CCBE1 Enhances Lymphangiogenesis Via ADAMTS3-Mediated VEGF-C Processing
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Role of Proteases in Dysfunctional Placental Vascular Remodelling in Preeclampsia
Accepted Manuscript Role of proteases in dysfunctional placental vascular remodelling in preeclampsia Jaime A. Gutiérrez, Isabel Gómez, Delia I. Chiarello, Rocío Salsoso, Andrés D. Klein, Enrique Guzmán-Gutiérrez, Fernando Toledo, Luis Sobrevia PII: S0925-4439(19)30115-2 DOI: https://doi.org/10.1016/j.bbadis.2019.04.004 Reference: BBADIS 65448 To appear in: BBA - Molecular Basis of Disease Received date: 23 February 2018 Revised date: 20 December 2018 Accepted date: 6 January 2019 Please cite this article as: J.A. Gutiérrez, I. Gómez, D.I. Chiarello, et al., Role of proteases in dysfunctional placental vascular remodelling in preeclampsia, BBA - Molecular Basis of Disease, https://doi.org/10.1016/j.bbadis.2019.04.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Role of proteases in dysfunctional placental vascular remodelling in preeclampsia Jaime A. Gutiérrez1,7 *, Isabel Gómez1, Delia I Chiarello7, Rocío Salsoso5,7†, Andrés D Klein2, Enrique Guzmán-Gutiérrez3, Fernando Toledo4,7, Luis Sobrevia5,6,7 * 1 Cellular Signaling and Differentiation Laboratory (CSDL), School of Medical Technology, Health Sciences Faculty, Universidad San Sebastián, Santiago 7510157, Chile. 2 Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7590943, Chile. -
ADAMTS Proteases in Vascular Biology
Review MATBIO-1141; No. of pages: 8; 4C: 3, 6 ADAMTS proteases in vascular biology Juan Carlos Rodríguez-Manzaneque 1, Rubén Fernández-Rodríguez 1, Francisco Javier Rodríguez-Baena 1 and M. Luisa Iruela-Arispe 2 1 - GENYO, Centre for Genomics and Oncological Research, Pfizer, Universidad de Granada, Junta de Andalucía, 18016 Granada, Spain 2 - Department of Molecular, Cell, and Developmental Biology, Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA Correspondence to Juan Carlos Rodríguez-Manzaneque and M. Luisa Iruela-Arispe: J.C Rodríguez-Manzaneque is to be contacted at: GENYO, 15 PTS Granada - Avda. de la Ilustración 114, Granada 18016, Spain; M.L. Iruela-Arispe, Department of Molecular, Cell and Developmental Biology, UCLA, 615 Charles Young Drive East, Los Angeles, CA 90095, USA. [email protected]; [email protected] http://dx.doi.org/10.1016/j.matbio.2015.02.004 Edited by W.C. Parks and S. Apte Abstract ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) proteases comprise the most recently discovered branch of the extracellular metalloenzymes. Research during the last 15 years, uncovered their association with a variety of physiological and pathological processes including blood coagulation, tissue repair, fertility, arthritis and cancer. Importantly, a frequent feature of ADAMTS enzymes relates to their effects on vascular-related phenomena, including angiogenesis. Their specific roles in vascular biology have been clarified by information on their expression profiles and substrate specificity. Through their catalytic activity, ADAMTS proteases modify rather than degrade extracellular proteins. They predominantly target proteoglycans and glycoproteins abundant in the basement membrane, therefore their broad contributions to the vasculature should not come as a surprise. -
Secreted Metalloproteinase ADAMTS-3 Inactivates Reelin
The Journal of Neuroscience, March 22, 2017 • 37(12):3181–3191 • 3181 Cellular/Molecular Secreted Metalloproteinase ADAMTS-3 Inactivates Reelin Himari Ogino,1* Arisa Hisanaga,1* XTakao Kohno,1 Yuta Kondo,1 Kyoko Okumura,1 Takana Kamei,1 Tempei Sato,2 Hiroshi Asahara,2 Hitomi Tsuiji,1 Masaki Fukata,3 and Mitsuharu Hattori1 1Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan, 2Department of Systems BioMedicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan, and 3Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan The secreted glycoprotein Reelin regulates embryonic brain development and adult brain functions. It has been suggested that reduced Reelin activity contributes to the pathogenesis of several neuropsychiatric and neurodegenerative disorders, such as schizophrenia and Alzheimer’s disease; however, noninvasive methods that can upregulate Reelin activity in vivo have yet to be developed. We previously found that the proteolytic cleavage of Reelin within Reelin repeat 3 (N-t site) abolishes Reelin activity in vitro, but it remains controversial as to whether this effect occurs in vivo. Here we partially purified the enzyme that mediates the N-t cleavage of Reelin from the culture supernatant of cerebral cortical neurons. This enzyme was identified as a disintegrin and metalloproteinase with thrombospondin motifs-3 (ADAMTS-3). Recombinant ADAMTS-3 cleaved Reelin at the N-t site. ADAMTS-3 was expressed in excitatory neurons in the cerebral cortex and hippocampus. -
