DOCSLIB.ORG

In Vitro Study of the Structure / Function Relationship of the Proteins GASP-1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
In Vitro Study of the Structure / Function Relationship of the Proteins GASP-1 In vitro study of the structure / function relationship of the proteins GASP-1 and GASP-2 : Involvement of the second Kunitz domain in the functional duality of the GASP proteins Montasir Al Mansi To cite this version: Montasir Al Mansi. In vitro study of the structure / function relationship of the proteins GASP-1 and GASP-2 : Involvement of the second Kunitz domain in the functional duality of the GASP proteins. Human health and pathology. Université de Limoges, 2018. English. NNT : 2018LIMO0064. tel- 01980588 HAL Id: tel-01980588 https://tel.archives-ouvertes.fr/tel-01980588 Submitted on 14 Jan 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITY OF LIMOGES DOCTORAL SCHOOL 615 - Biological Sciences and Health PEIRENE EA7500, USC INRA 1061 Génomique AniMale, Amélioration, Adaptation A Thesis submitted for the degree of Doctor of Limoges University Discipline / Specialty: Molecular and Cellular Aspects of Biology Montasir Al MANSI Thèse de doctorat 14 December 2018 IN VITRO STUDY OF THE STRUCTURE / FUNCTION RELATIONSHIP OF THE PROTEINS GASP-1 AND GASP-2 : Involvement of the secund kunitz domain in the functional duality of the GASP proteins cosupervised by Pr. Véronique BLANQUET and Dr. Laure BREMAUD JURY President A. OULMOUDEN, Professor, Limoges Reviewers M.P. ELLIES-OURY, Assistant Professor, INRA, Clermont-Ferrand J.L. VILOTTE, Research Director, INRA, Jouy en Josas Examiners F. BRULE-MORABITO, Assistant Professor, Orléans L. BREMAUD, Assistant Professor, Limoges V. BLANQUET, Professor, Limoges Dedication To my father (RIP) and my mother, To my wife and my daughters, To my brothers and my sisters, To my father and my mother in law ACKNOWLEDGEMENT __________________________________________________________________________________________________________ This work would not have been possible without the financial support of the French Government through the French Embassy in Jordan. Special thanks to the French Ambassador, Mr. David BERTOLOTTI and his dedicated staff: Mrs. Lisbeth NGOUANET, Dr. Salwa NACOUZI, and Mrs. Hind MELKAWI. This thesis was carried out at the PEIRENE Laboratory, GAMAA unit, Faculty of Science and Technology, Limoges University, France. I would like to thank the University of Limoges for giving me the opportunity to study and do this research. I would like to express my sincere gratitude to my advisor Professor Véronique BLANQUET for the continuous support of my PhD study and related research, for her patience, motivation, immense knowledge and continuous support. Her guidance helped me in all the time of research and writing of this thesis. I could not have imagined having a better advisor and mentor for my PhD study. I would like to express my deep gratitude to Dr. Laure BRÉMAUD for her patience, encouragement and support during my work in the laboratory through the years that I spent on this work, really I am very grateful for her support. My sincere thanks and gratitude go to the members of the jury, especially to Dr. Marie-Pierre ELLIES-OURY and Dr. Jean-Luc VILOTTE for accepting to report this thesis. Thanks also to Professor Ahmad OULMOUDEN for agreeing to judge this work and to chair the jury, and Dr. BRULE-MORABITO who has agreed to judge this work as an examiner. I would like to express my sincere gratitude and my thanks and appreciation to Dr. Didier DELOURME, for his invaluable support and guidance during all stages of my study. I cannot forget Dr. Patrick PELISSIER for his invaluable help with all the necessary analyses. He has always done everything possible to help me, I really do appreciate it. I would like to express my gratitude for Professor Tariq AL-NAJJAR for his continuous support and help during all the time. Very special thanks to Dr. Khalid ABU KHADRA, for the countless, valuable and interesting scientific conversations, with my best wishes for him in his career. I would like to express my sincere appreciation to my friend Dr. Saleem AL-MOGHRABI for his encouragement and support. A very special thanks to my father in