DOCSLIB.ORG

Evaluation of Chloride Intracellular Channels 4 and 1 Functions in Developmental and Pathological Angiogenesis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Evaluation of Chloride Intracellular Channels 4 and 1 Functions in Developmental and Pathological Angiogenesis Jennifer Jean Tung Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2012 © 2012 Jennifer Jean Tung All Rights Reserved ABSTRACT Evaluation of Chloride Intracellular Channels 4 and 1 Functions in Developmental and Pathological Angiogenesis Jennifer Jean Tung Members of the chloride intracellular channel (CLIC) protein family have been implicated as regulators of tubulogenesis, a critical step in the formation of new blood vessels during angiogenesis. We sought to determine CLIC4 and CLIC1 function in angiogenesis. We hypothesized that CLIC4 and CLIC1 act in endothelial lumen formation and promote both developmental and pathological angiogenesis. Using in vitro studies, we found that CLIC4 promotes endothelial proliferation, network formation, capillary-like sprouting, and lumen formation. In vivo, Clic4 knockout mice display a mild defect in retinal vascular development and an apparent decrease in retinal macrophage content. By implanting murine tumor cells in Clic4 knockout mice, we discovered that Clic4 affects the establishment of lung metastases. Endothelial and smooth muscle cell content of tumors are comparable to wild type, but overall vessel architecture is altered. In studying CLIC1, we found that CLIC1 knockdown results in reduced endothelial proliferation, directed migration, network formation, and capillary-like sprouting in vitro . In vivo analysis revealed no apparent angiogenic phenotype in the developing retinas of Clic1 knockout mice. We developed Clic4 -/-;Clic1 -/- double mutant embryos, which were unable to develop beyond 9.5 dpc. Whole mount staining of Clic4 -/-;Clic1 -/- 9.5 dpc embryos for vasculature revealed an angiogenic defect, most notable along the intersomitic vessels and in the brain. Endothelial content is reduced in Clic4;Clic1 double knockout embryos, and double nullizygous embryos were growth retarded. Preliminary histological analysis of Clic4 -/-;Clic1 -/- 9.5 dpc embryos suggests altered aortic development, reduced proliferation, and increased apoptosis. I conclude that CLIC4 and CLIC1 function in endothelial proliferation and morphogenesis and that Clic4 and Clic1 are required for embryonic development. Together, our findings indicate that CLIC4 and CLIC1 are important in developmental angiogenesis and should be considered in elucidating the molecular mechanisms of tubulogenesis. Contents List of Figures ……………………………………………………………………... iii List of Tables ……………………………………………………………………... vi Acknowledgements ……………………………………………………………... vii Chapter 1. Introduction …………………………………………………….... 1 1.1 Overview of angiogenesis in development and pathology ..…….… 1 1.2 Mechanisms of tubulogenesis ….………………………………...... 2 1.3 Chloride intracellular channels ....……………………….………… 4 1.4 Evidence for CLIC function in angiogenesis ..….…………………. 6 1.5 Figures ...…………………………………………………………... 11 Chapter 2. CLIC4 is involved in endothelial cell proliferation and morphogenesis in vitro …………………………………………... 13 2.1 Abstract .…………………………………………………………… 13 2.2 Introduction .……………………………………………………….. 14 2.3 Altered CLIC4 expression does not affect endothelial cell migration .………………………………………………………….. 17 2.4 CLIC4 expression promotes endothelial cell proliferation ..…...…. 18 2.5 CLIC4 promotes endothelial capillary-like network formation …... 19 2.6 Altered CLIC4 expression affects capillary-like sprouting and lumen formation .……………………………………………….….. 21 2.7 Discussion .………………………………………………………… 22 2.8 Figures ……………………………………………………….......... 26 2.9 Additional discussion ..…………………………………………….. 40 2.10 Supplementary figures ...…………………………………………... 41 Chapter 3. Generation and characterization of Clic4 knockout mice ….….. 47 3.1 Abstract .…………………………………………………………… 47 3.2 Introduction .……………………………………………………….. 48 3.3 Clic4 targeting scheme …………………………………………….. 49 3.4 Clic4 knockout mice are underrepresented, but viable and fertile .…………………………………………………………. 51 3.5 Clic4 knockout mice display subtle defects in postnatal angiogenesis and may have reduced macrophage content in the developing retina ….………………………………………… 52 3.6 Clic4 knockout may enhance tumor growth and metastasis ..…..... 53 3.7 Discussion …………..…………………………………………...… 55 3.8 Figures ………………………………………………..…………… 59 3.9 Tables ……………………………………………………………… 69 i Chapter 4. Chloride intracellular channel 1 functions in endothelial cell growth and migration ………………………………….…… 70 4.1 Abstract .…………………………………………………………… 70 4.2 Introduction .……………………………………………………….. 71 4.3 Generation of endothelial cell lines with stable CLIC1 knockdown .………………………………………………………... 73 4.4 CLIC1 knockdown inhibits endothelial cell growth .