DOCSLIB.ORG

Type I Collagen Is a Molecular Target for Inhibition of Angiogenesis by Endogenous Thrombospondin-1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Type I Collagen Is a Molecular Target for Inhibition of Angiogenesis by Endogenous Thrombospondin-1 Oncogene (2006) 25, 536–545 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc ORIGINAL ARTICLE Type I collagen is a molecular target for inhibition of angiogenesis by endogenous thrombospondin-1 L Zhou1, JS Isenberg1, Z Cao and DD Roberts Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Three-dimensional explant cultures of muscle tissue were stat-Saslow et al., 1994; Tenan et al., 2000; Streit et al., used to characterize secreted proteins regulated by 2002).TSP1 gene expression is lost during progression endogenous levels of the angiogenesis modulator thrombo- of a number of cancer types, but TSP1 levels in some spondin (TSP)-1. Explants from TSP1 null mice exhibit tumor types remain high due to induced expression of enhanced neovascularization associated with increased TSP1 by stromal cells (reviewed in Lawler and Detmar, endothelial outgrowth but decreased outgrowth of peri- (2004)).Studies using transgenic mice confirmed that vascular smooth muscle cells . The absence of endogenous host endogenous TSP1 plays an important role in TSP1 did not diminish activation of latent transforming limiting neovascularization of tumors (Lawler et al., growth factor-b and moderately decreased matrixmetal- 2001; Hamano et al., 2004). loproteinase levels. However, significant changes in other Antiangiogenic fragments and peptides derived from secreted proteins were observed. Endogenous TSP1 TSP1 can inhibit angiogenesis and tumor growth in decreased mRNA levels for collagens Ia1, Ia2, and IIIa1 animals (Tolsma et al., 1993; Guo et al., 1997b; and laminin a4 and increased collagen IVa1 mRNA Bogdanov Jr et al., 1999; Iruela-Arispe et al., 1999; expression. Endogenous TSP1 also decreased the level of Westphal, 2004; Yee et al., 2004). However, adverse type I collagen protein produced by the vascular out- tumor responses to other TSP1 constructs have been growths. Collagens Ia1, Ia2, and IIIa1 are known tumor observed (de Fraipont et al., 2004), and some TSP1 endothelial markers, suggesting that TSP1 coordinately fragments have clear proangiogenic activities (Chandra- regulates a set of extracellular matrix genes that reverse sekaran et al., 2000; Calzada et al., 2004). Furthermore, the angiogenic switch. Suppression of collagen Ia1orIa2 some tumors become resistant to TSP1 (Filleur et al., mRNAs using antisense morpholinos inhibited outgrowth 2001), so successful use of TSP1-derived drugs will in TSP1 null explants and proliferation of TSP1 null require a deeper understanding of the mechanisms by endothelial cells, indicating that type I collagen synthesis which TSP1 regulates angiogenesis. is limiting for this neovascularization response. At least eight TSP1 receptors mediate its effects on Oncogene (2006) 25, 536–545. doi:10.1038/sj.onc.1209069; endothelial cells, and of these CD36 (Jimenez et al., published online 10 October 2005 2000; Jimenez et al., 2001), heparan sulfate proteogly- cans (Guo et al., 1997a; Iruela-Arispe et al., 1999), Keywords: 3D culture; endothelial cells; angiogenesis CD47 (Kanda et al., 1999), and a3b1 (Chandrasekaran inhibitors; collagens et al., 2000) and a4b1 integrins modulate angiogenesis (Calzada et al., 2004). TSP1 induces expression of matrix metalloproteinase (MMP)-2 and MMP-9 in endothelial cells (Qian et al., 1997; Taraboletti et al., Introduction 2000), but direct interactions of TSP1 with MMPs may counteract this by inhibiting MMP activities or Thrombospondins (TSPs) are a family of five secreted mediating their degradation (Bein and Simons, 2000; proteins that are transiently or constitutively expressed Rodriguez-Manzaneque et al., 2001). Activation of in the