T, Weisenhorn DM, Trokovic N, Wurst W, Partanen J. Fgfr1-dependent boundary cells between developing mid- and hindbrain. Developmental Biology. 2005 Feb 15; 278(2): 428- 39. IV. Kala K, Jukkola T, Pata I, Partanen J. Analysis of the midbrain-hindbrain boundary cell fate using a boundary cell-specifi c Cre-mouse line. Manuscript submitted to Genesis. SUMMARY REVIEW OF THE LITERATURE ............................................................................. 1 1. The early brain development ..................................................................................... 1 1.1. Neural induction and neurulation .......................................................................1 1.2. Molecular events of neural induction and neurulation ....................................... 1 2. Mechanisms of brain patterning ................................................................................. 2 2.1. Anterioposterior patterning ................................................................................ 2 2.2. Isthmic organizer ................................................................................................ 2 2.2.1. Induction and localization of isthmic organizer ....................................... 5 2.3. Neuronal development and regionalization of the midbrain .............................. 9 2.4. Neuronal development and regionalization of the hindbrain ........................... 11 2.4.1. Segmentation and compartmentalization in hindbrain ........................... 12 3. Intercellular communication in the midbrain-R1 region .......................................... 14 3.1. FGF signaling in the midbrain-R1 development .............................................. 14 3.1.1. The FGF and FGFR molecules ............................................................... 14 3.1.2. Expression patterns of FGFs and FGFRs in the mouse midbrain-R1 .......................................................................................... 15 3.1.3. FGFRs in the mouse midbrain-R1 development .................................... 16 3.1.4. FGFR signal transduction ....................................................................... 17 3.2. WNT signaling in the midbrain-R1 development ............................................. 21 4. Cell proliferation in the developing brain .................................................................23 4.1. Interkinetic nuclear migration .......................................................................... 23 4.2. Cell cycle regulators ......................................................................................... 25 4.2.1. Cyclins, Cdks and their inhibitors .......................................................... 25 4.2.2. Cyclins and Cdks in neuronal development ........................................... 26 4.2.3. Cdk inhibitors in neuronal development ................................................ 27 4.3. Mechanisms controlling the cell polarity and asymmetric cleavage ................ 28 4.4. Cellular proliferation and regulation in the rhombomeric boundaries ............ 28 AIMS OF THE STUDY .............................................................................................. 30 MATERIALS AND METHODS ................................................................................ 31 RESULTS AND DISCUSSION .................................................................................. 34 1. Microarray analysis of Fgfr1 CKO mutants (I-III) .................................................. 34 2. Identifi cation of FGF regulated genes at the midbrain-R1 region (I, III and unpublished) ............................................................................................ 43 2.1. Down-regulated genes (I and unpublished) ..................................................... 43 2.1.1. Down-regulation of FGF-FGFR signaling components at E10.5 (I, III) ................................................................................................................ 43 2.1.2. Cnpy1 as a novel regulator of FGF signaling at the midbrain-R1 region (I and unpublished) ............................................................................... 45 2.1.3. Down-regulated genes expressed as a narrow stripe near the MHB (I and unpublished) .......................................................................................... 46 2.1.4. Other down-regulated genes in the Fgfr1 CKO mutants (I) ................... 48 2.2. Up-regulated genes show loss of expression gradients in Fgfr1 CKO mutant embryos (I).............................................................................................48 3. Neuronal progenitor cell populations are affected in Fgfr1 CKO mutant embryos (I) ..............................................................................................................
Load more

Recommended publications
  • STAT3-Ser/Hes3 Signaling: a New Molecular Component of the Neuroendocrine System?