……………… 74 4.5 CLIC1 knockdown inhibits endothelial migration .……………….. 75 4.6 CLIC1 influences expression of select integrins on endothelial cells .……………………………………………...…… 76 4.7 CLIC1 plays a role in capillary-like network formation .……..….. 77 4.8 Reduced CLIC1 expression affects capillary-like sprouting and branching .………………………………………………….….. 78 4.9 Discussion .………………………………………………………… 79 4.10 Figures ……………....…………………………………………….. 83 4.11 Additional discussion .…………………………………………...… 95 4.12 Supplementary figures …………………………………………….. 97 4.13 Supplementary tables ……………………………………………… 103 Chapter 5. Clic4 and Clic1 are required for embryonic development …….. 104 5.1 Abstract …………………………………………………………… 104 5.2 Introduction ……………………………………………………….. 105 5.3 Generation of Clic4 and Clic1 double mutants …………………… 107 5.4 Clic4 -/-;Clic1 -/- double knockout mice are embryonic lethal at 9.5 dpc ………………………………………………..…... 108 5.5 Clic4 -/-;Clic1 -/- double knockout mice display aberrant vascular development ………………………………………………109 5.6 Aortic development and proliferation may be altered in Clic4 -/-;Clic1 -/- embryos ………………………………………….. 110 5.7 Discussion …………………………………………………………. 111 5.8 Figures …………………………………………………………….. 116 5.9 Tables ……………………………………………………………… 134 Chapter 6. Conclusions and future directions ………………………………. 136 Chapter 7. Materials and methods …………………………………………... 147 Bibliography ………………………………………………………………………. 164 Appendix Regulation of cardiovascular development and integrity by the heart of glass–cerebral cavernous malformation protein pathway …………………………………….. 176 ii List of Figures Chapter 1. Fig 1.1 Cell hollowing and cord hollowing models for tubulogenic mechanisms …………………………………………... 11 Chapter 2 Fig 2.1 Establishing CLIC4 knockdown and overexpression in endothelial cells ……………………………………………….... 26 Fig 2.2 CLIC4 expression has no effect on endothelial cell migration ….... 28 Fig 2.3 CLIC4 expression promotes endothelial cell proliferation ……....... 30 Fig 2.4 Altering CLIC4 expression affects endothelial cell survival ……… 32 Fig 2.5 CLIC4 expression promotes in vitro endothelial network formation …......................................................................... 34 Fig 2.6 Reduced CLIC4 expression inhibits endothelial network formation independent of its proliferative defect ………………….. 36 Fig 2.7 CLIC4 expression affects capillary-like sprouting in vitro ………...38 Supp Fig 2.1 Clic1 and Clic4 are most highly expressed in cultured endothelial cells …………………………………………… 41 Supp Fig 2.2 CLIC4 expression affects endothelial morphogenesis in a three-dimensional extracellular matrix ……………..… 43 Supp Fig 2.3 CLIC4 expression does not affect ion conductance at the plasma membrane in HEK 293 cells …………………... 45 Chapter 3 Fig 3.1 Diagram of Clic4 targeting strategy and ES cell targeting confirmation …………………………………………....... 59 Fig 3.2 Confirmation of Clic4 knockout …………………………………... 61 Fig 3.3 Clic4 homozygous knockout mice are phenotypically normal at 9.5 dpc ………………………………………………...…63 iii Fig 3.4 Clic4 knockout mice show reduced retinal vasculature and macrophage content …………………………………………... 65 Fig 3.5 Tumorigenesis is enhanced by Clic4 knockout ………………........ 67 Chapter 4 Fig 4.1 Establishing human endothelial cell lines with CLIC1 knockdown ………………………………………………… 83 Fig 4.2 CLIC1 knockdown has mild effects on viability and significantly inhibits endothelial cell growth ……………………… 85 Fig 4.3 Reduced CLIC1 expression inhibits endothelial migration ……….. 87 Fig 4.4 CLIC1 expression plays a role in the expression of various integrins …………………………………………………… 89 Fig 4.5 Knocked down CLIC1 expression inhibits capillary-like network formation and branching morphogenesis ………………… 91 Fig 4.6 Reduced CLIC1 expression affects capillary-like sprouting and branching …………………………………………… 93 Supp Fig 4.1 Confirmation of CLIC4 overexpression and CLIC1 knockdown ………………………………………… 97 Supp Fig 4.2 Partial rescue of the CLIC1 knockdown network formation defect by CLIC4 ………………………………... 99 Supp Fig 4.3 Loss of Clic1 does not affect postnatal retinal angiogenesis ……………………………………………….. 101 Chapter 5 Fig 5.1 Clic4;Clic1 double knockout embryos present cardiac edema at 10.5 dpc …………………………………………………. 116 Fig 5.2 Embryos missing three Clic alleles are represented at 10.5 dpc ….. 118 Fig 5.3 Clic4 +/+ ;Clic1 -/- 9.5 dpc embryos are indistinguishable from Clic4 +/+ ;Clic1 +/+ embryos …………………………………... 120 Fig 5.4 In utero death for Clic4 -/-;Clic1 -/- embryos occurs at 9.5 dpc with growth retardation and an angiogenic defect …...……………. 122 iv Fig 5.5 Endothelial content is reduced in Clic4 -/-;Clic1 -/- developing embryos ……………………………………………….. 124 Fig 5.6 Aortic development may be altered in Clic4 -/-;Clic1 -/-
Recommended publications
  • Screening and Identification of Key Biomarkers in Clear Cell Renal Cell Carcinoma Based on Bioinformatics Analysis