extracellular matrices of various tissues (Born- latent TGFb also mediates some effects of TSP1 on stein, 2001; Adams and Lawler, 2004).Two members of endothelial cell proliferation (reviewed in Murphy- this family, TSP1 and TSP2, are potent inhibitors of Ullrich and Poczatek, (2000)) and tumor growth (Yee angiogenesis and have antitumor activities in several et al., 2004). Signaling through the CD36 receptor tumor xenograft models (Dameron et al., 1994; Wein- results in phosphorylation of c-Jun N-terminal kinase, which is required for inhibition of angiogenesis in vivo Correspondence: Dr DD Roberts, Biochemical Pathology Section, (Jimenez et al., 2001). A cascade involving phosphoryla- National Cancer Institute, National Institutes of Health, Building 10 tion of p59fyn, caspase-3 like proteases, and p38 Room 2A33, 10 Center Dr MSC 1500, Bethesda, MD 20892-1500, mitogen-activated protein kinases is also stimulated by USA. TSP1 through CD36 and mediates induction of Fas- E-mail: [email protected] 1These two authors contributed equally to this work. dependent endothelial cell apoptosis (Jimenez et al., Received 24 March 2005; revised 1 July 2005; accepted 1 August 2005; 2000; Volpert et al., 2002). TSP1 also regulates published online 10 October 2005 cytoskeletal actin in endothelial cells and inhibits Thrombospondin-1 targets in angiogenesis L Zhou et al 537 formation of lamellipodia associated with increased response to serum and growth factors in the lower phosphorylation of hsp27 and cofilin (Keezer et al., chamber was counted (Figure 1a).More vascular cells 2003). from the TSP1 null explants migrated through the In addition to endothelial cells, angiogenesis involves membrane than did those from WT explants.Therefore, pericytes, fibroblasts, immune cells, and mast cells. expression of endogenous TSP1 in the WT explants These cells express cytokines and growth factors that inhibits migration of vascular outgrowth cells. regulate endothelial cell proliferation, migration, inva- Invasive activity of outgrowth cells from muscle sion, tube formation, and vessel stabilization (Eliceiri explants was evaluated using 8 mm inserts precoated and Cheresh, 2001).Many of these cell types also with a barrier of polymerized type I collagen respond directly to TSP1 in vitro (Majack et al., 1986; (Figure 1b).The inserts were placed into wells contain- Sunderkotter et al., 1994; Chen et al., 1999; Isenberg ing MDA-MB-435 breast cancer cells to supply angio- et al., 2005). Therefore, interactions of TSP1 with genic factors, and the muscle explants were placed into several receptors and with several cell types probably the upper compartments.After 6 days, more cells from contribute to its modulation of angiogenesis.Specific the TSP1 null mice muscle explants invaded through the TSP1 receptors may also be differentially expressed or collagen barrier than did those cells from WT explants. utilized in specific types of developmental and patho- MDA-MB-435 cells do not express significant TSP1 logical angiogenesis. (Zabrenetzky et al., 1994). Therefore, endogenous TSP1 Given this complexity in cellular responses to TSP1, produced by the explants also suppresses the invasive we must first establish experimental systems wherein the functions of multiple receptors and vascular cell types in responding to TSPs can be quantified simultaneously to understand how TSP1 influences tumor angiogenesis. We recently established an ex vivo model for this purpose that can be used to identify the cellular and molecular targets of endogenous TSP1 in angiogenic responses (Calzada et al., 2004; Isenberg et al., 2005). Muscle explants from TSP1 null mice grown in three- dimensional (3D) cultures showed the predicted increase in endothelial outgrowth, whereas vascular smooth muscle cell outgrowth was deficient in the absence of endogenous TSP1 (Isenberg et al., 2005). Using the same explant model, we