DOCSLIB.ORG

Gap Junction Enhancer As an Anti-Cancer Agent Via Gjic-Independent and -Dependent Pathways

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Gap Junction Enhancer As an Anti-Cancer Agent Via Gjic-Independent and -Dependent Pathways GAP JUNCTION ENHANCER AS AN ANTI-CANCER AGENT VIA GJIC-INDEPENDENT AND -DEPENDENT PATHWAYS by YING DING B.E., Tianjin University, Tianjin, China, 2004 B.B.A., Tianjin University, Tianjin, China, 2004 M.S., Tianjin University, Tianjin, China, 2007 AN ABSTRACT OF A DISSERTATION submitted in partial fulfillment of the requirements for the degree DOCTOR OF PHILOSOPHY Department of Biochemistry and Molecular Biophysics College of Arts and Sciences KANSAS STATE UNIVERSITY Manhattan, Kansas 2013 Abstract Gap junctions (GJ) are intercellular channels connecting adjacent cells, allowing small molecules to transport between cells, thereby maintaining all homeostasis. Loss of gap junctional intercellular communication (GJIC) and/or connexins, the gap junction proteins, is a hallmark of cancer. Restoration of GJIC and/or increase of connexin expression have been related to the reduction of tumorigenesis. Connexins have been reported as tumor suppressors due to both GJIC-independent and -dependent mechanisms. Therefore, development of effective agents or methods to enhance GJIC and restore connexin expression in cancer cells is a new strategy in cancer treatment. PQ1, 6-Methoxy-8-[(3-aminopropyl)amino]-4-methyl-5-(3-trifluoromethyl- phenyloxy)quinoline, has been demonstrated to increase GJIC, restore connexin expression, and exert anti-cancer effects on T47D breast cancer cells. Studies of apoptotic pathways showed that PQ1 activated both extrinsic and intrinsic apoptotic pathways, indicating that PQ1 exerts its anti- cancer effects via a GJIC-independent mechanism through the induction of apoptosis. Combinational treatment of PQ1 and cisplatin showed that PQ1 counteracted cisplatin-induced inhibition of GJIC and reduction of connexin expression, thereby increasing the efficacy of cisplatin in T47D cancer cells via a GJIC-dependent mechanism. Further studies of drug distribution and toxicity revealed that administration of PQ1 by oral gavage can be achieved with low toxicity to normal vital organs. All the results suggest that PQ1, a gap junction enhancer, can function as an anti-cancer agent and potentiate the efficacy of antineoplastic drugs via both GJIC-independent and -dependent pathways. GAP JUNCTION ENHANCER AS AN ANTI-CANCER AGENT VIA GJIC-INDEPENDENT AND -DEPENDENT PATHWAYS by YING DING B.E., Tianjin University, Tianjin, China, 2004 B.B.A., Tianjin University, Tianjin, China, 2004 M.S., Tianjin University, Tianjin, China, 2007 A DISSERTATION submitted in partial fulfillment of the requirements for the degree DOCTOR OF PHILOSOPHY Department of Biochemistry and Molecular Biophysics College of Arts and Sciences KANSAS STATE UNIVERSITY Manhattan, Kansas 2013 Approved by: Major Professor Thu Annelise Nguyen Abstract Gap junctions (GJ) are intercellular channels connecting adjacent cells, allowing small molecules to transport between cells, thereby maintaining all homeostasis. Loss of gap junctional intercellular communication (GJIC) and/or connexins, the gap junction proteins, is a hallmark of cancer. Restoration of GJIC and/or increase of connexin expression have been related to the reduction of tumorigenesis. Connexins have been reported as tumor suppressors due to both GJIC-independent and -dependent mechanisms. Therefore, development of effective agents or methods to enhance GJIC and restore connexin expression in cancer cells is a new strategy in cancer treatment. PQ1, 6-Methoxy-8-[(3-aminopropyl)amino]-4-methyl-5-(3-trifluoromethyl- phenyloxy)quinoline, has been demonstrated to increase GJIC, restore connexin expression, and exert anti-cancer effects on T47D breast cancer cells. Studies of apoptotic pathways showed that PQ1 activated both extrinsic and intrinsic apoptotic pathways, indicating that PQ1 exerts its anti- cancer effects via a GJIC-independent mechanism through the induction of apoptosis. Combinational treatment of PQ1 and cisplatin showed that PQ1 counteracted cisplatin-induced inhibition of GJIC and reduction of connexin expression, thereby increasing the efficacy of cisplatin in T47D cancer cells via a GJIC-dependent mechanism. Further studies of drug distribution and toxicity revealed that administration of PQ1 by oral gavage can be achieved with low toxicity to normal vital organs. All the results suggest that PQ1, a gap junction enhancer, can function as an anti-cancer agent and potentiate the efficacy of antineoplastic drugs via both GJIC-independent and -dependent pathways. Table of Contents List of Figures ................................................................................................................................ ix List of Tables ................................................................................................................................. xi Acknowledgements ....................................................................................................................... xii Dedication .................................................................................................................................... xiv Chapter 1 - Review of Literature .................................................................................................... 