    Screening and Identification of Key Biomarkers in Clear Cell Renal Cell Carcinoma Based on Bioinformatics Analysis

    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.21.423889; this version posted December 23, 2020. 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. Screening and identification of key biomarkers in clear cell renal cell carcinoma based on bioinformatics analysis Basavaraj Vastrad1, Chanabasayya Vastrad*2 , Iranna Kotturshetti 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. 3. Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, Karnataka 562209, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2020.12.21.423889; this version posted December 23, 2020. 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 Clear cell renal cell carcinoma (ccRCC) is one of the most common types of malignancy of the urinary system. The pathogenesis and effective diagnosis of ccRCC have become popular topics for research in the previous decade. In the current study, an integrated bioinformatics analysis was performed to identify core genes associated in ccRCC. An expression dataset (GSE105261) was downloaded from the Gene Expression Omnibus database, and included 26 ccRCC and 9 normal kideny samples. Assessment of the microarray dataset led to the recognition of differentially expressed genes (DEGs), which was subsequently used for pathway and gene ontology (GO) enrichment analysis.
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus

    A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus

    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
  • The Inactive X Chromosome Is Epigenetically Unstable and Transcriptionally Labile in Breast Cancer

    The Inactive X Chromosome Is Epigenetically Unstable and Transcriptionally Labile in Breast Cancer