defined a role for its receptor a4b1 integrin in mediating effects of endogenous TSP1 on vascular outgrowth and showed that an antagonist of a4b1 selectively inhibited outgrowth of wild-type (WT) explants (Calzada et al., 2004). We have now used the 3D explant assay to identify secreted molecular targets of TSP1 in neovascularization and to test the function of secreted proteins that are known targets of TSP1.By this approach, we found type I collagen expression to be dependent on endogenous TSP1.Levels of mRNA for several other collagen genes and laminin a4 differed between vascular outgrowths from null and WT explants.Using antisense morpholinos, we found that collagen Ia1orIa2 are limiting for angiogenic responses of TSP1 null explants in a 3D matrix.As these changes mirror those recently identified for the same collagen Figure 1 Endogenous TSP1 inhibits random migration and genes in human tumor endothelium (St Croix et al., directed invasion of outgrowth cells from murine muscle explants. 2000; Madden et al., 2004) and metastatic tumors (a) Outgrowth cell migration was examined by culturing muscle explants to the upper compartments of 8 mm polycarbonate (Ramaswamy et al., 2003), the muscle explant assay membrane tissue culture inserts in EBM medium.After 6 days, may facilitate study of the angiogenic switch in cancer. cells that migrated to the underside of the filters were counted in five randomly chosen microscope fields.( b) The invasion of vascular cells from muscle was evaluated.Polycarbonate inserts (8 mm) were precoated with 50 mg collagen I and placed in the upper compartments of 24-well plate to which 5000 MDA-MB-435 Results human breast cancer cells/well were plated in RPMI 1640 medium containing 10% FBS to supply angiogenic factors.Muscle explants Endogenous TSP1 inhibits invasion of outgrowth cells were placed into the upper compartments and cultured in EBM To better quantify migratory activity
Load more

Recommended publications
  • A Diverse Host Thrombospondin-Type-1
    RESEARCH ARTICLE A diverse host thrombospondin-type-1 repeat protein repertoire promotes symbiont colonization during establishment of cnidarian-dinoflagellate symbiosis Emilie-Fleur Neubauer1, Angela Z Poole2,3, Philipp Neubauer4, Olivier Detournay5, Kenneth Tan3, Simon K Davy1*, Virginia M Weis3* 1School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand; 2Department of Biology, Western Oregon University, Monmouth, United States; 3Department of Integrative Biology, Oregon State University, Corvallis, United States; 4Dragonfly Data Science, Wellington, New Zealand; 5Planktovie sas, Allauch, France Abstract The mutualistic endosymbiosis between cnidarians and dinoflagellates is mediated by complex inter-partner signaling events, where the host cnidarian innate immune system plays a crucial role in recognition and regulation of symbionts. To date, little is known about the diversity of thrombospondin-type-1 repeat (TSR) domain proteins in basal metazoans or their potential role in regulation of cnidarian-dinoflagellate mutualisms. We reveal a large and diverse repertoire of TSR proteins in seven anthozoan species, and show that in the model sea anemone Aiptasia pallida the TSR domain promotes colonization of the host by the symbiotic dinoflagellate Symbiodinium minutum. Blocking TSR domains led to decreased colonization success, while adding exogenous *For correspondence: Simon. TSRs resulted in a ‘super colonization’. Furthermore, gene expression of TSR proteins was highest [email protected] (SKD); weisv@ at early time-points during symbiosis establishment. Our work characterizes the diversity of oregonstate.edu (VMW) cnidarian TSR proteins and provides evidence that these proteins play an important role in the Competing interests: The establishment of cnidarian-dinoflagellate symbiosis. authors declare that no DOI: 10.7554/eLife.24494.001 competing interests exist.
