Identification of Trichoplein, a Novel Keratin Filament- Binding Protein
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Inhibiting TNIK for Treating Colon Cancer
(19) & (11) EP 2 305 717 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 06.04.2011 Bulletin 2011/14 C07K 16/40 (2006.01) C12N 15/11 (2006.01) C12Q 1/48 (2006.01) C12Q 1/68 (2006.01) (2006.01) (21) Application number: 09170853.7 G01N 33/50 (22) Date of filing: 21.09.2009 (84) Designated Contracting States: • Mahmoudi, Tokameh AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 3515 XS, Utrecht (NL) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL • Clevers, Johannes Carolus PT RO SE SI SK SM TR 3712 AP, Huis ter Heide (NL) (71) Applicant: KoninklijkeNederlandse Akademie van (74) Representative: Swinkels, Bart Willem Wetenschappen Nederlandsch Octrooibureau 1011 JV Amsterdam (NL) J. W. Frisolaan 13 2517 JS Den Haag (NL) (72) Inventors: • Wing Li, Vivian Sze 3572 SH, Utrecht (NL) (54) Inhibiting TNIK for treating colon cancer (57) The invention relates to an inhibitor of TNIK and its use for treating cancer. EP 2 305 717 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 305 717 A1 Description Field of the invention 5 [0001] The invention relates to an inhibitor of TNIK and its use as a medicament for treating cancer. Background of the invention [0002] The primary function of the intestinal tract involves the digestion and absorption of nutrients. The intestinal 10 lumen is lined with a specialized simple epithelium, which performs the primary functions of digestion, water and nutrient absorption and forms a barrier against luminal pathogens. -
Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-Like Mouse Models: Tracking the Role of the Hairless Gene
University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 5-2006 Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene Yutao Liu University of Tennessee - Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Life Sciences Commons Recommended Citation Liu, Yutao, "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino- like Mouse Models: Tracking the Role of the Hairless Gene. " PhD diss., University of Tennessee, 2006. https://trace.tennessee.edu/utk_graddiss/1824 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Yutao Liu entitled "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, with a major in Life Sciences. Brynn H. Voy, Major Professor We have read this dissertation and recommend its acceptance: Naima Moustaid-Moussa, Yisong Wang, Rogert Hettich Accepted for the Council: Carolyn R. -
Associated Palmoplantar Keratoderma
DR ABIGAIL ZIEMAN (Orcid ID : 0000-0001-8236-207X) Article type : Review Article Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: New insight into skin epithelial homeostasis and avenues for treatment Authors: A. G. Zieman1 and P. A. Coulombe1,2 # Affiliations: 1Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; 2Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA #Corresponding author: Pierre A. Coulombe, PhD, 3071 Biomedical Sciences Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA. Tel: 734-615-7509. Email: [email protected]. Funding Sources: These studies were supported by grant AR044232 issued to P.A.C. from the National Institute of Arthritis, Musculoskeletal and Skin Disease (NIAMS). A.G.Z. received support from grant T32 CA009110 from the National Cancer Institute. Author Manuscript 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: 10.1111/BJD.18033 This article is protected by copyright. All rights reserved Conflict of interest disclosures: None declared. Bulleted statements: What’s already known about this topic? Pachyonychia congenita is a rare genodermatosis caused by mutations in KRT6A, KRT6B, KRT6C, KRT16, KRT17, which are normally expressed in skin appendages and induced following injury. Individuals with PC present with multiple clinical symptoms that usually include thickened and dystrophic nails, palmoplantar keratoderma (PPK), glandular cysts, and oral leukokeratosis. -