    Supplemental Information The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer Ronan Chaligné1,2,3,8, Tatiana Popova1,4, Marco-Antonio Mendoza-Parra5, Mohamed-Ashick M. Saleem5 , David Gentien1,6, Kristen Ban1,2,3,8, Tristan Piolot1,7, Olivier Leroy1,7, Odette Mariani6, Hinrich Gronemeyer*5, Anne Vincent-Salomon*1,4,6,8, Marc-Henri Stern*1,4,6 and Edith Heard*1,2,3,8 Extended Experimental Procedures Cell Culture Human Mammary Epithelial Cells (HMEC, Invitrogen) were grown in serum-free medium (HuMEC, Invitrogen). WI- 38, ZR-75-1, SK-BR-3 and MDA-MB-436 cells were grown in Dulbecco’s modified Eagle’s medium (DMEM; Invitrogen) containing 10% fetal bovine serum (FBS). DNA Methylation analysis. We bisulfite-treated 2 µg of genomic DNA using Epitect bisulfite kit (Qiagen). Bisulfite converted DNA was amplified with bisulfite primers listed in Table S3. All primers incorporated a T7 promoter tag, and PCR conditions are available upon request. We analyzed PCR products by MALDI-TOF mass spectrometry after in vitro transcription and specific cleavage (EpiTYPER by Sequenom®). For each amplicon, we analyzed two independent DNA samples and several CG sites in the CpG Island. Design of primers and selection of best promoter region to assess (approx. 500 bp) were done by a combination of UCSC Genome Browser (http://genome.ucsc.edu) and MethPrimer (http://www.urogene.org). All the primers used are listed (Table S3). NB: MAGEC2 CpG analysis have been done with a combination of two CpG island identified in the gene core. Analysis of RNA allelic expression profiles (based on Human SNP Array 6.0) DNA and RNA hybridizations were normalized by Genotyping console.
  • Emerging Roles for Multifunctional Ion Channel Auxiliary Subunits in Cancer T ⁎ Alexander S

    Emerging Roles for Multifunctional Ion Channel Auxiliary Subunits in Cancer T ⁎ Alexander S

    Cell Calcium 80 (2019) 125–140 Contents lists available at ScienceDirect Cell Calcium journal homepage: www.elsevier.com/locate/ceca Emerging roles for multifunctional ion channel auxiliary subunits in cancer T ⁎ Alexander S. Hawortha,b, William J. Brackenburya,b, a Department of Biology, University of York, Heslington, York, YO10 5DD, UK b York Biomedical Research Institute, University of York, Heslington, York, YO10 5DD, UK ARTICLE INFO ABSTRACT Keywords: Several superfamilies of plasma membrane channels which regulate transmembrane ion flux have also been Auxiliary subunit shown to regulate a multitude of cellular processes, including proliferation and migration. Ion channels are Cancer typically multimeric complexes consisting of conducting subunits and auxiliary, non-conducting subunits. Calcium channel Auxiliary subunits modulate the function of conducting subunits and have putative non-conducting roles, further Chloride channel expanding the repertoire of cellular processes governed by ion channel complexes to processes such as trans- Potassium channel cellular adhesion and gene transcription. Given this expansive influence of ion channels on cellular behaviour it Sodium channel is perhaps no surprise that aberrant ion channel expression is a common occurrence in cancer. This review will − focus on the conducting and non-conducting roles of the auxiliary subunits of various Ca2+,K+,Na+ and Cl channels and the burgeoning evidence linking such auxiliary subunits to cancer. Several subunits are upregu- lated (e.g. Cavβ,Cavγ) and downregulated (e.g. Kvβ) in cancer, while other subunits have been functionally implicated as oncogenes (e.g. Navβ1,Cavα2δ1) and tumour suppressor genes (e.g. CLCA2, KCNE2, BKγ1) based on in vivo studies. The strengthening link between ion channel auxiliary subunits and cancer has exposed these subunits as potential biomarkers and therapeutic targets.
  • Investigation of Copy Number Variations on Chromosome 21 Detected by Comparative Genomic Hybridization

    Investigation of Copy Number Variations on Chromosome 21 Detected by Comparative Genomic Hybridization