    [Show full text]
  • Thrombospondin-1, Human (ECM002)
    Thrombospondin-1, human recombinant, expressed in HEK 293 cells suitable for cell culture Catalog Number ECM002 Storage Temperature –20 C Synonyms: THBS1, THBS, TSP1, TSP This product is supplied as a powder, lyophilized from phosphate buffered saline. It is aseptically filled. Product Description Thrombospondin-1 (TSP1) is believed to play a role in The biological activity of recombinant human cell migration and proliferation, during embryogenesis thrombospondin-1 was tested in culture by measuring and wound repair.1-2 TSP1 expression is highly the ability of immobilized DTT-treated regulated by different hormones and cytokines, and is thrombospondin-1 to support adhesion of SVEC4-10 developmentally controlled. TSP1 stimulates the growth cells. of vascular smooth muscle cells and human foreskin fibroblasts. A combination of interferon and tumor Uniprot: P07996 necrosis factor inhibits TSP1 production in these cells.3 In endothelial cells, it controls adhesion and Purity: 95% (SDS-PAGE) migration as well as proliferation. It also exhibits antiangiogenic properties and regulates immune Endotoxin level: 1.0 EU/g FN (LAL) processes.4-5 TSP1 binds to various cell surface receptors, such as integrins and integrin-associated Precautions and Disclaimer protein CD47.1 It also plays a crucial role in This product is for R&D use only, not for drug, inflammatory processes and post-inflammatory tissue household, or other uses. Please consult the Safety dynamics.6 TSP1 has been used as a potential Data Sheet for information regarding hazards and safe regulator of tumor growth and metastasis.5 It is handling practices. upregulated in rheumatoid synovial tissues and might be associated with rheumatoid arthritis.7 Variants of this Preparation Instructions gene might be linked with increased risk of autism.8 Briefly centrifuge the vial before opening.
    [Show full text]
  • Matrix Mechanotransduction Mediated by Thrombospondin-1/Integrin/YAP in the Vascular Remodeling
    Matrix mechanotransduction mediated by thrombospondin-1/integrin/YAP in the vascular remodeling Yoshito Yamashiroa,1, Bui Quoc Thangb, Karina Ramireza,c, Seung Jae Shina,d, Tomohiro Kohatae, Shigeaki Ohataf, Tram Anh Vu Nguyena,c, Sumio Ohtsukie, Kazuaki Nagayamaf, and Hiromi Yanagisawaa,g,1 aLife Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Ibaraki 305-8577, Japan; bDepartment of Cardiovascular Surgery, University of Tsukuba, Ibaraki 305-8575, Japan; cPh.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Ibaraki 305-8577, Japan; dGraduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki 305-8577, Japan; eFaculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan; fGraduate School of Mechanical Systems Engineering, Ibaraki University, Ibaraki 316-8511, Japan; and gDivision of Biomedical Science, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8577, Japan Edited by Kun-Liang Guan, University of California San Diego, La Jolla, CA, and accepted by Editorial Board Member Christine E. Seidman March 15, 2020 (received for review November 9, 2019) The extracellular matrix (ECM) initiates mechanical cues that highly context dependent, and extracellular regulators are not activate intracellular signaling through matrix–cell interactions. fully understood (6, 9). In blood vessels, additional mechanical cues derived from the pul- Thrombospondin-1 (Thbs1) is a homotrimeric glycoprotein satile blood flow and pressure play a pivotal role in homeostasis with a complex multidomain structure capable of interacting with and disease development. Currently, the nature of the cues from a variety of receptors such as integrins, cluster of differentiation the ECM and their interaction with the mechanical microenviron- (CD) 36, and CD47 (10).
