DOCSLIB.ORG

Stromal Modulators of TGF- in Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Stromal Modulators of TGF- in Cancer Journal of Clinical Medicine Review Stromal Modulators of TGF-β in Cancer Brunella Costanza 1,†, Ijeoma Adaku Umelo 1,†, Justine Bellier 1,†, Vincent Castronovo 1 and Andrei Turtoi 1,2,* 1 Metastasis Research Laboratory, GIGA-Cancer, University of Liege, 4000 Liege, Belgium; [email protected] (B.C.); [email protected] (I.A.U.); [email protected] (J.B.); [email protected] (V.C.) 2 Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Université Montpellier, Institut Régional du Cancer de Montpellier, 34298 Montpellier, France * Correspondence: [email protected]; Tel.: +33-467-61-3746 † These authors contributed equally to this work. Academic Editor: Emanuel F. Petricoin Received: 4 November 2016; Accepted: 23 December 2016; Published: 6 January 2017 Abstract: Transforming growth factor-β (TGF-β) is an intriguing cytokine exhibiting dual activities in malignant disease. It is an important mediator of cancer invasion, metastasis and angiogenesis, on the one hand, while it exhibits anti-tumor functions on the other hand. Elucidating the precise role of TGF-β in malignant development and progression requires a better understanding of the molecular mechanisms involved in its tumor suppressor to tumor promoter switch. One important aspect of TGF-β function is its interaction with proteins within the tumor microenvironment. Several stromal proteins have the natural ability to interact and modulate TGF-β function. Understanding the complex interplay between the TGF-β signaling network and these stromal proteins may provide greater insight into the development of novel therapeutic strategies that target the TGF-β axis. The present review highlights our present understanding of how stroma modulates TGF-β activity in human cancers. Keywords: cancer-associated fibroblasts; proteases; proteoglycans; TGF-β; stroma 1. Introduction The transforming growth factor-β ligands (TGF-β1, TGF-β2 and TGF-β3) are members of a super family of secreted cytokines that regulate a variety of physiological cellular processes, including proliferation, differentiation, migration, survival and immunity [1–3]. In its active form, TGF-β signals to the nucleus mainly through its cognate receptors, TGF-β type I and type II receptors (TGFβRI and TGFβRII), which phosphorylate canonical SMAD2/3 downstream transducers (Figure1)[ 4,5]. In addition, several factors, such as various mitogen-activated protein kinases (MAPKs; namely, the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK)and p38 MAPK), phosphatidylinositide 3-kinase (PI3K)/AKT, Rho-like GTPases (Rho) and TNF receptor-associated factor 4/6 (TRAF 4/6), can be activated by TGF-β via non-canonical signaling cascades (Figure1)[ 6]. Of note, emerging evidence has revealed that both TGF-β canonical and non-canonical signaling cascades can simultaneously occur through crosstalk of core pathway components and combined utilization of SMAD/non-SMAD transcription factors [7] (Figure1). A number of excellent reviews have extensively covered TGF-β signal transduction [8–11]. J. Clin. Med. 2017, 6, 7; doi:10.3390/jcm6010007 www.mdpi.com/journal/jcm J. Clin. Med. 2017, 6, 7 2 of 25 J. Clin. Med. 2017, 6, 7 2 of 24 Figure 1. Canonical and non-canonicalnon‐canonical TGF-TGF‐β β signaling pathways. ( (AA)) In In the canonical signaling pathway, biologically active TGF-TGF‐β β ligands bind to TGF βRII,RII, which in turn activates TGF βRI.RI. TGFβRIRI-regulated‐regulated SMAD2/3 proteins proteins are are phosphorylated phosphorylated at at their their C C-terminal‐terminal serine residues and form complexes with SMAD4 (co (co-SMAD),‐SMAD), initiating a number of biological processes through transcriptional regulation of target genes. ( B)) In the non-canonicalnon‐canonical signaling pathways, the TGF-TGF‐β β receptor complex transmits its signal through other factors, such as the mitogen-activatedmitogen‐activated protein kinases (MAPKs),(MAPKs), phosphatidylinositide phosphatidylinositide 3-kinase 3‐kinase (PI3K), (PI3K), TNF receptor-associated TNF receptor‐associated factor 