    Li et al. Molecular Cytogenetics (2018) 11:42 https://doi.org/10.1186/s13039-018-0391-3 RESEARCH Open Access Investigation of copy number variations on chromosome 21 detected by comparative genomic hybridization (CGH) microarray in patients with congenital anomalies Wenfu Li, Xianfu Wang and Shibo Li* Abstract Background: The clinical features of Down syndrome vary among individuals, with those most common being congenital heart disease, intellectual disability, developmental abnormity and dysmorphic features. Complex combination of Down syndrome phenotype could be produced by partially copy number variations (CNVs) on chromosome 21 as well. By comparing individual with partial CNVs of chromosome 21 with other patients of known CNVs and clinical phenotypes, we hope to provide a better understanding of the genotype-phenotype correlation of chromosome 21. Methods: A total of 2768 pediatric patients sample collected at the Genetics Laboratory at Oklahoma University Health Science Center were screened using CGH Microarray for CNVs on chromosome 21. Results: We report comprehensive clinical and molecular descriptions of six patients with microduplication and seven patients with microdeletion on the long arm of chromosome 21. Patients with microduplication have varied clinical features including developmental delay, microcephaly, facial dysmorphic features, pulmonary stenosis, autism, preauricular skin tag, eye pterygium, speech delay and pain insensitivity. We found that patients with microdeletion presented with developmental delay, microcephaly, intrauterine fetal demise, epilepsia partialis continua, congenital coronary anomaly and seizures. Conclusion: Three patients from our study combine with four patients in public database suggests an association between 21q21.1 microduplication of CXADR gene and patients with developmental delay. One patient with 21q22.13 microdeletion of DYRK1A shows association with microcephaly and scoliosis.
  • Transcriptomic Analysis of Native Versus Cultured Human and Mouse Dorsal Root Ganglia Focused on Pharmacological Targets Short

    Transcriptomic Analysis of Native Versus Cultured Human and Mouse Dorsal Root Ganglia Focused on Pharmacological Targets Short

    bioRxiv preprint doi: https://doi.org/10.1101/766865; this version posted September 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Transcriptomic analysis of native versus cultured human and mouse dorsal root ganglia focused on pharmacological targets Short title: Comparative transcriptomics of acutely dissected versus cultured DRGs Andi Wangzhou1, Lisa A. McIlvried2, Candler Paige1, Paulino Barragan-Iglesias1, Carolyn A. Guzman1, Gregory Dussor1, Pradipta R. Ray1,#, Robert W. Gereau IV2, # and Theodore J. Price1, # 1The University of Texas at Dallas, School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, 800 W Campbell Rd. Richardson, TX, 75080, USA 2Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine # corresponding authors [email protected], [email protected] and [email protected] Funding: NIH grants T32DA007261 (LM); NS065926 and NS102161 (TJP); NS106953 and NS042595 (RWG). The authors declare no conflicts of interest Author Contributions Conceived of the Project: PRR, RWG IV and TJP Performed Experiments: AW, LAM, CP, PB-I Supervised Experiments: GD, RWG IV, TJP Analyzed Data: AW, LAM, CP, CAG, PRR Supervised Bioinformatics Analysis: PRR Drew Figures: AW, PRR Wrote and Edited Manuscript: AW, LAM, CP, GD, PRR, RWG IV, TJP All authors approved the final version of the manuscript. 1 bioRxiv preprint doi: https://doi.org/10.1101/766865; this version posted September 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
  • Multiple Actions of Φ-LITX-Lw1a on Ryanodine Receptors Reveal a Functional Link Between Scorpion DDH and ICK Toxins

    Multiple Actions of Φ-LITX-Lw1a on Ryanodine Receptors Reveal a Functional Link Between Scorpion DDH and ICK Toxins