    [Show full text]
  • Cell Surface-Localized Matrix Metalloproteinase-9 Proteolytically Activates TGF-␤ and Promotes Tumor Invasion and Angiogenesis
    Downloaded from genesdev.cshlp.org on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-␤ and promotes tumor invasion and angiogenesis Qin Yu and Ivan Stamenkovic1 Molecular Pathology Unit, Massachusetts General Hospital, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02129 USA We have uncovered a novel functional relationship between the hyaluronan receptor CD44, the matrix metalloproteinase-9 (MMP-9) and the multifunctional cytokine TGF-␤ in the control of tumor-associated tissue remodeling. CD44 provides a cell surface docking receptor for proteolytically active MMP-9 and we show here that localization of MMP-9 to cell surface is required for its ability to promote tumor invasion and angiogenesis. Our observations also indicate that MMP-9, as well as MMP-2, proteolytically cleaves latent TGF-␤, providing a novel and potentially important mechanism for TGF-␤ activation. In addition, we show that MMP-9 localization to the surface of normal keratinocytes is CD44 dependent and can activate latent TGF-␤. These observations suggest that coordinated CD44, MMP-9, and TGF-␤ function may provide a physiological mechanism of tissue remodeling that can be adopted by malignant cells to promote tumor growth and invasion. [Key Words: MMP-9; CD44; TGF-␤; tumor angiogenesis; tumor invasion] Received September 10, 1999; revised version accepted December 7, 1999. The ability of tumor cells to establish a functional rela- nals transduced by integrins following engagement by tionship with their host tissue microenvironment and to ligands may provide tumor cells with critical survival utilize the local resources to their advantage are key fac- signals within the host tissue microenvironment (Frisch tors in determining tumor cell survival, local tumor de- and Ruoslahti 1997).
    [Show full text]
  • Extracellular Matrix Retention of Thrombospondin 1 Is Controlled by Its Conserved C-Terminal Region
    784 Research Article Extracellular matrix retention of thrombospondin 1 is controlled by its conserved C-terminal region Josephine C. Adams1,2,*, Amber A. Bentley1, Marc Kvansakul3,‡, Deborah Hatherley4 and Erhard Hohenester3 1Department of Cell Biology, Lerner Research Institute, and 2Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA 3Division of Cell and Molecular Biology, Imperial College London, Biophysics Section, Blackett Laboratory, London, SW7 2AZ, UK 4Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK *Author for correspondence (e-mail: [email protected]) ‡Present address: Structural Biology Division, The Walter and Eliza Hall Institute, 3050 Parkville, Victoria, Australia Accepted 3 December 2007 J. Cell Sci. 121, 784-795 Published by The Company of Biologists 2008 doi:10.1242/jcs.021006 Summary Thrombospondins (TSPs) are an evolutionarily ancient family domain or type 1 repeats. Using a novel mRFP-tagged TSP1 of extracellular calcium-binding glycoproteins. The five C-terminal trimer, we demonstrate that ECM retention involves mammalian TSPs collectively have important roles in the RGD site and a novel site in the L-lectin domain with angiogenesis and vascular biology, synaptogenesis, wound repair structural similarity to the ligand-binding site of cargo transport and connective tissue organisation. Their complex functions proteins. CD47 and ␤1 integrins are dispensable for ECM relate to the multiple postsecretion fates of TSPs that can involve retention, but ␤1 integrins enhance activity. These novel data endocytic uptake, proteolysis or retention within the advance concepts of the molecular processes that lead to ECM extracellular matrix (ECM).
    [Show full text]
  • Thrombospondin-1 Peptides Signaling by Thrombospondin-1
    b 1 Integrin- and Proteoglycan-Mediated Stimulation of T Lymphoma Cell Adhesion and Mitogen-Activated Protein Kinase Signaling by Thrombospondin-1 and Thrombospondin-1 Peptides Katherine E. Wilson,1 Zhuqing Li, Murat Kara, Kevin L. Gardner, and David D. Roberts2 Cell-cell and cell-matrix interactions play important regulatory roles in lymphocyte homeostasis. Thrombospondin-1 (TSP1) is a matricellular protein that differentially promotes the adhesion of resting and activated T cells. In this work, we show that adhesion b of Jurkat T cells on substrates coated with TSP1 or TSP1-derived peptides is mediated by 1 integrins, CD47, and heparan sulfate proteoglycans. Interactions with TSP1 or TSP1 peptides stimulated CD3-induced Ras activation and tyrosine phosphorylation of several T cell proteins. The signals from TSP1 and its derived peptides differentially synergized with activation of the TCR to induce phosphorylation of linker for activation of T cells (LAT) and extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase, and p38 kinases. The phosphorylation of ERK in the presence of full-length TSP1 was transient and dependent b on a 1 integrin receptor. Interestingly, peptides derived from the type 1 repeats of TSP1 and a CD47-binding peptide from the carboxyl-terminal domain of TSP1 also stimulated mitogen-activated protein (MAP) kinase phosphorylation. Moreover, the TSP1 heparin-binding peptide synergized with Ab-ligated TCR to transduce signals to the nucleus, detected by activation of AP-1- and Elk-dependent transcription. This TSP1 peptide-dependent activation of AP-1 was inhibited by both heparin and the MAP/ERK kinase inhibitor PD98059, providing a functional link between adhesion molecule interaction and nuclear transactivation events via the MAP kinase pathways.