Loss-Of-Function Mutations in the Gene Encoding Filaggrin Cause Ichthyosis
LETTERS Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris Frances J D Smith1, Alan D Irvine2, Ana Terron-Kwiatkowski1, Aileen Sandilands1, Linda E Campbell1, Yiwei Zhao1, Haihui Liao1, Alan T Evans3, David R Goudie4, Sue Lewis-Jones5, Gehan Arseculeratne5, Colin S Munro6, Ann Sergeant6, Gra´inne O’Regan2, Sherri J Bale7, John G Compton7, John J DiGiovanna8,9, Richard B Presland10,11, Philip Fleckman11 & W H Irwin McLean1 Ichthyosis vulgaris (OMIM 146700) is the most common composed of the 400-kDa protein profilaggrin. Following a short, inherited disorder of keratinization and one of the most unique N-terminal domain, most of the profilaggrin molecule consists frequent single-gene disorders in humans. The most widely of 10–12 repeats of the 324-residue filaggrin sequence6. Upon terminal cited incidence figure is 1 in 250 based on a survey of differentiation of granular cells, profilaggrin is proteolytically cleaved 1 B http://www.nature.com/naturegenetics 6,051 healthy English schoolchildren . We have identified into 37-kDa filaggrin peptides and the N-terminal domain contain- homozygous or compound heterozygous mutations R501X and ing an S100-like calcium binding domain. Filaggrin rapidly aggregates 2282del4 in the gene encoding filaggrin (FLG) as the cause of the keratin cytoskeleton, causing collapse of the granular cells into moderate or severe ichthyosis vulgaris in 15 kindreds. In flattened anuclear squames. This condensed cytoskeleton is cross- addition, these mutations are semidominant; heterozygotes linked by transglutaminases during formation of the cornified cell show a very mild phenotype with incomplete penetrance. envelope (CCE). The CCE is the outermost barrier layer of the skin The mutations show a combined allele frequency of B4% which not only prevents water loss but also impedes the entry of in populations of European ancestry, explaining the high allergens and infectious agents7. -
An Abridged Compendium of Words. a Discussion of Them and Opinions About Them
DERMATOLOGY PRACTICAL & CONCEPTUAL www.derm101.com Dermatopathology: An abridged compendium of words. A discussion of them and opinions about them. Part 6 (I-L) Bruce J. Hookerman1 1 Dermatology Specialists, Bridgeton, Missouri, USA Citation: Hookerman BJ. Dermatopathology: An abridged compendium of words. A discussion of them and opinions about them. Part 6 (I-L). Dermatol Pract Concept. 2014;4(4):1. http://dx.doi.org/10.5826/dpc.0404a01 Copyright: ©2014 Hookerman. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Corresponding author: Bruce J. Hookerman, M.D., 12105 Bridgeton Square Drive, St. Louis, MO 63044, USA. Email: [email protected] – I – term “id reaction” only for a spongiotic dermatitis manifested by tiny vesicles on the hands of patients with florid dermato- ICHTHYOSIS: a generic term for skin conditions character- phytosis at another site, usually the feet, or for an analogue ized by what are said to be fishlike scales, i.e., scales that are of that phenomenon such as widespread vesicles that appear broad and polygonal with free edges, as are seen in ichthyosis subsequent to injudicious treatment, i.e., with Gentian violet vulgaris (and its look-alike, acquired ichthyosis), X-linked (known sardonically in times past as “Gentian violent”) of ichthyosis, and lamellar ichthyosis. Conditions reputed to be an exuberant spongiotic dermatitis, usually on the feet, such ichthyosis, such as ichthyosis hystrix and ichthyosis linearis as an allergic contact dermatitis. A time-honored explana- circumflexa, do not qualify because they are not associated tion for an “id” reaction is hematogenous dissemination of with broad polygonal scales. -
Genetic Background Effects of Keratin 8 and 18 in a DDC-Induced Hepatotoxicity and Mallory-Denk Body Formation Mouse Model