    Multiple actions of φ-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins Jennifer J. Smitha, Irina Vettera, Richard J. Lewisa, Steve Peigneurb, Jan Tytgatb, Alexander Lamc, Esther M. Gallantc, Nicole A. Beardd, Paul F. Alewooda,1,2, and Angela F. Dulhuntyc,1,2 aChemical and Structural Biology, Institute for Molecular Biosciences, University of Queensland, St. Lucia, QLD 4072, Australia; bLaboratory of Toxicology, University of Leuven, 3000 Leuven, Belgium; cDepartment of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia; and dDiscipline of Biomedical Sciences, Faculty of Education, Science, Technology and Mathematics, University of Canberra, Canberra, ACT 2601, Australia Edited by Clara Franzini-Armstrong, University of Pennsylvania Medical Center, Philadelphia, PA, and approved April 23, 2013 (received for review August 26, 2012) We recently reported the isolation of a scorpion toxin named U1- mutations, atypical posttranslational modifications of RyRs, liotoxin-Lw1a (U1-LITX-Lw1a) that adopts an unusual 3D fold termed including hyperphosphorylation and S-nitrosylation, have been the disulfide-directed hairpin (DDH) motif, which is the proposed implicated in heart failure and pathologic muscle fatigue (10– evolutionary structural precursor of the three-disulfide-containing 12). Because of their wide distribution, there is mounting evidence inhibitor cystine knot (ICK) motif found widely in animals and plants. to suggest that dysregulation of RyRs also plays a role in a plethora Here we reveal that U1-LITX-Lw1a targets and activates the mam- of other disease states, including chronic pain, neurodegenerative malian ryanodine receptor intracellular calcium release channel (RyR) disorders such as Alzheimer’s disease, and intellectual deficit (13– with high (fM) potency and provides a functional link between DDH 15).
  • Expression Profiling of Ion Channel Genes Predicts Clinical Outcome in Breast Cancer

    Expression Profiling of Ion Channel Genes Predicts Clinical Outcome in Breast Cancer

    UCSF UC San Francisco Previously Published Works Title Expression profiling of ion channel genes predicts clinical outcome in breast cancer Permalink https://escholarship.org/uc/item/1zq9j4nw Journal Molecular Cancer, 12(1) ISSN 1476-4598 Authors Ko, Jae-Hong Ko, Eun A Gu, Wanjun et al. Publication Date 2013-09-22 DOI http://dx.doi.org/10.1186/1476-4598-12-106 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Ko et al. Molecular Cancer 2013, 12:106 http://www.molecular-cancer.com/content/12/1/106 RESEARCH Open Access Expression profiling of ion channel genes predicts clinical outcome in breast cancer Jae-Hong Ko1, Eun A Ko2, Wanjun Gu3, Inja Lim1, Hyoweon Bang1* and Tong Zhou4,5* Abstract Background: Ion channels play a critical role in a wide variety of biological processes, including the development of human cancer. However, the overall impact of ion channels on tumorigenicity in breast cancer remains controversial. Methods: We conduct microarray meta-analysis on 280 ion channel genes. We identify candidate ion channels that are implicated in breast cancer based on gene expression profiling. We test the relationship between the expression of ion channel genes and p53 mutation status, ER status, and histological tumor grade in the discovery cohort. A molecular signature consisting of ion channel genes (IC30) is identified by Spearman’s rank correlation test conducted between tumor grade and gene expression. A risk scoring system is developed based on IC30. We test the prognostic power of IC30 in the discovery and seven validation cohorts by both Cox proportional hazard regression and log-rank test.
  • Cdk15 Igfals Lingo4 Gjb3 Tpbg Lrrc38 Serpinf1 Apod Trp73 Lama4 Chrnd Col9a1col11a1col5a2 Fgl2 Pitx2 Col2a1 Col3a1 Lamb3 Col24a1

    Cdk15 Igfals Lingo4 Gjb3 Tpbg Lrrc38 Serpinf1 Apod Trp73 Lama4 Chrnd Col9a1col11a1col5a2 Fgl2 Pitx2 Col2a1 Col3a1 Lamb3 Col24a1