    [Show full text]
  • The Kinetics of C9, Vitronectin and the Terminal Complement
    CERTIFICATE OF ORIGINALITY I hereby declare that this submission is my own work and that, to the best of my knowledge and belief, it contains no material previously published or written by another person nor material which to a substantial extent has been accepted for the award of any other degree or diploma of a university or other institute of higher learning, except where due acknowledgement is made in the text. I also declare that the intellectual content of this thesis is the product of my own work, even though I may have received assistance from others on style, presentation and language expression. (Signee THE KINETICS OF C9, VITRONECTIN AND THE TERMINAL COMPLEMENT COMPLEX by James David Greenstein Department of Nephrology, Prince Henry Hospital, Sydney, Australia and Faculty of Medicine, University of New South Wales, Sydney, Australia Submitted/or the degree ofDoctor ofPhilosophy 1997 u i'J s vv 1 4 MAY 1998 LlBHARY A n ABSTRACT The primary pathways of complement activation converge to produce the terminal complement complex (TCC). Assembly of the TCC on a cell surface may result in the formation of a cytolytic pore, or membrane attack complex (MAC, i.e. C5b- 9(m)), composed of the five terminal complement components. Alternatively, complement activation in the plasma produces the soluble form, SC5b-9, which by the inclusion of regulatory proteins, vitronectin (S-protein) and clusterin, is rendered unable to disrupt cells. Activation of the complement system occurs in several autoimmune diseases although the role of the terminal complex in their pathogenesis remains uncertain. Measurement of its concentration in the plasma, or that of its components, provides limited information about terminal complement pathway activity.
    [Show full text]
  • Regulation of Innate Immune Responses by The
    UNIVERSIDAD COMPLUTENSE DE MADRID FACULTAD DE CIENCIAS BIOLÓGICAS Departamento de Bioquímica y Biología Molecular I REGULACIÓN DE LA RESPUESTA INMUNE INNATA POR LA PROTEÍNA DE MATRIZ EXTRACELULAR TROMBOESPONDINA-1 MEMORIA PARA OPTAR AL GRADO DE DOCTOR PRESENTADA POR María Gema Martín Manso Madrid, 2008 • ISBN: 978-84-692-2767-1 REGULATION OF INNATE IMMUNE RESPONSES BY THE EXTRACELLULAR MATRIX PROTEIN THROMBOSPONDIN-1 I REGULATION OF INNATE IMMUNE RESPONSES BY THE EXTRACELLULAR MATRIX PROTEIN THROMBOSPONDIN-1 A THESIS DISSERTATION SUBMITTED TO THE DEPARTMENT OF BIOCHEMISTRY AND MOLECULAR BIOLOGY UNIVERSIDAD COMPLUTENSE DE MADRID BY María Gema Martín Manso Laboratory of Pathology National Cancer Institute, NIH Bethesda II Dedicada a las niñas de mis ojos, María y Beatriz. A mi Juanma, a mi hermano Ricardo y a mis queridos padres. III Contents Acknowledgments……………………………………………XIV Abbreviations………………………………………………….XVII I A.INTRODUCCIÓN..............................................................1 1. Las Trombospondinas.…………………………………….2 1.1. La Trombospondina-1……………………………………..8 IV 1.1.1. Organización estructural ……………………………....8 1.1.1. A. Dominio N-terminal ……………………………….9 1.1.1. B. Dominio trimérico de oligomerización …………11 1.1.1. C. Dominio con el Factor de von Willebrand (vWF) de tipo C……………………………………………………...11 1.1.1. D. Dominios de repetición o TSRs………………...12 1.1.1. E Dominio de identidad………….………………….13 1.1.2. Principales sitios de expresión……………………….15 1.1.3. Conexiones moleculares……………………………….16 1.1.4. Funciones de Trombospondina-1…………………….18 1.1.4.A. Regulación de las Respuestas Inmunes………..26 1.1.4.B. Regulación de las Respuestas Inmunes Innatas………………………………………………………..30 1.1.4.C. Regulación de la Respuesta Inmune Innata mediada por macrófagos contra el tumor………………...35 V B.INTRODUCTION.............................................................37 1.