Laboratory Investigation (2012) 92, 857–867 & 2012 USCAP, Inc All rights reserved 0023-6837/12 $32.00 Genetic background effects of keratin 8 and 18 in a DDC-induced hepatotoxicity and Mallory-Denk body formation mouse model Johannes Haybaeck1, Cornelia Stumptner1, Andrea Thueringer1, Thomas Kolbe2, Thomas M Magin3, Michael Hesse4, Peter Fickert5, Oleksiy Tsybrovskyy1, Heimo Mu¨ller1, Michael Trauner5,6, Kurt Zatloukal1 and Helmut Denk1 Keratin 8 (K8) and keratin 18 (K18) form the major hepatocyte cytoskeleton. We investigated the impact of genetic loss of either K8 or K18 on liver homeostasis under toxic stress with the hypothesis that K8 and K18 exert different functions. krt8À/À and krt18À/À mice crossed into the same 129-ola genetic background were treated by acute and chronic ad- ministration of 3,5-diethoxy-carbonyl-1,4-dihydrocollidine (DDC). In acutely DDC-intoxicated mice, macrovesicular steatosis was more pronounced in krt8À/À and krt18À/À compared with wild-type (wt) animals. Mallory-Denk bodies (MDBs) appeared in krt18À/À mice already at an early stage of intoxication in contrast to krt8À/À mice that did not display MDB formation when fed with DDC. Keratin-deficient mice displayed significantly lower numbers of apoptotic hepatocytes than wt animals. krt8À/À, krt18À/À and control mice displayed comparable cell proliferation rates. Chronically DDC-intoxicated krt18À/À and wt mice showed a similarly increased degree of steatohepatitis with hepatocyte ballooning and MDB formation. In krt8À/À mice, steatosis was less, ballooning, and MDBs were absent. krt18À/À mice developed MDBs whereas krt8À/À mice on the same genetic background did not, highlighting the significance of different structural properties of keratins. -
Keratin 9 Point Mutation in the Pedigree of Epidermolytic Hereditary Palmoplantar Keratoderma Perturbs Keratin Intermediate Filament Network Formation
FEBS 17004 FEBS Letters 386 (1996) 149-155 Keratin 9 point mutation in the pedigree of epidermolytic hereditary palmoplantar keratoderma perturbs keratin intermediate filament network formation Setsu Kobayashi, Toshihiro Tanaka*, Norihisa Matsuyoshi, Sadao Imamura Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, 606 Japan Received 12 January 1996; revised version received 4 April 1996 Abstract Keratins form an intracellular keratin filament net- point mutations in the K9 gene in EHPPK [4-8] but none work in keratinocytes. Point mutations in the epidermal keratins showed a function assay with these mutations. Here, we pro- could lead to the disruption of keratin filament formation, vide the first demonstration that the point mutation found in developing skin diseases such as epidermolytic hereditary a pedigree of EHPPK has a dominant-negative effect on the palmoplantar keratoderma (EHPPK). We found a G to A assembly of keratin intermediate filaments in the cells. transition in keratin 9 (K9) cDNA, resulting in the substitution of glutamine for arginine at 162, in all patients of a pedigree of 2. Materials and methods EHPPK. Transfection into MDCK cells and DJM-1 cells revealed that the plasmid CMX vector containing normal keratin 2.1. PCR and DNA sequence 9 cDNA showed normal keratin network formation, whereas the Genomic DNA was extracted and purified from blood or biopsy vector with a G to A point mutated keratin 9 cDNA showed specimens from the patients. The primers were designed at nucleotide disrupted keratin filaments with droplet formation in the cells. 263 282 and 664-683 based on the K9 cDNA sequence [9]. -
Deimination, Intermediate Filaments and Associated Proteins