Identi Ed a Disintegrin and Metalloproteinase with Thrombospondin Motifs 6 Serve As a Novel Gastric Cancer Prognostic Biomarker
Identied a Disintegrin and Metalloproteinase with Thrombospondin Motifs 6 Serve as a Novel Gastric Cancer Prognostic Biomarker by Integrating Analysis of Gene Expression Prole Ya-zhen Zhu GuangXi University of Chinese Medicine https://orcid.org/0000-0001-6932-698X Yi Liu Guangxi Cancer Hospital and Guangxi Medical University Aliated Cancer Hospital Xi-wen Liao Guangxi Cancer Hospital and Guangxi Medical University Aliated Cancer Hospital Xian-wei Mo Guangxi Cancer Hospital and Guangxi Medical University Aliated Cancer Hospital Yuan Lin Guangxi Cancer Hospital and Guangxi Medical University Aliated Cancer Hospital Wei-zhong Tang Guangxi Cancer Hospital and Guangxi Medical University Aliated Cancer Hospital Shan-shan Luo ( [email protected] ) Research article Keywords: ADAMTS, mRNA, gastric cancer, prognosis Posted Date: July 14th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-41038/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/31 Abstract Objective: We aimed to explore the prognostic value of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) genes in gastric cancer (GC). Methods: The RNA-sequencing (RNA-seq) expression data for 351 GC patients and other relevant clinical data was acquired from The Cancer Genome Atlas (TCGA). Survival analysis and a genome-wide gene set enrichment analysis (GSEA) were performed to dene the underlying molecular value of the ADAMTS genes in GC development. Results: The Log rank test with both Cox regression and Kaplan–Meier survival analysis showed that ADAMTS6 expression prole correlated with the GC patients’ clinical outcome. Patients with a high expression of ADAMTS6 were associated with poor overall survival (OS). -
Proteolytic Activation Defines Distinct Lymphangiogenic Mechanisms for VEGFC and VEGFD
Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD Hung M. Bui, … , Kari Alitalo, Mark L. Kahn J Clin Invest. 2016;126(6):2167-2180. https://doi.org/10.1172/JCI83967. Research Article Vascular biology Lymphangiogenesis is supported by 2 homologous VEGFR3 ligands, VEGFC and VEGFD. VEGFC is required for lymphatic development, while VEGFD is not. VEGFC and VEGFD are proteolytically cleaved after cell secretion in vitro, and recent studies have implicated the protease a disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3) and the secreted factor collagen and calcium binding EGF domains 1 (CCBE1) in this process. It is not well understood how ligand proteolysis is controlled at the molecular level or how this process regulates lymphangiogenesis, because these complex molecular interactions have been difficult to follow ex vivo and test in vivo. Here, we have developed and used biochemical and cellular tools to demonstrate that an ADAMTS3-CCBE1 complex can form independently of VEGFR3 and is required to convert VEGFC, but not VEGFD, into an active ligand. Consistent with these ex vivo findings, mouse genetic studies revealed that ADAMTS3 is required for lymphatic development in a manner that is identical to the requirement of VEGFC and CCBE1 for lymphatic development. Moreover, CCBE1 was required for in vivo lymphangiogenesis stimulated by VEGFC but not VEGFD. Together, these studies reveal that lymphangiogenesis is regulated by two distinct proteolytic mechanisms of ligand activation: one in which VEGFC activation by ADAMTS3 and CCBE1 spatially and temporally patterns developing lymphatics, and one in which VEGFD activation by a distinct […] Find the latest version: https://jci.me/83967/pdf The Journal of Clinical Investigation RESEARCH ARTICLE Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD Hung M. -