    Review 77 STAT3-Ser/Hes3 Signaling: A New Molecular Component of the Neuroendocrine System? Authors P. Nikolakopoulou1, S. W. Poser1, J. Masjkur1, M. Fernandez Rubin de Celis1, L. Toutouna1, C. L. Andoniadou2, R. D. McKay3, G. Chrousos4, M. Ehrhart-Bornstein1, S. R. Bornstein1, A. Androutsellis-Theotokis1, 5, 6 Affiliations Affiliation addresses are listed at the end of the article Key words Abstract evidence suggests that a common non-canonical ●▶ STAT3 ▼ signaling pathway regulates adult progenitors in ●▶ Hes3 The endocrine system involves communication several different tissues, rendering it as a poten- ▶ stem cells ● among different tissues in distinct organs, includ- tially valuable starting point to explore their ing the pancreas and components of the Hypo- biology. The STAT3-Ser/Hes3 Signaling Axis was thalamic-Pituitary-Adrenal Axis. The molecular first identified as a major regulator of neural mechanisms underlying these complex interac- stem cells and, subsequently, cancer stem cells. In tions are a subject of intense study as they may the endocrine/neuroendocrine system, this path- hold clues for the progression and treatment of a way operates on several levels, regulating other variety of metabolic and degenerative diseases. A types of plastic cells: (a) it regulates pancreatic plethora of signaling pathways, activated by hor- islet cell function and insulin release; (b) insulin mones and other endocrine factors have been in turn activates the pathway in broadly distrib- implicated in this communication. Recent uted neural progenitors and possibly also hypo- advances in the stem cell field introduce a new thalamic tanycytes, cells with important roles in level of complexity: adult progenitor cells appear the control of the adrenal gland; (c) adrenal pro- to utilize distinct signaling pathways than the genitors themselves operate this pathway.
    [Show full text]
  • I LITERATURE-BASED DISCOVERY of KNOWN and POTENTIAL NEW
    LITERATURE-BASED DISCOVERY OF KNOWN AND POTENTIAL NEW MECHANISMS FOR RELATING THE STATUS OF CHOLESTEROL TO THE PROGRESSION OF BREAST CANCER BY YU WANG THESIS Submitted in partial fulfillment of the requirements for the degree of Master of Science in Bioinformatics with a concentration in Library and Information Science in the Graduate College of the University of Illinois at Urbana-Champaign, 2019 Urbana, Illinois Adviser: Professor Vetle I. Torvik Professor Erik Russell Nelson i ABSTRACT Breast cancer has been studied for a long period of time and from a variety of perspectives in order to understand its pathogeny. The pathogeny of breast cancer can be classified into two groups: hereditary and spontaneous. Although cancer in general is considered a genetic disease, spontaneous factors are responsible for most of the pathogeny of breast cancer. In other words, breast cancer is more likely to be caused and deteriorated by the dysfunction of a physical molecule than be caused by germline mutation directly. Interestingly, cholesterol, as one of those molecules, has been discovered to correlate with breast cancer risk. However, the mechanisms of how cholesterol helps breast cancer progression are not thoroughly understood. As a result, this study aims to study known and discover potential new mechanisms regarding to the correlation of cholesterol and breast cancer progression using literature review and literature-based discovery. The known mechanisms are further classified into four groups: cholesterol membrane content, transport of cholesterol, cholesterol metabolites, and other. The potential mechanisms, which are intended to provide potential new treatments, have been identified and checked for feasibility by an expert.
    [Show full text]
  • Abstracts from the 9Th Biennial Scientific Meeting of The
    International Journal of Pediatric Endocrinology 2017, 2017(Suppl 1):15 DOI 10.1186/s13633-017-0054-x MEETING ABSTRACTS Open Access Abstracts from the 9th Biennial Scientific Meeting of the Asia Pacific Paediatric Endocrine Society (APPES) and the 50th Annual Meeting of the Japanese Society for Pediatric Endocrinology (JSPE) Tokyo, Japan. 17-20 November 2016 Published: 28 Dec 2017 PS1 Heritable forms of primary bone fragility in children typically lead to Fat fate and disease - from science to global policy a clinical diagnosis of either osteogenesis imperfecta (OI) or juvenile Peter Gluckman osteoporosis (JO). OI is usually caused by dominant mutations affect- Office of Chief Science Advsor to the Prime Minister ing one of the two genes that code for two collagen type I, but a re- International Journal of Pediatric Endocrinology 2017, 2017(Suppl 1):PS1 cessive form of OI is present in 5-10% of individuals with a clinical diagnosis of OI. Most of the involved genes code for proteins that Attempts to deal with the obesity epidemic based solely on adult be- play a role in the processing of collagen type I protein (BMP1, havioural change have been rather disappointing. Indeed the evidence CREB3L1, CRTAP, LEPRE1, P4HB, PPIB, FKBP10, PLOD2, SERPINF1, that biological, developmental and contextual factors are operating SERPINH1, SEC24D, SPARC, from the earliest stages in development and indeed across generations TMEM38B), or interfere with osteoblast function (SP7, WNT1). Specific is compelling. The marked individual differences in the sensitivity to the phenotypes are caused by mutations in SERPINF1 (recessive OI type obesogenic environment need to be understood at both the individual VI), P4HB (Cole-Carpenter syndrome) and SEC24D (‘Cole-Carpenter and population level.