4/6 (TRAF4/6)factor 4/6 (TRAF4/6)and Rho family and Rho of small family GTPases. of small Activated GTPases. MAPKs Activated can exert MAPKs transcriptional can exert transcriptional regulation either regulation through eitherdirect interactionthrough direct with interaction the nuclear with SMAD the protein nuclear complex SMAD or protein via other complex downstream or via proteins.other downstream Moreover, proteins.activated Moreover, JNK/p38/ERK activated act in JNK/p38/ERK concert with act SMADs in concert to regulate with SMADs cellular to apoptosis regulate cellular and proliferation, apoptosis whereasand proliferation, they mediate whereas metastasis, they mediate angiogenesis metastasis, and cellular angiogenesis growth and through cellular other growth transcription through factors, other transcriptionsuch as c-JUN factors, and ATF. such RhoA/ROCK as c‐JUN and can ATF. be activated RhoA/ROCK by TGF- canβ beto activated induce actin by TGF stress‐β fiberto induce formation actin stressduring fiber EMT formation via a non-transcriptional during EMT via a mechanism. non‐transcriptional TGF-β can mechanism. activate PI3K TGF‐β andcan AKT activate by inducing PI3K and a physicalAKT by interactioninducing a betweenphysical theinteraction PI3K p85 between subunit andthe PI3K the receptor p85 subunit complex and leading the receptor to translational complex leadingresponses to via translational mTOR/S6kinase responses activation. via mTOR/S6kinase TGF-β activation activation. of the TRAF TGF proteins‐β activation can initiate of the nuclear TRAF proteinsfactor-κB can (NF- initiateκB) signaling nuclear activity, factor‐κ leadingB (NF‐κ toB) the signaling inflammatory activity, response leading among to the other inflammatory processes. Theresponse arrows among indicate other activation/signaling processes. The arrows direction indicate of the activation/signaling respective pathway. direction of the respective pathway. Cancer cells use TGF-β in order to enhance their characteristic properties and features [2,12–14]. In theCancer transition cells use from TGF a‐β physiologicalin order to enhance to pathological their characteristic phenotype, properties TGF-β andcan features induce [2,12–14]. intrinsic Indichotomous the transition effects, from which a reflectphysiological both its tumorto pathological suppressive phenotype, and tumor promotingTGF‐β can function. induce Althoughintrinsic dichotomousthis dual role ofeffects, TGF-β whichin cancer reflect is poorly both understood its tumor [suppressive15,16], it is known and tumor that the promoting stage of progression function. Althoughand cellular this context dual role are of key TGF factors.‐β in cancer In epithelial is poorly cells understood and during [15,16], tumor it is initiation, known that TGF- theβ stageacts asof progressiona tumor suppressor and cellular by inhibiting context are the growthkey factors. of malignant In epithelial cells cells via canonical and during SMAD2/3 tumor initiation, signaling TGFactivity‐β acts [8,17 ].as Evidence a tumor also suppressor suggests thatby theinhibiting pro-apoptotic the growth effects of TGF-malignantβ contribute cells tovia its canonical observed SMAD2/3cytostatic featuressignaling during activity early [8,17]. tumor Evidence formation. also suggests TGF-β-induced that the apoptosis pro‐apoptotic has been effects observed of TGF‐β to contributeoccur with SMADto its observed [18], JNK [cytostatic19] and p38 features [20] signaling during activityearly tumor in neoplastic formation. epithelium. TGF‐β‐induced In later apoptosisstages of malignant has been progression,observed to however,occur with cells SMAD can induce [18], JNK the loss[19] ofand the p38 tumor [20] suppressive signaling activity activities in neoplasticof TGF-β signaling epithelium. by In acquiring later stages mutations of malignant or alterations progression, in canonical however, target cells genes.can induce This the switch loss inof theresponse tumor to suppressive TGF-β by tumor activities cells isof accompaniedTGF‐β signaling by epithelial-to-mesenchymal by acquiring mutations transitionor alterations (EMT), in canonicalas well