1 1.1 Gap Junctions and Connexins ............................................................................................... 1 1.1.1 Nomenclature and Distribution of Connexins ............................................................... 1 1.1.2 Structures of Connexins and Gap Junctions .................................................................. 4 1.1.3 Regulation Pathways of Connexins ............................................................................... 6 1.1.4 Functions of Gap Junctions .......................................................................................... 18 1.2 Gap Junctions and Diseases ................................................................................................ 20 1.2.1 Overview ...................................................................................................................... 20 1.2.2 Gap Junctions and Cancer ............................................................................................ 22 1.2.3 Gap Junctions and Breast Cancer ................................................................................ 28 1.3 Connexins and Gap Junctions as Therapeutic Targets ....................................................... 36 1.3.1 Therapeutic Approaches Related to GJIC .................................................................... 36 1.3.2 Therapeutic Approaches Related to Connexin Expression .......................................... 37 1.3.3 PQ1 as a Gap Junction Enhancer ................................................................................. 38 References ................................................................................................................................. 40 Chapter 2 - Hypotheses and Objectives ........................................................................................ 60 2.1 Hypotheses .......................................................................................................................... 60 2.2 Objectives ........................................................................................................................... 60 Chapter 3 - PQ1, a Quinoline Derivative, Induces Apoptosis in T47D Breast Cancer Cells through Activation of Caspase-8 and Caspase-9 ................................................................... 62 3.1 Abstract ............................................................................................................................... 62 3.2 Introduction ......................................................................................................................... 63 3.3 Meterial and Methods ......................................................................................................... 66 3.3.1 Reagents and Antibodies .............................................................................................. 66 3.3.2 Cell Line and Cell Culture ........................................................................................... 66 v 3.3.3 Cell Morphology .......................................................................................................... 66 3.3.4 Cell Viability Assay ..................................................................................................... 67 3.3.5 Flow Cytometry ........................................................................................................... 67 3.3.6 Mitochondria Isolation ................................................................................................. 67 3.3.7 Western Blot Analysis ................................................................................................. 68 3.3.8 Immunofluorescence and Confocal Microscopy ......................................................... 68 3.3.9 Caspase Inhibitor Assay ............................................................................................... 69 3.3.10 Statistical Analysis ..................................................................................................... 69 3.4 Results ................................................................................................................................. 70 3.4.1 PQ1 Changes Cell Morphology and Induces Cell Death in T47D Breast Cancer Cells ..............................................................................................................................................