International Journal of Molecular Sciences Review Deimination, Intermediate Filaments and Associated Proteins Julie Briot, Michel Simon and Marie-Claire Méchin * UDEAR, Institut National de la Santé Et de la Recherche Médicale, Université Toulouse III Paul Sabatier, Université Fédérale de Toulouse Midi-Pyrénées, U1056, 31059 Toulouse, France; [email protected] (J.B.); [email protected] (M.S.) * Correspondence: [email protected]; Tel.: +33-5-6115-8425 Received: 27 October 2020; Accepted: 16 November 2020; Published: 19 November 2020 Abstract: Deimination (or citrullination) is a post-translational modification catalyzed by a calcium-dependent enzyme family of five peptidylarginine deiminases (PADs). Deimination is involved in physiological processes (cell differentiation, embryogenesis, innate and adaptive immunity, etc.) and in autoimmune diseases (rheumatoid arthritis, multiple sclerosis and lupus), cancers and neurodegenerative diseases. Intermediate filaments (IF) and associated proteins (IFAP) are major substrates of PADs. Here, we focus on the effects of deimination on the polymerization and solubility properties of IF proteins and on the proteolysis and cross-linking of IFAP, to finally expose some features of interest and some limitations of citrullinomes. Keywords: citrullination; post-translational modification; cytoskeleton; keratin; filaggrin; peptidylarginine deiminase 1. Introduction Intermediate filaments (IF) constitute a unique macromolecular structure with a diameter (10 nm) intermediate between those of actin microfilaments (6 nm) and microtubules (25 nm). In humans, IF are found in all cell types and organize themselves into a complex network. They play an important role in the morphology of a cell (including the nucleus), are essential to its plasticity, its mobility, its adhesion and thus to its function. -
Comparative Genomics Analyses of Alpha-Keratins Reveal Insights Into
Sun et al. Frontiers in Zoology (2017) 14:41 DOI 10.1186/s12983-017-0225-x RESEARCH Open Access Comparative genomics analyses of alpha- keratins reveal insights into evolutionary adaptation of marine mammals Xiaohui Sun, Zepeng Zhang, Yingying Sun, Jing Li, Shixia Xu* and Guang Yang* Abstract Background: Diversity of hair in marine mammals was suggested as an evolutionary innovation to adapt aquatic environment, yet its genetic basis remained poorly explored. We scanned α-keratin genes, one major structural components of hair, in 16 genomes of mammalian species, including seven cetaceans, two pinnipeds, polar bear, manatee and five terrestrial species. Results: Extensive gene loss and high pseudogenization rate of α-keratin genes were identified in cetaceans when compared to terrestrial artiodactylans (average number of α-keratins 37.29 vs. 58.33; pseudogenization rate 29.89% vs. 8.00%), especially of hair follicle-specific keratin genes (average pseudogenization rate in cetaceans of 43.88% relative to 3.80% artiodactylian average). Compared to toothed whale, the much more number of intact functional α-keratin genes was examined in the baleen whale that had specific keratinized baleen. In contrast, the number of keratin genes in pinnipeds, polar bear and manatee were comparable to those of their respective terrestrial relatives. Additionally, four keratin genes (K39, K9, K42, and K74) were found to be pseudogenes or lost uniquely in cetaceans and manatees. Conclusions: Species-specific evolution of α-keratin gene family identified in the marine mammals might be responsible for their different hair characteristics. Increased gene loss and pseudogenization rate identified in cetacean lineages was likely to contribute to hair-less phenotype to adaptation for complete aquatic environment. -
Proteomic Approaches Identify Members of Cofilin Pathway Involved in Oral Tumorigenesis
Proteomic Approaches Identify Members of Cofilin Pathway Involved in Oral Tumorigenesis Giovana M. Polachini1, Lays M. Sobral2, Ana M. C. Mercante3, Adriana F. Paes-Leme4, Fla´via C. A. Xavier5, Tiago Henrique1, Douglas M. Guimara˜es6, Alessandra Vidotto1, Erica E. Fukuyama7, Jose´ F. Go´ is-Filho7, Patricia M. Cury8, Ota´vio A. Curioni9, Pedro Michaluart Jr10, Adriana M. A. Silva11, Victor Wu¨ nsch-Filho12, Fabio D. Nunes6, Andre´ia M. Leopoldino2, Eloiza H. Tajara1,13* 1 Departamento de Biologia Molecular; Faculdade de Medicina (FAMERP), Sa˜oJose´ do Rio Preto, SP, Brazil, 2 Departamento de Ana´lises Clı´nicas, Toxicolo´gicas e Bromatolo´gicas, Faculdade de Cieˆncias Farmaceˆuticas da Universidade de Sa˜o Paulo, Ribeira˜o Preto, SP, Brazil, 3 Laborato´rio de Patologia, Hospital Helio´polis, Sa˜o