as thetarget enhancement genes. This of switch a number in ofresponse cancer cellto hallmarks,TGF‐β by includingtumor cells angiogenesis, is accompanied invasion by epithelialand metastasis‐to‐mesenchymal [8,21]. Accordingly, transition pre-clinical(EMT), as well and as clinical the enhancement observations of a support number the of cancer prevailing cell hallmarks,hypothesis thatincluding TGF-β angiogenesis,exhibits two opposing invasion effectsand metastasis in tumor control[8,21]. andAccordingly, progression. pre Experimental‐clinical and clinicalevidence observations suggests that support the TGF- theβ prevailingsignaling hypothesis network can that indeed TGF‐β switchexhibits from two tumor opposing suppressor effects toin tumor control and progression. Experimental evidence suggests that the TGF‐β signaling network tumor promoter, especially in the presence of oncogenic events and epigenetic perturbations [17]. can indeed switch from tumor suppressor to tumor promoter, especially in the presence of oncogenic events and epigenetic perturbations [17]. Recently, PEAK1 (a novel non‐receptor tyrosine J. Clin. Med. 2017, 6, 7 3 of 25 Recently, PEAK1 (a novel non-receptor tyrosine kinase), highly expressed in invasive breast cancer, has been described as relevant for switching TGF-β
Load more

Recommended publications
  • Decorin As a Multivalent Therapeutic Agent Against Cancer
    Thomas Jefferson University Jefferson Digital Commons Department of Pathology, Anatomy, and Cell Department of Pathology, Anatomy, and Cell Biology Faculty Papers Biology 2-1-2016 Decorin as a multivalent therapeutic agent against cancer. Thomas Neill Thomas Jefferson University Liliana Schaefer Goethe University Renato V. Iozzo Thomas Jefferson University Follow this and additional works at: https://jdc.jefferson.edu/pacbfp Part of the Biochemistry Commons, Cancer Biology Commons, Cell Biology Commons, and the Molecular Biology Commons Let us know how access to this document benefits ouy Recommended Citation Neill, Thomas; Schaefer, Liliana; and Iozzo, Renato V., "Decorin as a multivalent therapeutic agent against cancer." (2016). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 199. https://jdc.jefferson.edu/pacbfp/199 This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Department of Pathology, Anatomy, and Cell Biology Faculty Papers by an authorized administrator of the Jefferson
    [Show full text]
  • Differences in Molecular Regulation Between Osteochondroma and Bizarre Parosteal Osteochondromatous Proliferation
    MOLECULAR MEDICINE REPORTS 16: 801-805, 2017 Differences in molecular regulation between osteochondroma and bizarre parosteal osteochondromatous proliferation XINRONG ZHOU, LIHUI DENG, XINSHENG HAN, YI CHEN, JIAO WANG and SHENGNAN DU Department of Stomatology, Nanchong Central Hospital, Nanchong, Sichuan 637000, P.R. China Received April 13, 2016; Accepted March 24, 2017 DOI: 10.3892/mmr.2017.6634 Abstract. The differences in molecular mechanisms between exhibit a cauliflower-like shape. Histologically, there is a osteochondroma and bizarre parosteal osteochondromatous fibrous perichondrium, which covers the cartilage cap and proliferation (BPOP) remain to be fully elucidated. In the exhibits continuity with the periosteum of the underlying bone present study, the differentially expressed genes between marrow. Bizarre parosteal osteochondromatous proliferation BPOP and osteochondroma were obtained from the Gene (BPOP) is a rare, benign osteocartilaginous lesion, which Expression Omnibus online database, and the associations can occur in the hands, feet, zygoma, maxilla and mandible. among these genes were analyzed using the Database for The histological features of BPOP include osteocartilaginous Annotation, Visualization, and Integrated Discovery (DAVID) interfaces, a scattering of bizarre enlarged chondrocytes and online bioinformatics software. The results revealed several hypercellular spindle cells (1,3). Previous studies have shown differentially expressed genes between human BPOP and that BPOP arises from periosteal tissues through
    [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]