law Dr. Musa AJLOUNI and Eng. Mohammad AJLOUNI for their encouragement and for all the hours they spent in re-reading and fine-tuning of this thesis. Many thanks to the staff of the laboratory and the PhD students with whom I shared unforgettable moments: Alexis, Caroline, Tiffany, Jessica, Melanie and Abdel Majeed. My thanks are extended also to Eric LAPEYRONNIE who just finished his Master’s degree and has started his PhD. I wish him a very fruitful and successful future. My heartfelt gratitude is extended to my friends in Limoges, Saleck SALEM VALL and Abdel Rahman ALKOUNA, for their support during my study. I would like to thank my mother, my brothers and my sisters; whose love and guidance me in whatever I pursue. I wish to thank my loving and supportive wife, Amal, and my four wonderful children; Raneem, Rand Noor and Rayyan, who provide unending motivation and inspiration. ABREVIATIONS __________________________________________________________________________________________________________________ ActRIIA/B : activin Receptor type-IIA/B MTS : (3-(4,4-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4- Akt : Protein kinase B sulfophenyl)-2H-tetrazolium) Alk : Activin-like kinase muRF1 : Muscle RING-Finger protein-1 BMP : Bone Morphogenic Protein MW : Molecular Weight bp : base pair Myf : Myogenic Factor BPTI : Bovine Pancreatic Trypsin Inhibitor MyoD : Myoblast Determination Protein 1 Cdk : Cyclin-dependent kinase NTR : Netrin Da : Dalton OD : Optic Density DNA : DeoxyriboNucleic Acid PA clan : Proteases of mixed nucleophile, ERK : Extracellular signal-Regulated Kinase superfamily A GASP : GDF-Associated Serum Protein PAGE : PolyAcrylamide Gel Electrophoresis GDF : Growth and Differentiation Factor Pax : Paired box protein GST : Glutathion S-Transferase PCR : Polymerase Chain Reaction FLRG : Follistatin related-gene PDB ID : Protein Data Bank Identifiant FoxO : Forkhead box protein O PI3K: PhosphoInositide 3-Kinase FST/FS : Follistatin RCL : Reactive Center Loop IgC2 : Immunoglobulin C2-type R-SMAD : Receptor-regulated SMAD IGF : Insulin-like Growth Factor sFRP : secreted Frizzled-Related Protein IPTG : IsoPropyl β-D-1 shRNA : short hairpin RNA ThioGalactopyranoside SMAD : Sma and Mad related protein JNK : Inhibition constant SVF : Fetal bovine serum Ki : Inhibition constant TGF : Transforming Growth Factor Km : Michaelis constant TIMP : Tissue Inhibitor of MetalloProtease LTBP : Latent TGF-β-Binding Protein WAP : Whey Acidic Protein MAPK : Mitogen-activated protein Kinase WFIKKN : WAP, Follistatin, Immunoglobulin, MMP : Matrix MetalloProtease kazal, Kunitz, Netrin-containing protein MRF : Myogenic Regulatory Factor MSTN : Myostatin mTOR : mammalian Target Of Rapamycin SUMMARY _______________________________________________________________________________________________________________ FOREWORD .................................................................................................................... 1 BIBLIOGRAPHIC REVIEW.............................................................................................. 5 CHAPTER I: MYOSTATIN AND ITS SIGNALING PATHWAY ........................................ 6 I.1. Transforming Growth Factor beta (TGF-β) superfamily ...................................... 6 I.1.1. Biosynthesis and maturation of TGF-β proteins .............................................. 6 I.1.2. TGF-β signaling pathways .............................................................................. 8 I.2. Myostatin ................................................................................................................ 9 I.2.1. Structural organization and expression of myostatin.....................................10 I.2.2. Myostatin pathway and its regulations .......................................................... 13 I.2.2.1. The SMADs mediated canonical signaling pathway ......................... 13 I.2.2.2. The non-canonical signaling pathway ............................................... 14 I.2.2.3. Regulation of myostatin expression by intracellular factors............... 16 I.2.2.4. Extracellular factors .......................................................................... 17 I.2.3. Roles of Myostatin ........................................................................................ 