Load more

Recommended publications
  • A Rare Missense Mutation in GJB3 (Cx31g45e) Is Associated with a Unique Cellular Phenotype Resulting in Necrotic Cell Death Easton, J
    University of Dundee A rare missense mutation in GJB3 (Cx31G45E) is associated with a unique cellular phenotype resulting in necrotic cell death Easton, J. A.; Alboulshi, A. K.; Kamps, M. A. F.; Brouns, G. H.; Broers, M. R.; Coull, B. J.; Oji, V.; van Geel, M.; van Steensel, M. A. M.; Martin, P. E. Published in: Experimental Dermatology DOI: 10.1111/exd.13542 Publication date: 2018 Document Version Peer reviewed version Link to publication in Discovery Research Portal Citation for published version (APA): Easton, J. A., Alboulshi, A. K., Kamps, M. A. F., Brouns, G. H., Broers, M. R., Coull, B. J., ... Martin, P. E. (2018). A rare missense mutation in GJB3 (Cx31G45E) is associated with a unique cellular phenotype resulting in necrotic cell death. Experimental Dermatology. https://doi.org/10.1111/exd.13542 General rights Copyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal. Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
    [Show full text]
  • GJA4/Connexin 37 Mutations Correlate with Secondary Lymphedema Following Surgery in Breast Cancer Patients
    biomedicines Article GJA4/Connexin 37 Mutations Correlate with Secondary Lymphedema Following Surgery in Breast Cancer Patients Mahrooyeh Hadizadeh 1,2, Seiied Mojtaba Mohaddes Ardebili 1, Mansoor Salehi 2, Chris Young 3, Fariborz Mokarian 4, James McClellan 5, Qin Xu 6, Mohammad Kazemi 2, Elham Moazam 4, Behzad Mahaki 7 ID and Maziar Ashrafian Bonab 8,* 1 Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran; [email protected] (M.H.); [email protected] (S.M.M.A.) 2 Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan 81746753461, Iran; [email protected] (M.S.); [email protected] (M.K.) 3 School of Allied Health Sciences, Faculty of Health and Life Sciences, De Montfort University, Leicester LE1 9BH, UK; [email protected] 4 Cancer Prevention Research Centre, Isfahan University of Medical Sciences, Isfahan 8184917911, Iran; [email protected] (F.M.); [email protected] (E.M.) 5 School of Biological Sciences, University of Portsmouth, Portsmouth PO1 2DY, UK; [email protected] 6 School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, Leicester LE1 9BH, UK; [email protected] 7 Department of Occupational Health Engineering, School of Health, Isfahan University of Medical Sciences, Isfahan 8174673461, Iran; [email protected] 8 Department of Biological Sciences, University of Chester, Chester CH1 4BJ, UK * Correspondence: [email protected]; Tel.: +44-(0)1244-513-056 Received: 31 December 2017; Accepted: 13 February 2018; Published: 22 February 2018 Abstract: Lymphedema is a condition resulting from mutations in various genes essential for lymphatic development and function, which leads to obstruction of the lymphatic system.
    [Show full text]
  • Localized Calcium Signaling and the Control of Coupling at Cx36 Gap Junctions
    Research Article: New Research | Novel Tools and Methods Localized calcium signaling and the control of coupling at Cx36 gap junctions https://doi.org/10.1523/ENEURO.0445-19.2020 Cite as: eNeuro 2020; 10.1523/ENEURO.0445-19.2020 Received: 25 October 2019 Revised: 29 January 2020 Accepted: 21 February 2020 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.eneuro.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2020 Moore et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 Localized calcium signaling and the control of coupling at Cx36 gap junctions 2 3 Abbreviated title: Calcium signaling at Cx36 gap junctions 4 5 Keith B. Moore1,†, Cheryl K. Mitchell1, Ya-Ping Lin1, Yuan-Hao Lee1, Eyad Shihabeddin1,2, and 6 John O'Brien1,2,* 7 8 1. Richard S. Ruiz, M.D. Department of Ophthalmology & Visual Science, McGovern Medical 9 School, The University of Texas Health Science Center at Houston, Houston, Texas, USA. 10 2. The MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, 11 Houston, Texas, USA. 12 †. Current Address: School of Public Health, The University of Texas Health Science Center at 13 Houston, Houston, Texas, USA.