    Bnc2 Wdr72 Ptchd1 Abtb2 Spag5 Zfp385a Trim17 Ier2 Il1rapl1 Tpd52l1 Fam20a Car8 Syt5 Plxnc1 Sema3e Ndrg4 Snph St6galnac5 Mcpt2 B3galt2 Sphkap Arhgap24 Prss34 Lhfpl2 Ermap Rnf165 Shroom1 Grm4 Mobp Dock2 Tmem9b Slc35d3 Otud7b Serpinb3a Sh3d19 Syt6 Zan Trim67 Clec18a Mcoln1 Tob1 Slc45a2 Pcdhb9 Pcdh17 Plscr1 Gpr143 Cela1 Frem1 Sema3f Lgi2 Igsf9 Fjx1 Cpne4 Adgb Depdc7 Gzmm C1qtnf5 Capn11 Sema3c H2-T22 Unc5c Sytl4 Galnt5 Sytl2 Arhgap11a Pcdha1 Cdh20 Slc35f2 Trim29 B3gnt5 Dock5 Trim9 Padi4 Pcdh19 Abi2 Cldn11 Slitrk1 Fam13a Nrgn Cpa4 Clmp Il1rap Trpm1 Fat4 Nexn Pmel Mmp15 Fat3 H2-M5 Prss38 Wdr41 Prtg Mlana Mettl22 Tnrc6b Cdh6 Sema3b Ptgfrn Cldn1 Cntn4 Bcl2a1b Capn6 Capn5 Pcdhb19 Tcf15 Bmf Rgs8 Tecrl Tyrp1 Rhot1 Rnf123 Cldn6 Adam9 Hlx Rilpl1 Disp1 Atcay Vwc2 Fat2 Srpx2 Cldn3 Unc13c Creb3l1 Rab39b Robo3 Gpnmb Bves Orai2 Slc22a2 Prss8 Cdh10 Scg3 Adam33 Nyx Dchs1 Chmp4c Syt9 Ap1m2 Megf10 Cthrc1 Penk Igsf9b Akap2 Ltbp3 Dnmbp Tff2 Pnoc Vldlr Cpa3 Snx18 Capn3 Btla Htr1b Gm17231 Pcdh9Rab27a Grm8 Cnih2 Scube2 Id2 Reep1 Cpeb3 Mmp16 Slc18b1 Snx33 Clcn5 Cckbr Pkp2 Drp2 Mapk8ip1 Lrrc3b Cxcl14 Zfhx3 Esrp1 Prx Dock3 Sec14l1 Prokr1 Pstpip2 Usp2 Cpvl Syn2 Ntn1 Ptger1 Rxfp3 Tyr Snap91 Htr1d Mtnr1a Gadd45g Mlph Drd4 Foxc2 Cldn4 Birc7 Cdh17 Twist2 Scnn1b Abcc4 Pkp1 Dlk2 Rab3b Amph Mreg Il33 Slit2 Hpse Micu1 Creb3l2 Dsp Lifr S1pr5 Krt15 Svep1 Ahnak Kcnh1 Sphk1 Vwce Clcf1 Ptch2 Pmp22 Sfrp1 Sema6a Lfng Hs3st5 Efcab1 Tlr5 Muc5acKalrn Vwa2 Fzd8 Lpar6 Bmp5 Slc16a9 Cacng4 Arvcf Igfbp2 Mrvi1 Dusp15 Krt5 Atp13a5 Dsg1a Kcnj14 Edn3Memo1 Ngef Prickle2 Cma1 Alx4 Bmp3 Blnk GastAgtr2
  • V45n4a03.Pdf

    V45n4a03.Pdf

    Montoya JC/et al/Colombia Médica - Vol. 45 Nº4 2014 (Oct-Dec) Colombia Médica colombiamedica.univalle.edu.co Original Article Global differential expression of genes located in the Down Syndrome Critical Region in normal human brain Expresión diferencial global de genes localizados en la Región Crítica del Síndrome de Down en el cerebro humano normal Julio Cesar Montoya1,3, Dianora Fajardo2, Angela Peña2 , Adalberto Sánchez1, Martha C Domínguez1,2, José María Satizábal1, Felipe García-Vallejo1,2 1 Department of Physiological Sciences, School of Basic Sciences, Faculty of Health, Universidad del Valle. 2 Laboratory of Molecular Biology and Pathogenesis LABIOMOL. Universidad del Valle, Cali, Colombia. 3 Faculty of Basic Sciences, Universidad Autónoma de Occidente, Cali, Colombia. Montoya JC , Fajardo D, Peña A , Sánchez A, Domínguez MC, Satizábal JM, García-Vallejo F.. Global differential expression of genes located in the Down Syndrome Critical Region in normal human brain. Colomb Med. 2014; 45(4): 154-61. © 2014 Universidad del Valle. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Article history Abstract Resumen Background: The information of gene expression obtained from Introducción: La información de la expresión de genes consignada Received: 2 July 2014 Revised: 10 November 2014 databases, have made possible the extraction and analysis of data en bases de datos, ha permitido extraer y analizar información acerca Accepted: 19 December 2014 related with several molecular processes involving not only in procesos moleculares implicados tanto en la homeostasis cerebral y su brain homeostasis but its disruption in some neuropathologies; alteración en algunas neuropatologías.
  • Transmembrane Protein with Unknown Function 16A Overexpression Promotes Glioma Formation Through the Nuclear Factor‑Κb Signaling Pathway