Study of the Requirement of the CCBE1 Growth Factor in the Generation of Cardiac Myocytes from Hes Cells
Study of the requirement of the CCBE1 growth factor in the generation of cardiac myocytes from hES cells MS.c Thesis in Biomedical Science Rita Catarina Vaz Drago Study of the requirement of the CCBE1 growth factor in the generation of cardiac myocytes from hES cells MS.c Thesis in Biomedical Science Rita Catarina Vaz Drago Orientador: Professor Doutor José António Belo Co-orientador: Doutora Andreia Bernardo Faro, 2012 ii MS.c Thesis proposal in Biomedical Science Area of Developmental Biology by the Universidade do Algarve Study of the requirement of the CCBE1 growth factor in the generation of cardiac myocytes from hES cells. Dissertação para obtenção do Grau de Mestre em Ciências Biomédicas Área de Biologia do Desenvolvimento pela Universidade do Algarve Estudo da função do factor de crescimento CCBE1 na diferenciação de miócitos cardíacos a partir de células estaminais embrionárias humanas Declaro ser a autora deste trabalho, que é original e inédito. Autores e trabalhos consultados estão devidamente citados no texto e constam da listagem de referências incluída. Copyright. A Universidade do Algarve tem o direito, perpétuo e sem limites geográficos, de arquivar e publicitar este trabalho através de exemplares impressos reproduzidos em papel ou de forma digital, ou por qualquer outro meio conhecido ou que venha a ser inventado, de o divulgar através de repositórios científicos e de admitir a sua cópia e distribuição com objetivos educacionais ou de investigação, não comerciais, desde que seja dado crédito ao autor e editor. iii ACKNOWLEDGEMENTS I thank my supervisor, Prof. José Belo, for the support he provided me during this long journey and for the opportunity of working at his laboratory. -
Mutations in CCBE1 Cause Generalized Lymph Vessel Dysplasia
BRIEF COMMUNICATIONS Mutations in CCBE1 cause (Fig. 1a–f)8. Subsequently, subjects with lymphangiectasias in pleura, pericardium, thyroid gland and kidney and with hydrops fetalis were generalized lymph vessel dysplasia described9,10. The entity was designated lymphedema-lymphangiectasia– mental retardation or Hennekam syndrome (MIM 235510). Occurrence in humans of affected siblings, equal occurrence among sexes and frequent consanguinity indicated autosomal recessive inheritance9. 1 2 2 1 Marielle Alders , Benjamin M Hogan , Evisa Gjini , Faranak Salehi , We collected blood samples from a series of 27 subjects with Hennekam 3 4 5 Lihadh Al-Gazali , Eric A Hennekam , Eva E Holmberg , syndrome born to 22 families. None of the subjects carried mutations 1 6 7,8 Marcel M A M Mannens , Margot F Mulder , G Johan A Offerhaus , in FLT4, FOXC2 or SOX18. We performed homozygosity mapping in 5 9 10 Trine E Prescott , Eelco J Schroor , Joke B G M Verheij , three unpublished subjects (A, B and C) originating from a small isolate 2 11,14 12 Merlijn Witte , Petra J Zwijnenburg , Mikka Vikkula , in The Netherlands. Pedigree analysis had shown the parents of subject 2,15 13–15 Stefan Schulte-Merker & Raoul C Hennekam A to be consanguineous and all three subjects to be related (Fig. 1g). We reasoned that occurrence of three cases of a rare disorder in a small Lymphedema, lymphangiectasias, mental retardation and isolate suggested homozygosity for a founder mutation. Homozygosity unusual facial characteristics define the autosomal recessive mapping identified a 5.7-Mb homozygous region on chromosome 18q21 Hennekam syndrome. Homozygosity mapping identified a with identical haplotypes in the three affected individuals (Fig. -
Prioritization of Genes Involved in Endothelial Cell Apoptosis by Their Implication in Lymphedema Using an Analysis of Associative Gene Networks with Andsystem Olga V