    [Show full text]
  • Characterization of a Variant of Gap Junction Protein Α8 Identified in a Family with Hereditary Cataract
    UCSF UC San Francisco Previously Published Works Title Characterization of a variant of gap junction protein α8 identified in a family with hereditary cataract. Permalink https://escholarship.org/uc/item/5x99q7m4 Journal PloS one, 12(8) ISSN 1932-6203 Authors Kuo, Debbie S Sokol, Jared T Minogue, Peter J et al. Publication Date 2017 DOI 10.1371/journal.pone.0183438 Peer reviewed eScholarship.org Powered by the California Digital Library University of California RESEARCH ARTICLE Characterization of a variant of gap junction protein α8 identified in a family with hereditary cataract Debbie S. Kuo1,2*, Jared T. Sokol3, Peter J. Minogue4, Viviana M. Berthoud4, Anne M. Slavotinek5, Eric C. Beyer4, Douglas B. Gould1,6 1 Department of Ophthalmology, University of California, San Francisco School of Medicine, San Francisco, CA, United States of America, 2 Department of Ophthalmology, Palo Alto Medical Foundation, Palo Alto, CA, United States of America, 3 Pritzker School of Medicine, University of Chicago, Chicago, IL, United States of America, 4 Department of Pediatrics, University of Chicago, Chicago, IL, United States of America, a1111111111 5 Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States of a1111111111 America, 6 Department of Anatomy and Institute of Human Genetics, University of California, San Francisco a1111111111 School of Medicine, San Francisco, CA, United States of America a1111111111 a1111111111 * [email protected] Abstract OPEN ACCESS Citation: Kuo DS, Sokol JT, Minogue PJ, Berthoud VM, Slavotinek AM, Beyer EC, et al. (2017) Purpose Characterization of a variant of gap junction protein Congenital cataracts occur in isolation in about 70% of cases or are associated with other α8 identified in a family with hereditary cataract.
    [Show full text]
  • In Silico Analysis of Non-Synonymous Single Nucleotide Polymorphisms (Nssnps) in the Human GJA3 Gene Associated with Congenital
    Zhang et al. BMC Molecular and Cell Biology (2020) 21:12 BMC Molecular and https://doi.org/10.1186/s12860-020-00252-7 Cell Biology RESEARCH ARTICLE Open Access In silico analysis of non-synonymous single nucleotide polymorphisms (nsSNPs) in the human GJA3 gene associated with congenital cataract Mingzhou Zhang1,2†, Chen Huang1,2,3†, Zhenyu Wang1,2, Huibin Lv1,2 and Xuemin Li1,2* Abstract Background: Gap junction protein alpha 3 (GJA3), an important pathogenic gene of congenital cataracts, encodes the transmembrane protein connexin46, which functions as an intercellular channel for voltage and chemical gating by forming dodecamers. This study systematically collected nsSNP information for the GJA3 gene from SNP databases and literature and screened for nsSNPs with high risks of pathogenicity. Results: A total of 379 nsSNPs of GJA3 were identified. A total of 88 high-risk pathogenic GJA3 nsSNPs were found, including 31 published nsSNPs associated with congenital cataracts and 57 novel nsSNPs predicted by all eight online tools. The 88 high-risk pathogenic mutations, which are related to 67 amino acids in the wild-type sequences, cause a decrease in protein stability according to I-Mutant 3.0, MUpro and INPS. G2 and R33 were predicted to participate in post-translational modification and ligand binding by ModPred, RaptorX Binding and COACH. Additionally, high-risk mutations were likely to involve highly conserved sites, random coils, alpha helixes, and extracellular loops and were accompanied by changes in amino acid size, charge, hydrophobicity and spatial structure. Conclusions: Eighty-eight high-risk pathogenic nsSNPs of GJA3 were screened out in the study, 57 of which were newly reported.
