Mouse Gpnmb Knockout Project (CRISPR/Cas9)
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The Role of GPNMB in Inflammation
REVIEW published: 12 May 2021 doi: 10.3389/fimmu.2021.674739 The Role of GPNMB in Inflammation Marina Saade, Giovanna Araujo de Souza, Cristoforo Scavone and Paula Fernanda Kinoshita* Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil Inflammation is a response to a lesion in the tissue or infection. This process occurs in a specific manner in the central nervous system and is called neuroinflammation, which is involved in neurodegenerative diseases. GPNMB, an endogenous glycoprotein, has been recently related to inflammation and neuroinflammation. GPNMB is highly expressed in macrophages and microglia, which are cells involved with innate immune response in the periphery and the brain, respectively. Some studies have shown increased levels of GPNMB in pro-inflammatory conditions, such as LPS treatment, and in pathological conditions, such as neurodegenerative diseases and cancer. However, the role of GPNMB in inflammation is still not clear. Even though most studies suggest that GPNMB might have an anti-inflammatory role by promoting inflammation resolution, there is evidence that GPNMB could be pro-inflammatory. In this review, we gather and Edited by: discuss the published evidence regarding this interaction. James Harris, Monash University, Australia Keywords: GPNMB, inflammation, neuroinflammation, macrophages, cancer, protection Reviewed by: Michelle Coleman, Seattle Children's Research Institute, United States INFLAMMATION James Vince, Walter and Eliza Hall Institute of Inflammation is a complex response to microbial infections or tissue damage involving interactions Medical Research, Australia between soluble molecules and cellular effectors to restore homeostasis (1–3). Tissue-resident *Correspondence: macrophages and mast cells are relevant to an efficient and rapid immune response that prevents the Paula Fernanda Kinoshita infection from spreading and/or tissue damage. -
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. -
Cytotoxic Effects and Changes in Gene Expression Profile
Toxicology in Vitro 34 (2016) 309–320 Contents lists available at ScienceDirect Toxicology in Vitro journal homepage: www.elsevier.com/locate/toxinvit Fusarium mycotoxin enniatin B: Cytotoxic effects and changes in gene expression profile Martina Jonsson a,⁎,MarikaJestoib, Minna Anthoni a, Annikki Welling a, Iida Loivamaa a, Ville Hallikainen c, Matti Kankainen d, Erik Lysøe e, Pertti Koivisto a, Kimmo Peltonen a,f a Chemistry and Toxicology Research Unit, Finnish Food Safety Authority (Evira), Mustialankatu 3, FI-00790 Helsinki, Finland b Product Safety Unit, Finnish Food Safety Authority (Evira), Mustialankatu 3, FI-00790 Helsinki, c The Finnish Forest Research Institute, Rovaniemi Unit, P.O. Box 16, FI-96301 Rovaniemi, Finland d Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, FI-00014, Finland e Plant Health and Biotechnology, Norwegian Institute of Bioeconomy, Høyskoleveien 7, NO -1430 Ås, Norway f Finnish Safety and Chemicals Agency (Tukes), Opastinsilta 12 B, FI-00521 Helsinki, Finland article info abstract Article history: The mycotoxin enniatin B, a cyclic hexadepsipeptide produced by the plant pathogen Fusarium,isprevalentin Received 3 December 2015 grains and grain-based products in different geographical areas. Although enniatins have not been associated Received in revised form 5 April 2016 with toxic outbreaks, they have caused toxicity in vitro in several cell lines. In this study, the cytotoxic effects Accepted 28 April 2016 of enniatin B were assessed in relation to cellular energy metabolism, cell proliferation, and the induction of ap- Available online 6 May 2016 optosis in Balb 3T3 and HepG2 cells. The mechanism of toxicity was examined by means of whole genome ex- fi Keywords: pression pro ling of exposed rat primary hepatocytes. -
Gpnmb in Inflammatory and Metabolic Diseases
Functional characterization of Gpnmb in inflammatory and metabolic diseases Dissertation zur Erlangung des akademischen Grades D octor rerum naturalium (Dr. rer. nat.) eingereicht an der Lebenswissenschaftlichen Fakultät der Humboldt-Universität zu Berlin von M.Sc., Bernadette Nickl Präsidentin der Humboldt-Universität zu Berlin Prof. Dr.-Ing. Dr. Sabine Kunst Dekan der Lebenswissenschaftlichen Fakultät Prof. Dr. Bernhard Grimm Gutachter: Prof. Dr. Michael Bader Prof. Dr. Karl Stangl Prof. Dr. Thomas Sommer Tag der mündlichen Prüfung: 28. Februar 2020 For Sayeeda Summary Summary In 2018, the World Health Organization reported for the first time that “Overweight and obesity are linked to more deaths worldwide than underweight”A. Obesity increases the risk for the development of diabetes, atherosclerosis and cardiovascular diseases. Those metabolic diseases are associated with inflammation and the expression of glycoprotein nonmetastatic melanoma protein b (Gpnmb), a transmembrane protein that is expressed by macrophages and dendritic cells. We studied the role of Gpnmb in genetically- and diet-induced atherosclerosis as well as diet-induced obesity in Gpnmb-knockout and respective wildtype control mice. To this purpose, a mouse deficient in Gpnmb was created using Crispr-Cas9 technology. Body weight and blood lipid parameters remained unaltered in both diseases. Gpnmb was strongly expressed in atherosclerotic lesion-associated macrophages. Nevertheless, the absence of Gpnmb did not affect the development of aortic lesion size. However, macrophage and inflammation markers in epididymal fat tissue were increased in Gpnmb-deficient mice. In comparison to atherosclerosis, the absence of Gpnmb elicited stronger effects in obesity. For the first time, we observed a positive influence of Gpnmb on insulin and glucose plasma levels. -