    [Show full text]
  • A Review of the Complement Membrane Attack Complex
    Downloaded from http://rstb.royalsocietypublishing.org/ on July 18, 2017 The mystery behind membrane insertion: a review of the complement membrane rstb.royalsocietypublishing.org attack complex Charles Bayly-Jones1,2, Doryen Bubeck3 and Michelle A. Dunstone1,2 1Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, 2ARC Centre of Excellence Review in Advanced Molecular Imaging, Biomedicine Discovery Institute, Monash University, Clayton Campus, Melbourne, Victoria 3800, Australia Cite this article: Bayly-Jones C, Bubeck D, 3Department of Life Sciences, Imperial College London, South Kensington Campus, London SW2 7AZ, UK Dunstone MA. 2017 The mystery behind MAD, 0000-0002-6026-648X membrane insertion: a review of the complement membrane attack complex. Phil. The membrane attack complex (MAC) is an important innate immune effect- Trans. R. Soc. B 372: 20160221. or of the complement terminal pathway that forms cytotoxic pores on the http://dx.doi.org/10.1098/rstb.2016.0221 surface of microbes. Despite many years of research, MAC structure and mechanism of action have remained elusive, relying heavily on modelling and inference from biochemical experiments. Recent advances in structural Accepted: 8 November 2016 biology, specifically cryo-electron microscopy, have provided new insights into the molecular mechanism of MAC assembly. Its unique ‘split-washer’ One contribution of 17 to a discussion meeting shape, coupled with an irregular giant b-barrel architecture, enable an atyp- issue ‘Membrane pores: from structure and ical mechanism of hole punching and represent a novel system for which to assembly, to medicine and technology’. study pore formation. This review will introduce the complement terminal pathway that leads to formation of the MAC.
    [Show full text]
  • Association of Serum Cyr61 Levels with Peripheral Arterial Disease In
    Feng et al. Cardiovasc Diabetol (2020) 19:194 https://doi.org/10.1186/s12933-020-01171-9 Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Association of serum Cyr61 levels with peripheral arterial disease in subjects with type 2 diabetes Bin Feng1, Guidong Xu2, Kangyun Sun2, Kaipeng Duan3, Bimin Shi1 and Nannan Zhang2* Abstract Background: The prevalence of peripheral artery disease (PAD) is obviously increased in patients with diabetes. Exist- ing evidence shows that cysteine-rich angiogenic inducer 61 (Cyr61), a 40-kD secreted protein, plays important roles in regulating cellular physiological processes. Recent studies have demonstrated a signifcant correlation between serum Cyr61 and atherosclerosis. However, the relationship between Cyr61 levels and PAD in patients with type 2 diabetes (T2DM) remains obscure. Methods: Data from a total of 306 subjects with T2DM were cross-sectionally analysed. The extent of PAD was deter- mined by using the Fontaine classifcation, which defnes four stages. We measured serum Cyr61 concentrations by ELISA in subjects with and without PAD at Fontaine’s stage II, III, or IV. Logistic regression models were used to examine the independent association of Cyr61 with PAD. Results: Out of the 306 subjects enrolled, 150 were free from PAD, while 156 had clinically signifcant PAD. In subjects with PAD, the prevalences of Fontaine classifcation stages II, III and IV were 48.7%, 32.1%, and 19.2%, respectively. Patients with more advanced PAD had signifcantly higher Cyr61 (P for trend < 0.001). The prevalence of PAD on the basis of severity increased with increasing Cyr61 quartiles (all P values for trends < 0.001), and the severity of PAD was positively correlated with Cyr61 quartiles (r 0.227, P 0.006).