  • Latent TGF-Beta Binding Protein-1 Plays an Important Role in Craniofacial Development
    Original Article http://dx.doi.org/10.1590/1678-7757-2020-0262 Latent TGF-beta binding protein-1 plays an important role in craniofacial development Abstract Yiting XIONG1# Objective: This study aims to replicate the phenotype of Ltbp1 knockout mice in zebrafish, and to address the function of LTBP1 in craniofacial Rongrong SUN1# development. Methods: Whole mount in situ hybridization (WISH) of ltbp1 Jingyu LI2 was performed at critical periods of zebrafish craniofacial development to Yue WU2 explore the spatial-temporal expression pattern. Furthermore, we generated 1 Jingju ZHANG morpholino based knockdown model of ltbp1 to study the craniofacial phenotype. Results: WISH of ltbp1 was mainly detected in the mandibular jaw region, brain trunk, and internal organs such as pancreas and gallbladder. And ltbp1 colocalized with both sox9a and ckma in mandibular region. Morpholino based knockdown of ltbp1 results in severe jaw malformation. Alcian blue staining revealed severe deformity of Meckel’s cartilage along with the absence of ceratobranchial. Three-dimension measurements of ltbp1 morphants jaws showed decrease in both mandible length and width and increase in open mouth distance. Expression of cartilage marker sox9a and muscle marker ckma was decreased in ltbp1 morphants. Conclusions: Our experiments found that ltbp1 was expressed in zebrafish mandibular jaw cartilages and the surrounding muscles. The ltbp1 knockdown zebrafish exhibited phenotypes consistent with Ltbp1 knockout mice. And loss of ltbp1 function lead to significant mandibular jaw defects and affect both jaw cartilages and surrounding muscles. Keywords: LTBP1. Craniofacial anomalies. Developmental biology. Zebrafish. Submitted: April 24, 2020 Modification: June 31, 2020 Accepted: July 29, 2020 Corresponding address: ¹Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Jingju Zhang Department of Orthodontics, School & Hospital of Stomatology, Shanghai, China.
    [Show full text]
  • Decorin Causes Autophagy in Endothelial Cells Via Peg3 PNAS PLUS
    Decorin causes autophagy in endothelial cells via Peg3 PNAS PLUS Simone Buraschia,b,1, Thomas Neilla,b,1, Atul Goyala,b, Chiara Poluzzia,b, James Smythiesa,b, Rick T. Owensc, Liliana Schaeferd, Annabel Torresa,b, and Renato V. Iozzoa,b,2 aDepartment of Pathology, Anatomy and Cell Biology, and the bCell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107; cLifeCell Corporation, Branchburg, NJ 08876; and dPharmazentrum Frankfurt, Goethe University, 60590 Frankfurt, Germany Edited by Carlo M. Croce, The Ohio State University, Columbus, Ohio, and approved May 29, 2013 (received for review March 27, 2013) Soluble decorin affects the biology of several receptor tyrosine capable of significantly inhibiting neovascularization of triple- kinases by triggering receptor internalization and degradation. We negative basal cell breast carcinomas (23). found that decorin induced paternally expressed gene 3 (Peg3), an During preclinical studies focusing on identifying decorin- imprinted tumor suppressor gene, and that Peg3 relocated into induced genes in vivo, we found that systemic delivery of decorin autophagosomes labeled by Beclin 1 and microtubule-associated protein core to mice carrying orthotopic mammary carcinoma light chain 3. Decorin evoked Peg3-dependent autophagy in both xenografts induced expression of a small subset of genes (24). microvascular and macrovascular endothelial cells leading to sup- Notably, these genes were induced exclusively in the tumor stroma pression of angiogenesis. Peg3 coimmunoprecipitated with Beclin 1 of mouse origin but not in the mammary carcinomas of human and LC3 and was required for maintaining basal levels of Beclin 1. origin (24). One of the most up-regulated genes was Paternally Decorin, via Peg3, induced transcription of Beclin 1 and microtu- expressed gene 3 (Peg3), an imprinted putative tumor-suppressor bule-associated protein 1 light chain 3 alpha genes, thereby leading gene frequently silenced by promoter hypermethylation and/or to a protracted autophagic program.