19 I.2.3.1. Myostatin and muscle development .................................................19 I.2.3.2. Myostatin and metabolism ................................................................ 21 CHAPTER II: THE GASP PROTEINS ........................................................................... 23 II.1. Evolution and structure of the GASP genes ..................................................... 23 II.2. Structural organization and evolution of the GASP proteins........................... 25 II.2.1. Structural organization in domains of the GASP proteins ............................ 25 II.2.2. Evolution of the GASP proteins ................................................................... 28 II.2.3. Tissular
Load more

Recommended publications
  • Two Locus Inheritance of Non-Syndromic Midline Craniosynostosis Via Rare SMAD6 and 4 Common BMP2 Alleles 5 6 Andrew T
    1 2 3 Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and 4 common BMP2 alleles 5 6 Andrew T. Timberlake1-3, Jungmin Choi1,2, Samir Zaidi1,2, Qiongshi Lu4, Carol Nelson- 7 Williams1,2, Eric D. Brooks3, Kaya Bilguvar1,5, Irina Tikhonova5, Shrikant Mane1,5, Jenny F. 8 Yang3, Rajendra Sawh-Martinez3, Sarah Persing3, Elizabeth G. Zellner3, Erin Loring1,2,5, Carolyn 9 Chuang3, Amy Galm6, Peter W. Hashim3, Derek M. Steinbacher3, Michael L. DiLuna7, Charles 10 C. Duncan7, Kevin A. Pelphrey8, Hongyu Zhao4, John A. Persing3, Richard P. Lifton1,2,5,9 11 12 1Department of Genetics, Yale University School of Medicine, New Haven, CT, USA 13 2Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA 14 3Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA 15 4Department of Biostatistics, Yale University School of Medicine, New Haven, CT, USA 16 5Yale Center for Genome Analysis, New Haven, CT, USA 17 6Craniosynostosis and Positional Plagiocephaly Support, New York, NY, USA 18 7Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA 19 8Child Study Center, Yale University School of Medicine, New Haven, CT, USA 20 9The Rockefeller University, New York, NY, USA 21 22 ABSTRACT 23 Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2,000 24 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To 25 identify mutations contributing to common non-syndromic midline (sagittal and metopic) 26 craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 27 additional probands.
    [Show full text]
  • Molecular Characterization of Latent GDF8 Reveals Mechanisms
    Molecular characterization of latent GDF8 reveals PNAS PLUS mechanisms of activation Ryan G. Walkera,1, Jason C. McCoya,1, Magdalena Czepnika, Melanie J. Millsb,c, Adam Haggd,e, Kelly L. Waltond, Thomas R. Cottonf, Marko Hyvönenf, Richard T. Leeb,c, Paul Gregorevice,g,h,i, Craig A. Harrisond,j,2, and Thomas B. Thompsona,2 aDepartment of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267; bHarvard Stem Cell Institute, Harvard University, Cambridge, MA 02138; cDepartment of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138; dBiomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, VIC 3800, Australia; eBaker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; fDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom; gDepartment of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; hDepartment of Physiology, University of Melbourne, Parkville, VIC 3010, Australia; iDepartment of Neurology, University of Washington School of Medicine, Seattle, WA 98195; and jHudson Institute of Medical Research, Clayton, VIC 3168, Australia Edited by Se-Jin Lee, Johns Hopkins University, Baltimore, MD, and approved December 7, 2017 (received for review August 22, 2017) Growth/differentiation factor 8 (GDF8), or myostatin, negatively the latent TGF-β1 crystal structure provided a molecular expla- regulates muscle mass. GDF8 is held in a latent state through nation for how latency is exerted by the prodomain via a co- interactions with its N-terminal prodomain, much like TGF-β. Using ordinated interaction between the N-terminal alpha helix (alpha- a combination of small-angle X-ray scattering and mutagenesis, 1), latency lasso, and fastener of the prodomain with type I and we characterized the interactions of GDF8 with its prodomain.