    [Show full text]
  • A Diverse Host Thrombospondin-Type-1 Repeat Protein Repertoire Promotes Symbiont Colonization During Establishment of Cnidarian
    1 A diverse host thrombospondin-type-1 repeat protein repertoire promotes symbiont 2 colonization during establishment of cnidarian-dinoflagellate symbiosis 3 4 Authors: Emilie-Fleur Neubauer1, Angela Z. Poole2,3, Philipp Neubauer4, Olivier Detournay5, 5 Kenneth Tan3, Simon K. Davy1* & Virginia M. Weis3* 6 1School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand 7 2Department of Biology, Western Oregon University, Monmouth, OR, USA 8 3Department of Integrative Biology, Oregon State University, Corvallis, OR, USA 9 4Dragonfly Data Science, Wellington, New Zealand 10 5 Planktovie sas, 13190 Allauch, France 11 12 13 Keywords: TSR, thrombospondin, coral, symbiosis, Symbiodinium, innate immunity, Aiptasia 14 pallida 15 16 Corresponding author: 17 *Corresponding authors: [email protected] ; Tel: +64-4-4635573, [email protected]; 18 Tel: 1-541-737-4359 19 20 1 21 Abstract 22 23 The mutualistic endosymbiosis between cnidarians and dinoflagellates is mediated by complex 24 inter-partner signaling events, where the host cnidarian innate immune system plays a crucial 25 role in recognition and regulation of symbionts. To date, little is known about the diversity of 26 thrombospondin-type-1 repeat (TSR) domain proteins in basal metazoans and or their potential 27 role in regulation of cnidarian-dinoflagellate mutualisms. We reveal a large and diverse 28 repertoire of TSR proteins in seven anthozoan species, and show that in the model sea anemone 29 Aiptasia pallida the TSR domain promotes colonization of the host by the symbiotic 30 dinoflagellate Symbiodinium minutum. Blocking TSR domains led to decreased colonization 31 success, while adding exogenous TSRs resulted in a ‘super colonization’.
    [Show full text]
  • Anti-ADAMTS4 Antibody (ARG56274)
    Product datasheet [email protected] ARG56274 Package: 100 μl anti-ADAMTS4 antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes ADAMTS4 Tested Reactivity Hu, Ms Tested Application WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name ADAMTS4 Antigen Species Human Immunogen Recombinant protein of Human ADAMTS4 Conjugation Un-conjugated Alternate Names ADAMTS-4; Aggrecanase-1; ADAMTS-2; EC 3.4.24.82; A disintegrin and metalloproteinase with thrombospondin motifs 4; ADAM-TS4; ADMP-1; ADAM-TS 4 Application Instructions Application table Application Dilution WB 1:500 - 1:2000 Application Note * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Positive Control H460 Calculated Mw 90 kDa Properties Form Liquid Purification Affinity purification with immunogen. Buffer PBS (pH 7.3), 0.02% Sodium azide and 50% Glycerol. Preservative 0.02% Sodium azide Stabilizer 50% Glycerol Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. Note For laboratory research only, not for drug, diagnostic or other use. www.arigobio.com 1/2 Bioinformation Database links GeneID: 240913 Mouse GeneID: 9507 Human Swiss-port # O75173 Human Swiss-port # Q8BNJ2 Mouse Gene Symbol ADAMTS4 Gene Full Name ADAM metallopeptidase with thrombospondin type 1 motif, 4 Background This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family.
    [Show full text]