Paulo, SP, Brazil, 4 Laborato´rio Nacional de Biocieˆncias (LNBio), Centro Nacional de Pesquisa em Energia e Materiais, Campinas, SP, Brazil, 5 Departamento de Propedeˆutica e Clı´nica Integrada, Faculdade de Odontologia da Universidade Federal da Bahia, Salvador,BA, Brazil, 6 Departamento de Estomatologia, Faculdade de Odontologia da Universidade de Sa˜o Paulo, Sa˜o Paulo, SP, Brazil, 7 Servic¸o de Cirurgia de Cabec¸a e Pescoc¸o, Instituto do Caˆncer Arnaldo Vieira de Carvalho, Sa˜o Paulo, SP, Brazil, 8 Departamento de Patologia e Medicina Legal, Faculdade de Medicina (FAMERP), Sa˜oJose´ do Rio Preto, SP, Brazil, 9 Departamento de Cirurgia de Cabec¸a e Pescoc¸o e Otorrinolaringologia, Hospital Helio´polis, Sa˜o Paulo, SP, Brazil, 10 Divisa˜o -
The Correlation of Keratin Expression with In-Vitro Epithelial Cell Line Differentiation
The correlation of keratin expression with in-vitro epithelial cell line differentiation Deeqo Aden Thesis submitted to the University of London for Degree of Master of Philosophy (MPhil) Supervisors: Professor Ian. C. Mackenzie Professor Farida Fortune Centre for Clinical and Diagnostic Oral Science Barts and The London School of Medicine and Dentistry Queen Mary, University of London 2009 Contents Content pages ……………………………………………………………………......2 Abstract………………………………………………………………………….........6 Acknowledgements and Declaration……………………………………………...…7 List of Figures…………………………………………………………………………8 List of Tables………………………………………………………………………...12 Abbreviations….………………………………………………………………..…...14 Chapter 1: Literature review 16 1.1 Structure and function of the Oral Mucosa……………..…………….…..............17 1.2 Maintenance of the oral cavity...……………………………………….................20 1.2.1 Environmental Factors which damage the Oral Mucosa………. ….…………..21 1.3 Structure and function of the Oral Mucosa ………………...….……….………...21 1.3.1 Skin Barrier Formation………………………………………………….……...22 1.4 Comparison of Oral Mucosa and Skin…………………………………….……...24 1.5 Developmental and Experimental Models used in Oral mucosa and Skin...……..28 1.6 Keratinocytes…………………………………………………….….....................29 1.6.1 Desmosomes…………………………………………….…...............................29 1.6.2 Hemidesmosomes……………………………………….…...............................30 1.6.3 Tight Junctions………………………….……………….…...............................32 1.6.4 Gap Junctions………………………….……………….….................................32 -
Immunohistochemistry in Undifferentiated Neoplasm/Tumor of Uncertain Origin
Immunohistochemistry in Undifferentiated Neoplasm/Tumor of Uncertain Origin Fan Lin, MD, PhD; Haiyan Liu, MD Context.—Immunohistochemistry has become an indis- predict prognostic outcomes, it is crucial to differentiate pensable ancillary study in the identification and classifi- the specific lineage of an undifferentiated neoplasm. cation of undifferentiated neoplasms/tumors of uncertain Application of appropriate immunohistochemical panels origin. The diagnostic accuracy has significantly improved enables the accurate classification of most undifferentiated because of the continuous discoveries of tissue-specific neoplasms. Knowing the utilities and pitfalls of each tissue- biomarkers and the development of effective immunohis- specific biomarker is essential for avoiding potential tochemical panels. diagnostic errors because an absolutely tissue-specific Objectives.—To identify and classify undifferentiated biomarker is exceptionally rare. We review frequently neoplasms/tumors of uncertain origin by immunohisto- used tissue-specific biomarkers, provide effective panels, chemistry. and recommend diagnostic algorithms as a standard Data Sources.—Literature review and authors’ research approach to undifferentiated neoplasms. data and personal practice experience were used. (Arch Pathol Lab Med. 2014;138:1583–1610; doi: Conclusions.—To better guide therapeutic decisions and 10.5858/arpa.2014-0061-RA) fter an extensive workup, combining clinical, radiologic, trefoil factor (TFF) 1, ankyrin repeat domain 30A (NY-BR-1), A morphologic, and