    [Show full text]
  • Thrombospondin 1 Promotes an Aggressive Phenotype Through Epithelial-To-Mesenchymal Transition in Human Melanoma
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 5, No. 14 Thrombospondin 1 promotes an aggressive phenotype through epithelial-to-mesenchymal transition in human melanoma Aparna Jayachandran1,2, Matthew Anaka1,2, Prashanth Prithviraj1,2, Christopher Hudson1, Sonja J McKeown3, Pu-Han Lo1, Laura J Vella1,2, Colin R Goding4, Jonathan Cebon1,2, Andreas Behren1,2 1 Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC 3084, Australia 2 Department of Medicine, University of Melbourne, Victoria, 3010, Australia 3 Department of Anatomy and Neuroscience, University of Melbourne, Victoria, 3010, Australia 4 Ludwig Institute for Cancer Research, University of Oxford, Oxford, OX3 7DQ, UK Correspondence to: Andreas Behren, e-mail: [email protected] Key words: Thrombospondin 1, melanoma, epithelial-to-mesenchymal transition, chick embryo, invasion, drug resistance Received: April 29, 2014 Accepted: June 23, 2014 Published: July 08, 2014 ABSTRACT Epithelial-to-mesenchymal transition (EMT), in which epithelial cells loose their polarity and become motile mesenchymal cells, is a determinant of melanoma metastasis. We compared gene expression signatures of mesenchymal-like melanoma cells with those of epithelial-like melanoma cells, and identified Thrombospondin 1 (THBS1) as highly up-regulated in the mesenchymal phenotype. This study investigated whether THBS1, a major physiological activator of transforming growth factor (TGF)-beta, is involved in melanoma EMT-like process. We sought to examine expression patterns in distinct melanoma phenotypes including invasive, de-differentiated, label-retaining and drug resistant populations that are putatively associated with an EMT-like process. Here we show that THBS1 expression and secretion was elevated in melanoma cells exhibiting invasive, drug resistant, label retaining and mesenchymal phenotypes and correlated with reduced expression of genes involved in pigmentation.
    [Show full text]
  • Thrombospondin-1 (TSP-1) and TSP-1-Derived Heparin-Binding Peptides Induce Promyelocytic Leukemia Cell Differentiation and Apoptosis
    ANTICANCER RESEARCH 25: 757-764 (2005) Thrombospondin-1 (TSP-1) and TSP-1-derived Heparin-binding Peptides Induce Promyelocytic Leukemia Cell Differentiation and Apoptosis ARLETTE BRUEL, MYRIEM TOUHAMI-CARRIER, ANNICK THOMAIDIS and CHANTAL LEGRAND Laboratoire "Hémostase, Endothélium, Angiogenèse", INSERM Unité 553, IFR 105, Institut Universitaire d'Hématologie Paris 7, Hôpital St Louis, 75475 Paris, France Abstract. Thrombospondin-1 (TSP-1) is a multifunctional neutrophils and die in vitro upon treatment with all-trans adhesive glycoprotein that is synthesized by several cell types retinoic acid (ATRA), a vitamin A derivative (1, 2). ATRA and modulates cell growth and differentiation. In this study, has been successfully used to induce remission of a majority we showed that the amount of TSP-1 secreted by two human of patients with acute promyelocytic leukemia, although leukemia cell lines, HL-60 and NB4, increased markedly ATRA-resistant relapses are still a major problem (3). The during differentiation of these cells by all-trans retinoic acid effect of ATRA on cells is mediated by nuclear receptors (ATRA) (10-7 M), reaching about 100 ng/106 cells after 3 days. acting as transcriptional factors, which modulate the Addition of purified TSP-1 alone (10-9 – 5 x 10-8 M) to HL-60 expression of many genes implicated in cell proliferation, or NB4 cell cultures dose-dependently inhibited cell growth and differentiation and survival (4). Among these, extracellular differentiation. Differently to ATRA, TSP-1-induced matrix proteins have the ability to transmit signals into cells differentiation of HL-60 and NB4 cells occurred independently via specific receptors, and act in concert with cytokines to of Bcl-2 regulation, as shown by immunofluorescence and influence cell functions (5, 6).