    [Show full text]
  • Revealing the Role of the Human Blood Plasma Proteome in Obesity Using Genetic Drivers
    ARTICLE https://doi.org/10.1038/s41467-021-21542-4 OPEN Revealing the role of the human blood plasma proteome in obesity using genetic drivers Shaza B. Zaghlool 1,11, Sapna Sharma2,3,4,11, Megan Molnar 2,3, Pamela R. Matías-García2,3,5, Mohamed A. Elhadad 2,3,6, Melanie Waldenberger 2,3,7, Annette Peters 3,4,7, Wolfgang Rathmann4,8, ✉ Johannes Graumann 9,10, Christian Gieger2,3,4, Harald Grallert2,3,4,12 & Karsten Suhre 1,12 Blood circulating proteins are confounded readouts of the biological processes that occur in 1234567890():,; different tissues and organs. Many proteins have been linked to complex disorders and are also under substantial genetic control. Here, we investigate the associations between over 1000 blood circulating proteins and body mass index (BMI) in three studies including over 4600 participants. We show that BMI is associated with widespread changes in the plasma proteome. We observe 152 replicated protein associations with BMI. 24 proteins also associate with a genome-wide polygenic score (GPS) for BMI. These proteins are involved in lipid metabolism and inflammatory pathways impacting clinically relevant pathways of adiposity. Mendelian randomization suggests a bi-directional causal relationship of BMI with LEPR/LEP, IGFBP1, and WFIKKN2, a protein-to-BMI relationship for AGER, DPT, and CTSA, and a BMI-to-protein relationship for another 21 proteins. Combined with animal model and tissue-specific gene expression data, our findings suggest potential therapeutic targets fur- ther elucidating the role of these proteins in obesity associated pathologies. 1 Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha, Qatar.
    [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]
  • Transcriptomic Profiles of High and Low Antibody Responders to Smallpox
    Genes and Immunity (2013) 14, 277–285 & 2013 Macmillan Publishers Limited All rights reserved 1466-4879/13 www.nature.com/gene ORIGINAL ARTICLE Transcriptomic profiles of high and low antibody responders to smallpox vaccine RB Kennedy1,2, AL Oberg1,3, IG Ovsyannikova1,2, IH Haralambieva1,2, D Grill1,3 and GA Poland1,2 Despite its eradication over 30 years ago, smallpox (as well as other orthopox viruses) remains a pathogen of interest both in terms of biodefense and for its use as a vector for vaccines and immunotherapies. Here we describe the application of mRNA-Seq transcriptome profiling to understanding immune responses in smallpox vaccine recipients. Contrary to other studies examining gene expression in virally infected cell lines, we utilized a mixed population of peripheral blood mononuclear cells in order to capture the essential intercellular interactions that occur in vivo, and would otherwise be lost, using single cell lines or isolated primary cell subsets. In this mixed cell population we were able to detect expression of all annotated vaccinia genes. On the host side, a number of genes encoding cytokines, chemokines, complement factors and intracellular signaling molecules were downregulated upon viral infection, whereas genes encoding histone proteins and the interferon response were upregulated. We also identified a small number of genes that exhibited significantly different expression profiles in subjects with robust humoral immunity compared with those with weaker humoral responses. Our results provide evidence that differential gene regulation patterns may be at work in individuals with robust humoral immunity compared with those with weaker humoral immune responses. Genes and Immunity (2013) 14, 277–285; doi:10.1038/gene.2013.14; published online 18 April 2013 Keywords: Next-generation sequencing; mRNA-Seq; vaccinia virus; smallpox vaccine INTRODUCTION these 44 subjects had two samples (uninfected and vaccinia Vaccinia virus (VACV) is the immunologically cross-protective infected).