    [Show full text]
  • SOX3 Is Required During the Formation of the Hypothalamo-Pituitary Axis
    ARTICLES SOX3 is required during the formation of the hypothalamo-pituitary axis Karine Rizzoti1,5, Silvia Brunelli1,4,5, Danielle Carmignac2, Paul Q Thomas3, Iain C Robinson2 & Robin Lovell-Badge1 The pituitary develops from the interaction of the infundibulum, a region of the ventral diencephalon, and Rathke’s pouch, a derivative of oral ectoderm. Postnatally, its secretory functions are controlled by hypothalamic neurons, which also derive from the ventral diencephalon. In humans, mutations affecting the X-linked transcription factor SOX3 are associated with hypopituitarism and mental retardation, but nothing is known of their etiology. We find that deletion of Sox3 in mice leads to defects of pituitary function and of specific central nervous system (CNS) midline structures. Cells in the ventral diencephalon, where Sox3 is usually http://www.nature.com/naturegenetics highly expressed, have altered properties in mutant embryos, leading to abnormal development of Rathke’s pouch, which does not express the gene. Pituitary and hypothalamic defects persist postnatally, and SOX3 may also function in a subset of hypothalamic neurons. This study shows how sensitive the pituitary is to subtle developmental defects and how one gene can act at several levels in the hypothalamic-pituitary axis. The development of complex organs composed of different cell types review see ref. 5), is implicated in a syndrome of X-linked hypopitu- frequently depends on reciprocal induction events occurring between itarism and mental retardation6. In a single family whose males were distinct tissue layers that lie adjacent to one another in the embryo. deficient in growth hormone, a mutation in SOX3 was identified.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • UNIVERSITY of CALIFORNIA, IRVINE Combinatorial Regulation By
    UNIVERSITY OF CALIFORNIA, IRVINE Combinatorial regulation by maternal transcription factors during activation of the endoderm gene regulatory network DISSERTATION submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Biological Sciences by Kitt D. Paraiso Dissertation Committee: Professor Ken W.Y. Cho, Chair Associate Professor Olivier Cinquin Professor Thomas Schilling 2018 Chapter 4 © 2017 Elsevier Ltd. © 2018 Kitt D. Paraiso DEDICATION To the incredibly intelligent and talented people, who in one way or another, helped complete this thesis. ii TABLE OF CONTENTS Page LIST OF FIGURES vii LIST OF TABLES ix LIST OF ABBREVIATIONS X ACKNOWLEDGEMENTS xi CURRICULUM VITAE xii ABSTRACT OF THE DISSERTATION xiv CHAPTER 1: Maternal transcription factors during early endoderm formation in 1 Xenopus Transcription factors co-regulate in a cell type-specific manner 2 Otx1 is expressed in a variety of cell lineages 4 Maternal otx1 in the endodermal conteXt 5 Establishment of enhancers by maternal transcription factors 9 Uncovering the endodermal gene regulatory network 12 Zygotic genome activation and temporal control of gene eXpression 14 The role of maternal transcription factors in early development 18 References 19 CHAPTER 2: Assembly of maternal transcription factors initiates the emergence 26 of tissue-specific zygotic cis-regulatory regions Introduction 28 Identification of maternal vegetally-localized transcription factors 31 Vegt and OtX1 combinatorially regulate the endodermal 33 transcriptome iii
    [Show full text]