Saik et al. BMC Medical Genomics 2019, 12(Suppl 2):47 https://doi.org/10.1186/s12920-019-0492-9 RESEARCH Open Access Prioritization of genes involved in endothelial cell apoptosis by their implication in lymphedema using an analysis of associative gene networks with ANDSystem Olga V. Saik1,3*, Vadim V. Nimaev2,3, Dilovarkhuja B. Usmonov3,4, Pavel S. Demenkov1,3, Timofey V. Ivanisenko1,3, Inna N. Lavrik1,5 and Vladimir A. Ivanisenko1,3 From 11th International Multiconference “Bioinformatics of Genome Regulation and Structure\Systems Biology” - BGRS\SB- 2018 Novosibirsk, Russia. 20-25 August 2018 Abstract Background: Currently, more than 150 million people worldwide suffer from lymphedema. It is a chronic progressive disease characterized by high-protein edema of various parts of the body due to defects in lymphatic drainage. Molecular-genetic mechanisms of the disease are still poorly understood. Beginning of a clinical manifestation of primary lymphedema in middle age and the development of secondary lymphedema after treatment of breast cancer can be genetically determined. Disruption of endothelial cell apoptosis can be considered as one of the factors contributing to the development of lymphedema. However, a study of the relationship between genes associated with lymphedema and genes involved in endothelial apoptosis, in the associative gene network was not previously conducted. Methods: In the current work, we used well-known methods (ToppGene and Endeavour), as well as methods previously developed by us, to prioritize genes involved in endothelial apoptosis and to find potential participants of molecular-genetic mechanisms of lymphedema among them. Original methods of prioritization took into account the overrepresented Gene Ontology biological processes, the centrality of vertices in the associative gene network, describing the interactions of endothelial apoptosis genes with genes associated with lymphedema, and the association of the analyzed genes with diseases that are comorbid to lymphedema. -
Ivtigation of the Effects of Mechanical Strain in Human Tenocytes
Investigation of the effects of Mechanical Strain in Human Tenocytes Eleanor Rachel Jones In partial fulfilment of the requirements for the Degree of Doctor of Philosophy University of East Anglia, Biological Sciences September 2012 This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and that use of any information derived there from must be in accordance with current UK Copyright Law. In addition, any quotation or extract must be included full attribution. Abstract Tendinopathies are a range of diseases characterised by pain and insidious degeneration. Although poorly understood, onset is often associated with physical activity. Metalloproteinases are regulated differentially in tendinopathy causing disruptions in extracellular matrix (ECM) homeostasis. An increase in the anti-inflammatory cytokine TGFβ has also been documented. This project aims to investigate the effect of cyclic tensile strain loading and TGFβ stimulation on protease and ECM protein expression by human tenocytes and begin to characterise the pathway of mechanotransduction. Human tenocytes were seeded at 1.5x106 cells/ml into collagen gels (rat tail type I, 1mg/ml) and stretched using a sinusoidal waveform of 0-5% at 1Hz using the Flexcell FX4000T™ system. Cultures were treated with or without 1ng/ml TGFβ1 or inhibitors of TGFβRI, metalloproteinases, RGD, Mannose-6-phosphate, integrin β1 and a thrombospondin as appropriate. qRT-PCR and a cell based luciferase assay were used to assess RNA and TGFβ activity respectively. The prolonged application of 5% cyclic mechanical strain in a 3D culture system induced an anabolic response in protease and matrix genes. -
Genetic Variants in the Metzincin Metallopeptidase Family Genes Predict Melanoma Survival
RESEARCH ARTICLE Genetic variants in the metzincin metallopeptidase family genes predict melanoma survival† An abbreviated title: Genetic variants in the metzincin metallopeptidase family genes predict melanoma survival Yinghui Xu1,2,3*, Yanru Wang1,2* , Hongliang Liu1,2, Qiong Shi4, Dakai Zhu5, Christopher I. Amos5, Shenying Fang6, Jeffrey E. Lee6, Terry Hyslop1,7, Xin Li8, Jiali Han9**, and Qingyi Wei1,2** 1 Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA 2 Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA 3 Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China 4 Department of Dermatology, Xijing Hospital, Xi’an, Shanxi 710032, China 5 Department of Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA 6 Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA 7 Department of Biostatistics and Bioinformatics, Duke University and Duke Clinical Research Institute, Durham, NC 27710, USA 8 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA 9 Department of Epidemiology, Fairbanks School of Public Health, and Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA †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: [10.1002/mc.22716] Additional Supporting Information may be found in the online version of this article. Received 20 March 2017; Accepted 8 August 2017 Molecular Carcinogenesis This article is protected by copyright. -
Genetic Epidemiology of Hypertension in Populations
GENETIC EPIDEMIOLOGY OF HYPERTENSION IN POPULATIONS: APPLICATIONS OF MODIFIED METHODS by PRIYA BHATIA SHETTY, M.S. Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Adviser: Xiaofeng Zhu, Ph.D. Department of Epidemiology and Biostatistics CASE WESTERN RESERVE UNIVERSITY January, 2014 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of Priya Bhatia Shetty, candidate for the Doctor of Philosophy degree*. Xiaofeng Zhu, PhD Robert C. Elston, PhD Jing Li, PhD Nathan Morris, PhD September 6, 2013 *We also certify that written approval has been obtained for any proprietary material contained therein. 2 Dedication This dissertation is dedicated to my husband Manju and our children Suvan, Poppy, Jujubee, and Sayali. 3 TABLE OF CONTENTS List of Tables………………………………………………………………….…………..5 List of Figures…………………………………………………………………………….6 Abstract……………………………………………………………………….…………..7 Chapter 1. Background……………………………………………………...….…………9 Chapter 2. Specific Aims………..……………………………………………………….53 Chapter 3. Variants in CXADR and F2RL1 are associated with blood pressure and obesity in African-Americans in regions identified through admixture mapping………………..60 Chapter 4. Novel variants for HDL-C, LDL-C and triglycerides identified from admixture mapping and fine-mapping analysis in families…...…………………………………….85 Chapter 5. Identification of admixture regions associated with risk of apparent treatment- resistant hypertension in African-Americans………..………………………………….117 Chapter 6. Discussion………………………………..………………………………....137 References………………………………………………………………………………142 4 List of Tables Chapter 1. Table 1. Genome-wide Association Studies of Hypertension………...……...40 Chapter 1. Table 2. Other Analysis Methods in the Genetic Analysis of Hypertension in Unrelated Subjects………………………………………………………………...……..51 Chapter 3. Table 1. Summary statistics…………………………………………...……..80 Chapter 3. Table 2. Results of gene-based multivariable regression models……..….….81 Chapter 3. -
Fibroblasts from the Human Skin Dermo-Hypodermal Junction Are
cells Article Fibroblasts from the Human Skin Dermo-Hypodermal Junction are Distinct from Dermal Papillary and Reticular Fibroblasts and from Mesenchymal Stem Cells and Exhibit a Specific Molecular Profile Related to Extracellular Matrix Organization and Modeling Valérie Haydont 1,*, Véronique Neiveyans 1, Philippe Perez 1, Élodie Busson 2, 2 1, 3,4,5,6, , Jean-Jacques Lataillade , Daniel Asselineau y and Nicolas O. Fortunel y * 1 Advanced Research, L’Oréal Research and Innovation, 93600 Aulnay-sous-Bois, France; [email protected] (V.N.); [email protected] (P.P.); [email protected] (D.A.) 2 Department of Medical and Surgical Assistance to the Armed Forces, French Forces Biomedical Research Institute (IRBA), 91223 CEDEX Brétigny sur Orge, France; [email protected] (É.B.); [email protected] (J.-J.L.) 3 Laboratoire de Génomique et Radiobiologie de la Kératinopoïèse, Institut de Biologie François Jacob, CEA/DRF/IRCM, 91000 Evry, France 4 INSERM U967, 92260 Fontenay-aux-Roses, France 5 Université Paris-Diderot, 75013 Paris 7, France 6 Université Paris-Saclay, 78140 Paris 11, France * Correspondence: [email protected] (V.H.); [email protected] (N.O.F.); Tel.: +33-1-48-68-96-00 (V.H.); +33-1-60-87-34-92 or +33-1-60-87-34-98 (N.O.F.) These authors contributed equally to the work. y Received: 15 December 2019; Accepted: 24 January 2020; Published: 5 February 2020 Abstract: Human skin dermis contains fibroblast subpopulations in which characterization is crucial due to their roles in extracellular matrix (ECM) biology.