    [Show full text]
  • Curcumin Alters Gene Expression-Associated DNA Damage, Cell Cycle, Cell Survival and Cell Migration and Invasion in NCI-H460 Human Lung Cancer Cells in Vitro
    ONCOLOGY REPORTS 34: 1853-1874, 2015 Curcumin alters gene expression-associated DNA damage, cell cycle, cell survival and cell migration and invasion in NCI-H460 human lung cancer cells in vitro I-TSANG CHIANG1,2, WEI-SHU WANG3, HSIN-CHUNG LIU4, SU-TSO YANG5, NOU-YING TANG6 and JING-GUNG CHUNG4,7 1Department of Radiation Oncology, National Yang‑Ming University Hospital, Yilan 260; 2Department of Radiological Technology, Central Taiwan University of Science and Technology, Taichung 40601; 3Department of Internal Medicine, National Yang‑Ming University Hospital, Yilan 260; 4Department of Biological Science and Technology, China Medical University, Taichung 404; 5Department of Radiology, China Medical University Hospital, Taichung 404; 6Graduate Institute of Chinese Medicine, China Medical University, Taichung 404; 7Department of Biotechnology, Asia University, Taichung 404, Taiwan, R.O.C. Received March 31, 2015; Accepted June 26, 2015 DOI: 10.3892/or.2015.4159 Abstract. Lung cancer is the most common cause of cancer CARD6, ID1 and ID2 genes, associated with cell survival and mortality and new cases are on the increase worldwide. the BRMS1L, associated with cell migration and invasion. However, the treatment of lung cancer remains unsatisfactory. Additionally, 59 downregulated genes exhibited a >4-fold Curcumin has been shown to induce cell death in many human change, including the DDIT3 gene, associated with DNA cancer cells, including human lung cancer cells. However, the damage; while 97 genes had a >3- to 4-fold change including the effects of curcumin on genetic mechanisms associated with DDIT4 gene, associated with DNA damage; the CCPG1 gene, these actions remain unclear. Curcumin (2 µM) was added associated with cell cycle and 321 genes with a >2- to 3-fold to NCI-H460 human lung cancer cells and the cells were including the GADD45A and CGREF1 genes, associated with incubated for 24 h.
    [Show full text]
  • Lymphocyte Early Activation Thrombospondin-1 Inhibits TCR
    Thrombospondin-1 Inhibits TCR-Mediated T Lymphocyte Early Activation Zhuqing Li, Liusheng He, Katherine E. Wilson and David D. Roberts This information is current as of September 28, 2021. J Immunol 2001; 166:2427-2436; ; doi: 10.4049/jimmunol.166.4.2427 http://www.jimmunol.org/content/166/4/2427 Downloaded from References This article cites 53 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/166/4/2427.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Thrombospondin-1 Inhibits TCR-Mediated T Lymphocyte Early Activation Zhuqing Li, Liusheng He,1 Katherine E. Wilson,2 and David D. Roberts3 Biological activities of the matrix glycoprotein thrombospondin-1 (TSP1) are cell type specific and depend on the relative expression or activation of several TSP1 receptors.