  • Supplemental Table 1. Complete Gene Lists and GO Terms from Figure 3C
    Supplemental Table 1. Complete gene lists and GO terms from Figure 3C. Path 1 Genes: RP11-34P13.15, RP4-758J18.10, VWA1, CHD5, AZIN2, FOXO6, RP11-403I13.8, ARHGAP30, RGS4, LRRN2, RASSF5, SERTAD4, GJC2, RHOU, REEP1, FOXI3, SH3RF3, COL4A4, ZDHHC23, FGFR3, PPP2R2C, CTD-2031P19.4, RNF182, GRM4, PRR15, DGKI, CHMP4C, CALB1, SPAG1, KLF4, ENG, RET, GDF10, ADAMTS14, SPOCK2, MBL1P, ADAM8, LRP4-AS1, CARNS1, DGAT2, CRYAB, AP000783.1, OPCML, PLEKHG6, GDF3, EMP1, RASSF9, FAM101A, STON2, GREM1, ACTC1, CORO2B, FURIN, WFIKKN1, BAIAP3, TMC5, HS3ST4, ZFHX3, NLRP1, RASD1, CACNG4, EMILIN2, L3MBTL4, KLHL14, HMSD, RP11-849I19.1, SALL3, GADD45B, KANK3, CTC- 526N19.1, ZNF888, MMP9, BMP7, PIK3IP1, MCHR1, SYTL5, CAMK2N1, PINK1, ID3, PTPRU, MANEAL, MCOLN3, LRRC8C, NTNG1, KCNC4, RP11, 430C7.5, C1orf95, ID2-AS1, ID2, GDF7, KCNG3, RGPD8, PSD4, CCDC74B, BMPR2, KAT2B, LINC00693, ZNF654, FILIP1L, SH3TC1, CPEB2, NPFFR2, TRPC3, RP11-752L20.3, FAM198B, TLL1, CDH9, PDZD2, CHSY3, GALNT10, FOXQ1, ATXN1, ID4, COL11A2, CNR1, GTF2IP4, FZD1, PAX5, RP11-35N6.1, UNC5B, NKX1-2, FAM196A, EBF3, PRRG4, LRP4, SYT7, PLBD1, GRASP, ALX1, HIP1R, LPAR6, SLITRK6, C16orf89, RP11-491F9.1, MMP2, B3GNT9, NXPH3, TNRC6C-AS1, LDLRAD4, NOL4, SMAD7, HCN2, PDE4A, KANK2, SAMD1, EXOC3L2, IL11, EMILIN3, KCNB1, DOK5, EEF1A2, A4GALT, ADGRG2, ELF4, ABCD1 Term Count % PValue Genes regulation of pathway-restricted GDF3, SMAD7, GDF7, BMPR2, GDF10, GREM1, BMP7, LDLRAD4, SMAD protein phosphorylation 9 6.34 1.31E-08 ENG pathway-restricted SMAD protein GDF3, SMAD7, GDF7, BMPR2, GDF10, GREM1, BMP7, LDLRAD4, phosphorylation
    [Show full text]
  • Regulation of Adult Neurogenesis in Mammalian Brain
    International Journal of Molecular Sciences Review Regulation of Adult Neurogenesis in Mammalian Brain 1,2, 3, 3,4 Maria Victoria Niklison-Chirou y, Massimiliano Agostini y, Ivano Amelio and Gerry Melino 3,* 1 Centre for Therapeutic Innovation (CTI-Bath), Department of Pharmacy & Pharmacology, University of Bath, Bath BA2 7AY, UK; [email protected] 2 Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK 3 Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, 00133 Rome, Italy; [email protected] (M.A.); [email protected] (I.A.) 4 School of Life Sciences, University of Nottingham, Nottingham NG7 2HU, UK * Correspondence: [email protected] These authors contributed equally to this work. y Received: 18 May 2020; Accepted: 7 July 2020; Published: 9 July 2020 Abstract: Adult neurogenesis is a multistage process by which neurons are generated and integrated into existing neuronal circuits. In the adult brain, neurogenesis is mainly localized in two specialized niches, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) adjacent to the lateral ventricles. Neurogenesis plays a fundamental role in postnatal brain, where it is required for neuronal plasticity. Moreover, perturbation of adult neurogenesis contributes to several human diseases, including cognitive impairment and neurodegenerative diseases. The interplay between extrinsic and intrinsic factors is fundamental in regulating neurogenesis. Over the past decades, several studies on intrinsic pathways, including transcription factors, have highlighted their fundamental role in regulating every stage of neurogenesis. However, it is likely that transcriptional regulation is part of a more sophisticated regulatory network, which includes epigenetic modifications, non-coding RNAs and metabolic pathways.