    [Show full text]
  • Restoration of Desmosomal Junction Protein Expression and Inhibition Of
    MOLECULAR AND CLINICAL ONCOLOGY 3: 171-178, 2015 Restoration of desmosomal junction protein expression and inhibition of H3K9‑specifichistone demethylase activity by cytostatic proline‑rich polypeptide‑1 leads to suppression of tumorigenic potential in human chondrosarcoma cells KARINA GALOIAN1, AMIR QURESHI1, GINA WIDEROFF1 and H.T. TEMPLE2 1Department of Orthopaedic Surgery; 2University of Miami Tissue Bank Division, Miller School of Medicine, University of Miami, Miami, FL 33136, USA Received September 18, 2014; Accepted October 8, 2014 DOI: 10.3892/mco.2014.445 Abstract. Disruption of cell-cell junctions and the concomi- and inhibits H3K9 demethylase activity, contributing to the tant loss of polarity, downregulation of tumor-suppressive suppression of tumorigenic potential in chondrosarcoma cells. adherens junctions and desmosomes represent hallmark phenotypes for several different cancer cells. Moreover, a Introduction variety of evidence supports the argument that these two common phenotypes of cancer cells directly contribute to Chondrosarcoma is a highly aggressive bone cancer of tumorigenesis. In this study, we aimed to determine the status mesenchymal origin, which is resistant to chemo- and radia- of intercellular junction proteins expression in JJ012 human tion therapies, leaving surgical resection as the only option. malignant chondrosarcoma cells and investigate the effect Metastatic spread of malignant cells eventually develops of the antitumorigenic cytokine, proline-rich polypeptide-1 following surgical resection. The malignant progression to (PRP-1) on their expression. The cell junction pathway array chondrosarcoma has been suggested to involve a degree of data indicated downregulation of desmosomal proteins, mesenchymal-to-epithelial transition (MET) and it has been such as desmoglein (1,428-fold), desmoplakin (620-fold) and demonstrated in an in vitro model that chondrosarcoma cells plakoglobin (442-fold).
    [Show full text]
  • Evidence of Decreased Gap Junction Coupling Between Astrocytes and Oligodendrocytes in the Anterior Cingulate Cortex of Depresse
    bioRxiv preprint doi: https://doi.org/10.1101/578807; this version posted March 16, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Evidence of decreased gap junction coupling between astrocytes and oligodendrocytes in the anterior cingulate cortex of depressed suicides Arnaud Tanti, Ph.D.1, Pierre-Eric Lutz M.D. Ph.D.1,2, John Kim B.Sc.1, Liam O’Leary B.Sc.1, Gustavo Turecki M.D. Ph.D.1,3 and Naguib Mechawar Ph.D.1,3 Affiliations: 1 McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Canada 2 Current address : Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France. 3 Department of Psychiatry, McGill University, Montréal, Canada Corresponding author: Naguib Mechawar Ph.D. McGill Group for Suicide Studies Douglas Mental Health Institute Department of Psychiatry McGill University [email protected] bioRxiv preprint doi: https://doi.org/10.1101/578807; this version posted March 16, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT Glial dysfunction is a major feature in the pathophysiology of mood disorders. While altered astrocyte (AS) and oligodendrocyte-lineage (OL) cell functions have been associated with depression, the crosstalk between these two major glial cell types has never been assessed in that context. AS are potent regulators of OL cells and myelination, in part through gap junction-mediated intercellular communication made possible by the heterotypic coupling of AS-specific (Cx30 and Cx43) and OL-specific (Cx32 and Cx47) connexins, allowing cytosolic transport and metabolic support to OL cells.