    [Show full text]
  • Influence of WFIKKN1 on BMP1‐Mediated
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Repository of the Academy's Library Influence of WFIKKN1 on BMP1-mediated activation of latent myostatin Gyorgy€ Szlama, Viktor Vas arhelyi, Maria Trexler and Laszl o Patthy Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary Keywords The NTR domain of WFIKKN1 protein has been shown to have signifi- BMP1; heparin; latent myostatin; myostatin; cant affinity for the prodomain regions of promyostatin and latent myo- WFIKKN1 statin but the biological significance of these interactions remained unclear. In view of its role as a myostatin antagonist, we tested the assumption that Correspondence L. Patthy, Institute of Enzymology, WFIKKN1 inhibits the release of myostatin from promyostatin and/or Research Centre for Natural Sciences, latent myostatin. WFIKKN1 was found to have no effect on processing of Hungarian Academy of Sciences, Budapest, promyostatin by furin, the rate of cleavage of latent myostatin by BMP1, P.O. Box 286, H-1519, Hungary however, was significantly enhanced in the presence of WFIKKN1 and Tel: +361 382 6751 this enhancer activity was superstimulated by heparin. Unexpectedly, E-mail: [email protected] WFIKKN1 was also cleaved by BMP1 and our studies have shown that the KKN1 fragment generated by BMP1-cleavage of WFIKKN1 con- (Received 26 May 2016, revised 19 September 2016, accepted 24 October tributes most significantly to the observed enhancer activity. Analysis of a 2016) pro-TGF-b -based homology model of homodimeric latent myostatin revealed that the BMP1-cleavage sites are buried and not readily accessible doi:10.1111/febs.13938 to BMP1.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • Ligand-Specific Transcriptional Mechanisms Underlie Aryl Hydrocarbon Receptor-Mediated Developmental Toxicity of Oxygenated Pahs
    Ligand-specific transcriptional mechanisms underlie aryl hydrocarbon receptor-mediated developmental toxicity of oxygenated PAHs Goodale, B.C.* †, La Du, J. *, Tilton, S.C.* ‡, Sullivan, C.M.* §, Bisson, W.H. *, Waters, K.M. ‡ and Tanguay, R.L.* *Department of Environmental and Molecular Toxicology, the Environmental Health Sciences Center, Oregon State University, Corvallis, OR, 97330 †Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, 604 Remsen Bldg., Hanover, NH 03755 ‡Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, 902 Battelle Blvd, Richland, WA 99354 §Center for Genome Research and Biocomputing, Oregon State University, Corvallis, OR, 97330 Corresponding author: Robert Tanguay, Ph.D., Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97330. Email: [email protected] Abstract Polycyclic aromatic hydrocarbons (PAHs) are priority environmental contaminants that exhibit mutagenic, carcinogenic, proinflammatory and teratogenic properties. Oxygen-substituted PAHs (OPAHs) are formed during combustion processes and via phototoxidation and biological degradation of parent (unsubstituted) PAHs. Despite their prevalence both in contaminated industrial sites and in urban air, OPAH mechanisms of action in biological systems are relatively understudied. Like parent PAHs, OPAHs exert structure-dependent mutagenic activities and activation of the aryl hydrocarbon receptor (AHR) and cytochrome p450 metabolic pathway (CYP1A). Four-ring OPAHs 1,9-benz-10-anthrone (BEZO) and benz(a)anthracene-7,12-dione (7,12-B[a]AQ) cause morphological aberrations and induce markers of oxidative stress in developing zebrafish with similar potency, but only 7,12-B[a]AQ induces robust Cyp1a protein expression. We investigated the role of the AHR in mediating the toxicity of BEZO and 7,12-B[a]AQ, and found that knockdown of AHR2 rescued developmental effects caused by both compounds.