    [Show full text]
  • Thrombospondin 1 Acts As a Strong Promoter of Transforming Growth
    673 LIVER Thrombospondin 1 acts as a strong promoter of Gut: first published as 10.1136/gut.2004.042911 on 14 April 2005. Downloaded from transforming growth factor b effects via two distinct mechanisms in hepatic stellate cells K Breitkopf, I Sawitza, J H Westhoff, L Wickert, S Dooley, A M Gressner ............................................................................................................................... Gut 2005;54:673–681. doi: 10.1136/gut.2004.042911 See end of article for authors’ affiliations Background and aims: Thrombospondin 1 (TSP-1) is an important activator of latent transforming growth ....................... factor b (TGF-b) but little is known of the expression patterns and functions of TSP-1 in liver cells. We Correspondence to: therefore analysed if and how TSP-1 acts on TGF-b during fibrogenesis. Dr K Breitkopf, Department Methods and results: Using reverse transcription-polymerase chain reaction, we demonstrated that of Medicine II, University hepatocytes from normal liver expressed no TSP-1 mRNA whereas Kupffer cells and sinusoidal endothelial Hospital Mannheim, University of Heidelberg, cells did. TSP-1 mRNA and protein were detected in quiescent and activated cultured hepatic stellate cells Theodor-Kutzer-Ufer 1-3, (HSC) and TSP-1 expression was highly inducible by platelet derived growth factor BB (PDGF-BB) and, to a 68167 Mannheim, lesser extent, by tumour necrosis factor a in activated HSC. Furthermore, addition of PDGF-BB directly led Germany; katja.breitkopf@ to enhanced TGF-b mRNA expression and a TSP-1 dependent increase in TGF-b/Smad signalling. Using med.ma.uni-heidelberg.de either a peptide specifically blocking the interaction of TSP-1 with latent TGF-b or antibodies against TSP-1 not only abrogated activation of latent TGF-b but also reduced the effects of the active dimer itself.
    [Show full text]
  • Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease
    Supplementary Online Content Ganz P, Heidecker B, Hveem K, et al. Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA. doi: 10.1001/jama.2016.5951 eTable 1. List of 1130 Proteins Measured by Somalogic’s Modified Aptamer-Based Proteomic Assay eTable 2. Coefficients for Weibull Recalibration Model Applied to 9-Protein Model eFigure 1. Median Protein Levels in Derivation and Validation Cohort eTable 3. Coefficients for the Recalibration Model Applied to Refit Framingham eFigure 2. Calibration Plots for the Refit Framingham Model eTable 4. List of 200 Proteins Associated With the Risk of MI, Stroke, Heart Failure, and Death eFigure 3. Hazard Ratios of Lasso Selected Proteins for Primary End Point of MI, Stroke, Heart Failure, and Death eFigure 4. 9-Protein Prognostic Model Hazard Ratios Adjusted for Framingham Variables eFigure 5. 9-Protein Risk Scores by Event Type This supplementary material has been provided by the authors to give readers additional information about their work. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Supplemental Material Table of Contents 1 Study Design and Data Processing ......................................................................................................... 3 2 Table of 1130 Proteins Measured .......................................................................................................... 4 3 Variable Selection and Statistical Modeling ........................................................................................
    [Show full text]
  • LTBP4 in Health and Disease
    G C A T T A C G G C A T genes Review LTBP4 in Health and Disease Chi-Ting Su 1,2,3 and Zsolt Urban 2,* 1 Department of Internal Medicine, Renal Division, National Taiwan University Hospital Yunlin Branch, Douliu 640, Taiwan; [email protected] 2 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA 3 Department of Medicine, National Taiwan University Cancer Center Hospital, Taipei 106, Taiwan * Correspondence: [email protected]; Tel.: +1-412-648-8269 Abstract: Latent transforming growth factor β (TGFβ)-binding protein (LTBP) 4, a member of the LTBP family, shows structural homology with fibrillins. Both these protein types are characterized by calcium-binding epidermal growth factor-like repeats interspersed with 8-cysteine domains. Based on its domain composition and distribution, LTBP4 is thought to adopt an extended structure, facilitating the linear deposition of tropoelastin onto microfibrils. In humans, mutations in LTBP4 result in autosomal recessive cutis laxa type 1C, characterized by redundant skin, pulmonary emphysema, and valvular heart disease. LTBP4 is an essential regulator of TGFβ signaling and is related to development, immunity, injury repair, and diseases, playing a central role in regulating inflammation, fibrosis, and cancer progression. In this review, we focus on medical disorders or diseases that may be manipulated by LTBP4 in order to enhance the understanding of this protein. Keywords: LTBP4; TGFβ; elastogenesis; medicine 1. Introduction Citation: Su, C.-T.; Urban, Z. LTBP4 Latent transforming growth factor β-binding proteins (LTBPs) serve as mediators to in Health and Disease. Genes 2021, 12, organize elements for matrix microfibril bundles and regulate the signaling of transforming 795.
    [Show full text]