    [Show full text]
  • Pannexins and Connexins: Their Relevance for Oocyte Developmental Competence
    International Journal of Molecular Sciences Review Pannexins and Connexins: Their Relevance for Oocyte Developmental Competence Paweł Kordowitzki 1,2, Gabriela Sokołowska 3, Marta Wasielak-Politowska 4, Agnieszka Skowronska 5 and Mariusz T. Skowronski 2,* 1 Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Bydgoska Street 7, 10-243 Olsztyn, Poland; [email protected] 2 Department of Basic and Preclinical Sciences, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Gagarina Street 7, 87-100 Torun, Poland 3 Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Jana Kili´nskiegoStreet 1, 15-089 Białystok, Poland; [email protected] 4 Center of Gynecology, Endocrinology and Reproductive Medicine—Artemida, Jagiello´nskaStreet 78, 10-357 Olsztyn, Poland; [email protected] 5 Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Warszawska Street 30, 10-357 Olsztyn, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-566-112-231 Abstract: The oocyte is the major determinant of embryo developmental competence in all mam- malian species. Although fundamental advances have been generated in the field of reproductive medicine and assisted reproductive technologies in the past three decades, researchers and clinicians are still trying to elucidate molecular factors and pathways, which could be pivotal for the oocyte’s developmental competence. The cell-to-cell and cell-to-matrix communications are crucial not only Citation: Kordowitzki, P.; for oocytes but also for multicellular organisms in general. This latter mentioned communication is Sokołowska, G.; Wasielak-Politowska, among others possibly due to the Connexin and Pannexin families of large-pore forming channels.
    [Show full text]
  • Structure and Function of Gap Junction Proteins: Role of Gap Junction Proteins in Embryonic Heart Development BHAVESH K
    Int. J. Dev. Biol. 58: 649-662 (2014) doi: 10.1387/ijdb.140188dp www.intjdevbiol.com Structure and function of gap junction proteins: role of gap junction proteins in embryonic heart development BHAVESH K. AHIR1 and MARGARET K. PRATTEN*,2 1National Center for Computational Toxicology (B205-01), U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA and 2School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham, UK ABSTRACT Intercellular (cell-to-cell) communication is a crucial and complex mechanism during embryonic heart development. In the cardiovascular system, the beating of the heart is a dynamic and key regulatory process, which is functionally regulated by the coordinated spread of electrical activity through heart muscle cells. Heart tissues are composed of individual cells, each bearing spe- cialized cell surface membrane structures called gap junctions that permit the intercellular exchange of ions and low molecular weight molecules. Gap junction channels are essential in normal heart function and they assist in the mediated spread of electrical impulses that stimulate synchronized contraction (via an electrical syncytium) of cardiac tissues. This present review describes the cur- rent knowledge of gap junction biology. In the first part, we summarise some relevant biochemical and physiological properties of gap junction proteins, including their structure and function. In the second part, we review the current evidence demonstrating the role of gap junction proteins in embryonic development with particular reference to those involved in embryonic heart develop- ment. Genetics and transgenic animal studies of gap junction protein function in embryonic heart development are considered and the alteration/disruption of gap junction intercellular communica- tion which may lead to abnormal heart development is also discussed.
    [Show full text]
  • The Impact of GJA8 Snps on Susceptibility to Age-Related Cataract
    Human Genetics (2018) 137:897–904 https://doi.org/10.1007/s00439-018-1945-5 ORIGINAL INVESTIGATION The impact of GJA8 SNPs on susceptibility to age-related cataract Xiaoning Yu1 · Xiyuan Ping1 · Xin Zhang1 · Yilei Cui1 · Hao Yang1 · Xiajing Tang1 · Yelei Tang2 · Xingchao Shentu1 Received: 13 July 2018 / Accepted: 12 October 2018 / Published online: 22 October 2018 © The Author(s) 2018 Abstract The gap junction protein alpha 8 (GJA8) gene has been widely studied in human congenital cataracts. However, little is known about its relationship with age-related cataract (ARC). In this study, three GJA8-tagged single nucleotide polymor- phisms related to an increased ARC risk were identified: rs2132397 for general ARC under both dominant and additive models; rs7541950 for general ARC under both recessive and additive models; and rs6657114 for cortical cataract under the recessive model. To uncover the underlying mechanisms, this study also sought to explore whether GJA8 is involved in the autophagy process in human lens epithelial cells. The results showed that GJA8 may participate in autophagy to maintain the intracellular environment, which may be a novel mechanism for cataract formation induced by GJA8. In conclusion, this study identified the genetic susceptibility of GJA8 polymorphisms on ARC and provides new clues for fully understanding the pathological mechanism of GJA8 variants in affecting lens opacity. Introduction and loci have been identified as related to congenital cata- ract formation (Mackay et al. 2014; Shiels and Hejtmancik Cataracts are the leading cause of blindness and a major 2013). The connexin genes, which account for a quarter of cause of vision impairment worldwide (Bourne et al.