    [Show full text]
  • Genomic Approach in Idiopathic Intellectual Disability Maria De Fátima E Costa Torres
    ESTUDOS DE 8 01 PDPGM 2 CICLO Genomic approach in idiopathic intellectual disability Maria de Fátima e Costa Torres D Autor. Maria de Fátima e Costa Torres D.ICBAS 2018 Genomic approach in idiopathic intellectual disability Genomic approach in idiopathic intellectual disability Maria de Fátima e Costa Torres SEDE ADMINISTRATIVA INSTITUTO DE CIÊNCIAS BIOMÉDICAS ABEL SALAZAR FACULDADE DE MEDICINA MARIA DE FÁTIMA E COSTA TORRES GENOMIC APPROACH IN IDIOPATHIC INTELLECTUAL DISABILITY Tese de Candidatura ao grau de Doutor em Patologia e Genética Molecular, submetida ao Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto Orientadora – Doutora Patrícia Espinheira de Sá Maciel Categoria – Professora Associada Afiliação – Escola de Medicina e Ciências da Saúde da Universidade do Minho Coorientadora – Doutora Maria da Purificação Valenzuela Sampaio Tavares Categoria – Professora Catedrática Afiliação – Faculdade de Medicina Dentária da Universidade do Porto Coorientadora – Doutora Filipa Abreu Gomes de Carvalho Categoria – Professora Auxiliar com Agregação Afiliação – Faculdade de Medicina da Universidade do Porto DECLARAÇÃO Dissertação/Tese Identificação do autor Nome completo _Maria de Fátima e Costa Torres_ N.º de identificação civil _07718822 N.º de estudante __ 198600524___ Email institucional [email protected] OU: [email protected] _ Email alternativo [email protected] _ Tlf/Tlm _918197020_ Ciclo de estudos (Mestrado/Doutoramento) _Patologia e Genética Molecular__ Faculdade/Instituto _Instituto de Ciências
    [Show full text]
  • Francine Blumental De Abreu
    VARIAÇÃO NO NÚMERO DE CÓPIAS GENÔMICAS NA AVALIAÇÃO DE GENES PRINCIPAIS DE PREDISPOSIÇÃO EM PACIENTES COM SÍNDROME DE MAMA-CÓLON TRIADOS PARA MUTAÇÕES NOS GENES BRCA1, BRCA2, TP53, CHEK2, MLH1 E MSH2 FRANCINE BLUMENTAL DE ABREU Tese apresentada à Fundação Antônio Prudente para obtenção do Título de Doutor em Ciências Área de concentração: Oncologia Orientadora: Profª Dra. Silvia Regina Rogatto São Paulo 2012 FICHA CATALOGRÁFICA Preparada pela Biblioteca da Fundação Antônio Prudente Abreu, Francine Blumental de Variação no número de cópias genômicas na avaliação de genes principais de predisposição em pacientes com síndrome de mama- cólon triados para mutações nos genes BRCA1, BRCA2, TP53, CHEK2, MLH1 E MSH2 / Francine Blumental de Abreu – São Paulo, 2012. 245p. Tese (Doutorado)-Fundação Antônio Prudente. Curso de Pós-Graduação em Ciências - Área de concentração: Oncologia. Orientadora: Silvia Regina Rogatto Descritores: 1. SÍNDROME DE LYNCH. 2. NEOPLASIAS DA MAMA. 3. VARIAÇÃO DO NÚMERO DE CÓPIA DO DNA. 4. HIBRIDIZAÇÃO GENÔMICA COMPARATIVA. DEDICATÓRIA A minha família!!!! AGRADECIMENTOS À minha família... Edilucia (II:5) e Antonio (II:6) por serem mais do que pais, por serem mais do que amigos, por serem os meus super heróis! Obrigada pelos abraços, pelas palavras de apoio e de ensinamento, pelo carinho, pelo amor incondicional! Obrigada por estarem sempre disponíveis, por estenderem as mãos depois de uma “rasteira” da vida, por enxugarem as minhas lágrimas! Obrigada principalmente por me fazerem acreditar que momentos difíceis existem,
    [Show full text]