    [Show full text]
  • Genome-Wide DNA Methylation Analysis of KRAS Mutant Cell Lines Ben Yi Tew1,5, Joel K
    www.nature.com/scientificreports OPEN Genome-wide DNA methylation analysis of KRAS mutant cell lines Ben Yi Tew1,5, Joel K. Durand2,5, Kirsten L. Bryant2, Tikvah K. Hayes2, Sen Peng3, Nhan L. Tran4, Gerald C. Gooden1, David N. Buckley1, Channing J. Der2, Albert S. Baldwin2 ✉ & Bodour Salhia1 ✉ Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. Recent studies suggest that DNA methylation changes may be stochastic in nature, while other groups propose distinct signaling pathways responsible for aberrant methylation. Better understanding of DNA methylation events associated with oncogenic KRAS expression could enhance therapeutic approaches. Here we analyzed the basal CpG methylation of 11 KRAS-mutant and dependent pancreatic cancer cell lines and observed strikingly similar methylation patterns. KRAS knockdown resulted in unique methylation changes with limited overlap between each cell line. In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 diferentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation. KRAS G12V overexpression in an isogenic lung model reveals >50,600 DM CpGs compared to non-transformed controls. In lung and pancreatic cells, gene ontology analyses of DM promoters show an enrichment for genes involved in diferentiation and development. Taken all together, KRAS-mediated DNA methylation are stochastic and independent of canonical downstream efector signaling. These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer. Activating KRAS mutations can be found in nearly 25 percent of all cancers1.
    [Show full text]
  • Appendix 2. Significantly Differentially Regulated Genes in Term Compared with Second Trimester Amniotic Fluid Supernatant
    Appendix 2. Significantly Differentially Regulated Genes in Term Compared With Second Trimester Amniotic Fluid Supernatant Fold Change in term vs second trimester Amniotic Affymetrix Duplicate Fluid Probe ID probes Symbol Entrez Gene Name 1019.9 217059_at D MUC7 mucin 7, secreted 424.5 211735_x_at D SFTPC surfactant protein C 416.2 206835_at STATH statherin 363.4 214387_x_at D SFTPC surfactant protein C 295.5 205982_x_at D SFTPC surfactant protein C 288.7 1553454_at RPTN repetin solute carrier family 34 (sodium 251.3 204124_at SLC34A2 phosphate), member 2 238.9 206786_at HTN3 histatin 3 161.5 220191_at GKN1 gastrokine 1 152.7 223678_s_at D SFTPA2 surfactant protein A2 130.9 207430_s_at D MSMB microseminoprotein, beta- 99.0 214199_at SFTPD surfactant protein D major histocompatibility complex, class II, 96.5 210982_s_at D HLA-DRA DR alpha 96.5 221133_s_at D CLDN18 claudin 18 94.4 238222_at GKN2 gastrokine 2 93.7 1557961_s_at D LOC100127983 uncharacterized LOC100127983 93.1 229584_at LRRK2 leucine-rich repeat kinase 2 HOXD cluster antisense RNA 1 (non- 88.6 242042_s_at D HOXD-AS1 protein coding) 86.0 205569_at LAMP3 lysosomal-associated membrane protein 3 85.4 232698_at BPIFB2 BPI fold containing family B, member 2 84.4 205979_at SCGB2A1 secretoglobin, family 2A, member 1 84.3 230469_at RTKN2 rhotekin 2 82.2 204130_at HSD11B2 hydroxysteroid (11-beta) dehydrogenase 2 81.9 222242_s_at KLK5 kallikrein-related peptidase 5 77.0 237281_at AKAP14 A kinase (PRKA) anchor protein 14 76.7 1553602_at MUCL1 mucin-like 1 76.3 216359_at D MUC7 mucin 7,
    [Show full text]