    [Show full text]
  • Connexins in the Heart: Regulation, Function and Involvement in Cardiac Disease
    International Journal of Molecular Sciences Review Connexins in the Heart: Regulation, Function and Involvement in Cardiac Disease Antonio Rodríguez-Sinovas 1,2,3,* , Jose Antonio Sánchez 1,2,3, Laura Valls-Lacalle 1,2,3, Marta Consegal 1,2,3 and Ignacio Ferreira-González 1,2,4,* 1 Cardiovascular Diseases Research Group, Department of Cardiology, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Vall d’Hebron Hospital Universitari, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain; [email protected] (J.A.S.); [email protected] (L.V.-L.); [email protected] (M.C.) 2 Departament de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain 3 Centro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain 4 Centro de Investigación Biomédica en Red (CIBER) de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, 28029 Madrid, Spain * Correspondence: [email protected] (A.R.-S.); [email protected] (I.F.-G.); Tel.: +34-93-4894184 (A.R.-S.) Abstract: Connexins are a family of transmembrane proteins that play a key role in cardiac physiology. Gap junctional channels put into contact the cytoplasms of connected cardiomyocytes, allowing the existence of electrical coupling. However, in addition to this fundamental role, connexins are also involved in cardiomyocyte death and survival. Thus, chemical coupling through gap junctions plays a key role in the spreading of injury between connected cells. Moreover, in addition to their involvement in cell-to-cell communication, mounting evidence indicates that connexins have additional gap junction-independent functions.
    [Show full text]
  • Connexin in Lens Physiology and Cataract Formation Mauricio A
    perim Ex en l & ta a l ic O p in l h t C h f Journal of Clinical & Experimental a Retamal et al. J Clinic Experiment Ophthalmol 2011, S:1 o l m l a o n l DOI: 10.4172/2155-9570.S1-001 r o g u y o J Ophthalmology ISSN: 2155-9570 ResearchReview Article Article OpenOpen Access Access Connexin in Lens Physiology and Cataract Formation Mauricio A. Retamal1*, Carmen G. León-Paravic1, Christian A. Verdugo5, Constanza A. Alcaino1,2, Rodrigo Moraga-Amaro3,4 and Jimmy Stehberg3,4 1Laboratorio de Fisiología, Facultad de Medicina. Clínica Alemana - Universidad del Desarrollo, Santiago, Chile 2Laboratorio de Neurobiología, Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile 3Laboratorio de Neurobiologia, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas & Facultad de Medicina, Universidad Andres Bello, Santiago, Chile 4Centro de Investigaciones Biomedicas, Facultad de Ciencias Biologicas & Facultad de Medicina, Universidad Andres Bello, Chile 5Tecnología Médica, Facultad de Medicina, Clínica Alemana - Universidad del Desarrollo, Santiago, Chile Abstract Connexins are a family of proteins that forms hemichannels that communicate the cytoplasm with the extracellular space. When two hemichannels [each one from two neighboring cells] make contact, they form a gap junction channel, which communicates the cytoplasm of adjacent cells. The molecular mechanisms that control the opening and closing of both functional hemichannels and gap junction channels is still matter of intense scrutiny. The lens is a transparent structure located in the anterior segment of the eye, which is critical for normal vision. Its main function is to refract the light, focusing it on the retina.
    [Show full text]