  • Influence of WFIKKN1 on BMP1-Mediated Activation of Latent
    Influence of WFIKKN1 on BMP1-mediated activation of latent myostatin Running title: WFIKKN1 and BMP1-activation of latent myostatin György Szláma, Viktor Vásárhelyi, Mária Trexler, László Patthy Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, P.O. Box 286, H-1519, Hungary Corresponding author: László Patthy, Tel: (361) 382 6751 e-mail: [email protected] Article Article type : Regular Paper Keywords: BMP1; heparin; latent myostatin; myostatin; WFIKKN1; Abbreviations: Act RIIB − activin receptor IIB; BMP1 − bone morphogenetic protein 1; KKN1 – The C- terminal half of WFIKKN1 protein, containing its Kunitz 1, Kunitz 2 and NTR domains; LM − latent myostatin; MSTN − myostatin gene; PCPE-1 − Procollagen C-Proteinase Enhancer-1; PMSF – phenylmethylsulfonyl fluoride; TGF − transforming growth factor; WFI1 – The N- terminal half of WFIKKN1 protein, containing its WAP, Follistatin and Immunoglobulin domains; WFIKKN1 and WFIKKN2 – multidomain proteins containing WAP, Follistatin, Immunoglobulin, Kunitz 1, Kunitz 2 and NTR domains; This article has been accepted for publication and 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: Accepted 10.1111/febs.13938 This article is protected by copyright. All rights reserved. Enzymes: furin: EC 3.4.21.75; BMP1, bone morphogentic protein 1 or procollagen C-endopeptidase: EC 3.4.24.19 Abstract The NTR domain of WFIKKN1 protein has been shown to have significant affinity for the prodomain regions of promyostatin and latent myostatin but the biological significance of these interactions remained unclear.
    [Show full text]
  • A Meta-Analysis of the Effects of High-LET Ionizing Radiations in Human Gene Expression
    Supplementary Materials A Meta-Analysis of the Effects of High-LET Ionizing Radiations in Human Gene Expression Table S1. Statistically significant DEGs (Adj. p-value < 0.01) derived from meta-analysis for samples irradiated with high doses of HZE particles, collected 6-24 h post-IR not common with any other meta- analysis group. This meta-analysis group consists of 3 DEG lists obtained from DGEA, using a total of 11 control and 11 irradiated samples [Data Series: E-MTAB-5761 and E-MTAB-5754]. Ensembl ID Gene Symbol Gene Description Up-Regulated Genes ↑ (2425) ENSG00000000938 FGR FGR proto-oncogene, Src family tyrosine kinase ENSG00000001036 FUCA2 alpha-L-fucosidase 2 ENSG00000001084 GCLC glutamate-cysteine ligase catalytic subunit ENSG00000001631 KRIT1 KRIT1 ankyrin repeat containing ENSG00000002079 MYH16 myosin heavy chain 16 pseudogene ENSG00000002587 HS3ST1 heparan sulfate-glucosamine 3-sulfotransferase 1 ENSG00000003056 M6PR mannose-6-phosphate receptor, cation dependent ENSG00000004059 ARF5 ADP ribosylation factor 5 ENSG00000004777 ARHGAP33 Rho GTPase activating protein 33 ENSG00000004799 PDK4 pyruvate dehydrogenase kinase 4 ENSG00000004848 ARX aristaless related homeobox ENSG00000005022 SLC25A5 solute carrier family 25 member 5 ENSG00000005108 THSD7A thrombospondin type 1 domain containing 7A ENSG00000005194 CIAPIN1 cytokine induced apoptosis inhibitor 1 ENSG00000005381 MPO myeloperoxidase ENSG00000005486 RHBDD2 rhomboid domain containing 2 ENSG00000005884 ITGA3 integrin subunit alpha 3 ENSG00000006016 CRLF1 cytokine receptor like
    [Show full text]