  • FARE2021WINNERS Sorted by Institute
    FARE2021WINNERS Sorted By Institute Swati Shah Postdoctoral Fellow CC Radiology/Imaging/PET and Neuroimaging Characterization of CNS involvement in Ebola-Infected Macaques using Magnetic Resonance Imaging, 18F-FDG PET and Immunohistology The Ebola (EBOV) virus outbreak in Western Africa resulted in residual neurologic abnormalities in survivors. Many case studies detected EBOV in the CSF, suggesting that the neurologic sequelae in survivors is related to viral presence. In the periphery, EBOV infects endothelial cells and triggers a “cytokine stormâ€. However, it is unclear whether a similar process occurs in the brain, with secondary neuroinflammation, neuronal loss and blood-brain barrier (BBB) compromise, eventually leading to lasting neurological damage. We have used in vivo imaging and post-necropsy immunostaining to elucidate the CNS pathophysiology in Rhesus macaques infected with EBOV (Makona). Whole brain MRI with T1 relaxometry (pre- and post-contrast) and FDG-PET were performed to monitor the progression of disease in two cohorts of EBOV infected macaques from baseline to terminal endpoint (day 5-6). Post-necropsy, multiplex fluorescence immunohistochemical (MF-IHC) staining for various cellular markers in the thalamus and brainstem was performed. Serial blood and CSF samples were collected to assess disease progression. The linear mixed effect model was used for statistical analysis. Post-infection, we first detected EBOV in the serum (day 3) and CSF (day 4) with dramatic increases until euthanasia. The standard uptake values of FDG-PET relative to whole brain uptake (SUVr) in the midbrain, pons, and thalamus increased significantly over time (p<0.01) and positively correlated with blood viremia (p≤0.01).
    [Show full text]
  • HER Tyrosine Kinase Family and Rhabdomyosarcoma: Role in Onset and Targeted Therapy
    cells Review HER Tyrosine Kinase Family and Rhabdomyosarcoma: Role in Onset and Targeted Therapy Carla De Giovanni 1,* , Lorena Landuzzi 2,†, Arianna Palladini 1 , Giordano Nicoletti 2, Patrizia Nanni 1 and Pier-Luigi Lollini 1,* 1 Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy; [email protected] (A.P.); [email protected] (P.N.) 2 Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; [email protected] (L.L.); [email protected] (G.N.) * Correspondence: [email protected] (C.D.G.); [email protected] (P.-L.L.); Tel.: +39-051-2094786 (P.-L.L.) † Co-first author. Abstract: Rhabdomyosarcomas (RMS) are tumors of the skeletal muscle lineage. Two main features allow for distinction between subtypes: morphology and presence/absence of a translocation be- tween the PAX3 (or PAX7) and FOXO1 genes. The two main subtypes are fusion-positive alveolar RMS (ARMS) and fusion-negative embryonal RMS (ERMS). This review will focus on the role of receptor tyrosine kinases of the human epidermal growth factor receptor (EGFR) family that is comprised EGFR itself, HER2, HER3 and HER4 in RMS onset and the potential therapeutic targeting of receptor tyrosine kinases. EGFR is highly expressed by ERMS tumors and cell lines, in some cases contributing to tumor growth. If not mutated, HER2 is not directly involved in control of RMS cell growth but can be expressed at significant levels. A minority of ERMS carries a HER2 mutation Citation: De Giovanni, C.; Landuzzi, with driving activity on tumor growth.
    [Show full text]