    Transmembrane Protein with Unknown Function 16A Overexpression Promotes Glioma Formation Through the Nuclear Factor‑Κb Signaling Pathway

    1068 MOLECULAR MEDICINE REPORTS 9: 1068-1074, 2014 Transmembrane protein with unknown function 16A overexpression promotes glioma formation through the nuclear factor‑κB signaling pathway JUN LIU1, YU LIU2, YINGANG REN1, LI KANG1 and LIHUA ZHANG1 Departments of 1Geriatrics and 2Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China Received July 18, 2013; Accepted January 2, 2014 DOI: 10.3892/mmr.2014.1888 Abstract. Ion channels have been suggested to be important in Introduction the development and progression of tumors, however, chloride channels have rarely been analyzed in tumorigenesis. More In previous years, the association between ion channels and recently, transmembrane protein with unknown function 16A tumors has drawn particular attention. Increasing evidence has (TMEM16A), hypothesized to be a candidate calcium-acti- demonstrated that ion channels are involved in the regulation vated Cl- channel, has been found to be overexpressed in a of tumor progression, including potassium (1-3), calcium (4) number of tumor types. Although several studies have impli- and sodium channels (5,6). Therefore, understanding the cated the overexpression of TMEM16A in certain tumor types, underlying molecular mechanisms of ion channels in tumori- the exact role of TMEM16A in gliomas and the underlying genesis, and tumor progression and migration provides novel mechanisms in tumorigenesis, remain poorly understood. In insights into tumor pathogenesis, and also identifies potential the present study, the role of TMEM16A in gliomas and the targets for tumor prevention and treatment. potential underlying mechanisms were analyzed. TMEM16A Chloride channels are expressed ubiquitously and are was highly abundant in various grades of gliomas and important in various cellular processes, including the cell cycle cultured glioma cells.
  • Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian

    Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian

    G C A T T A C G G C A T genes Article Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment Edmond Wonkam-Tingang 1, Isabelle Schrauwen 2 , Kevin K. Esoh 1 , Thashi Bharadwaj 2, Liz M. Nouel-Saied 2 , Anushree Acharya 2, Abdul Nasir 3 , Samuel M. Adadey 1,4 , Shaheen Mowla 5 , Suzanne M. Leal 2 and Ambroise Wonkam 1,* 1 Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa; [email protected] (E.W.-T.); [email protected] (K.K.E.); [email protected] (S.M.A.) 2 Center for Statistical Genetics, Sergievsky Center, Taub Institute for Alzheimer’s Disease and the Aging Brain, and the Department of Neurology, Columbia University Medical Centre, New York, NY 10032, USA; [email protected] (I.S.); [email protected] (T.B.); [email protected] (L.M.N.-S.); [email protected] (A.A.); [email protected] (S.M.L.) 3 Synthetic Protein Engineering Lab (SPEL), Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea; [email protected] 4 West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Accra LG 54, Ghana 5 Division of Haematology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa; [email protected] * Correspondence: [email protected]; Tel.: +27-21-4066-307 Received: 28 September 2020; Accepted: 20 October 2020; Published: 23 October 2020 Abstract: DNA samples from five members of a multiplex non-consanguineous Cameroonian family, segregating prelingual and progressive autosomal recessive non-syndromic sensorineural hearing impairment, underwent whole exome sequencing.