Structural Basis for Late Maturation Steps of the Human Mitoribosomal Large Subunit ✉ ✉ Miriam Cipullo1,2,5, Genís Valentín Gesé3,5, Anas Khawaja1,2, B
ARTICLE https://doi.org/10.1038/s41467-021-23617-8 OPEN Structural basis for late maturation steps of the human mitoribosomal large subunit ✉ ✉ Miriam Cipullo1,2,5, Genís Valentín Gesé3,5, Anas Khawaja1,2, B. Martin Hällberg 3,4 & Joanna Rorbach 1,2 Mitochondrial ribosomes (mitoribosomes) synthesize a critical set of proteins essential for oxidative phosphorylation. Therefore, mitoribosomal function is vital to the cellular energy supply. Mitoribosome biogenesis follows distinct molecular pathways that remain poorly 1234567890():,; understood. Here, we determine the cryo-EM structures of mitoribosomes isolated from human cell lines with either depleted or overexpressed mitoribosome assembly factor GTPBP5, allowing us to capture consecutive steps during mitoribosomal large subunit (mt- LSU) biogenesis. Our structures provide essential insights into the last steps of 16S rRNA folding, methylation and peptidyl transferase centre (PTC) completion, which require the coordinated action of nine assembly factors. We show that mammalian-specific MTERF4 contributes to the folding of 16S rRNA, allowing 16 S rRNA methylation by MRM2, while GTPBP5 and NSUN4 promote fine-tuning rRNA rearrangements leading to PTC formation. Moreover, our data reveal an unexpected involvement of the elongation factor mtEF-Tu in mt-LSU assembly, where mtEF-Tu interacts with GTPBP5, similar to its interaction with tRNA during translational elongation. 1 Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, Solna, Sweden. 2 Max Planck Institute Biology of Ageing—Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden. 3 Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Sweden. 4 Centre for Structural Systems Biology (CSSB) and Karolinska Institutet VR-RÅC, Hamburg, Germany. -
A Phase II Study of Glembatumumab Vedotin for Metastatic Uveal Melanoma
cancers Article A Phase II Study of Glembatumumab Vedotin for Metastatic Uveal Melanoma 1, 2, 3 4 Merve Hasanov y , Matthew J. Rioth y, Kari Kendra , Leonel Hernandez-Aya , Richard W. Joseph 5, Stephen Williamson 6 , Sunandana Chandra 7, Keisuke Shirai 8, Christopher D. Turner 9, Karl Lewis 2, Elizabeth Crowley 10, Jeffrey Moscow 11, Brett Carter 12 and Sapna Patel 1,* 1 Department of Melanoma Medical Oncology, Division of Cancer Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; [email protected] 2 Division of Medical Oncology and Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; [email protected] (M.J.R.); [email protected] (K.L.) 3 Division of Medical Oncology, Department of Medicine, the Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; [email protected] 4 Division of Medical Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.; [email protected] 5 Department of Hematology and Oncology, Mayo Clinic Hospital, Florida, Jacksonville, FL 32224, USA; [email protected] 6 Division of Medical Oncology, Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA; [email protected] 7 Division of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; [email protected] 8 Division of Hematology -
MALSU1 Human Sirna Oligo Duplex (Locus ID 115416
OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for SR314507 C7orf30 (MALSU1) Human siRNA Oligo Duplex (Locus ID 115416) Product data: Product Type: siRNA Oligo Duplexes Purity: HPLC purified Quality Control: Tested by ESI-MS Sequences: Available with shipment Stability: One year from date of shipment when stored at -20°C. # of transfections: Approximately 330 transfections/2nmol in 24-well plate under optimized conditions (final conc. 10 nM). Note: Single siRNA duplex (10nmol) can be ordered. RefSeq: NM_138446 Synonyms: C7orf30; mtRsfA Components: MALSU1 (Human) - 3 unique 27mer siRNA duplexes - 2 nmol each (Locus ID 115416) Included - SR30004, Trilencer-27 Universal Scrambled Negative Control siRNA Duplex - 2 nmol Included - SR30005, RNAse free siRNA Duplex Resuspension Buffer - 2 ml Summary: Required for normal mitochondrial ribosome function and mitochondrial translation (PubMed:22238375, PubMed:23171548). May play a role in ribosome biogenesis by preventing premature association of the 28S and 39S ribosomal subunits (Probable). Interacts with mitochondrial ribosomal protein L14 (MRPL14), probably blocking formation of intersubunit bridge B8, preventing association of the 28S and 39S ribosomal subunits (Probable). Addition to isolated mitochondrial ribosomal subunits partially inhibits translation, probably by interfering with the association of the 28S and 39S ribosomal subunits and the formation of functional ribosomes (Probable). May also participate in the assembly and/or regulation of the stability of the large subunit of the mitochondrial ribosome (PubMed:22238376, PubMed:23171548). May function as a ribosomal silencing factor (Probable).[UniProtKB/Swiss-Prot Function] This product is to be used for laboratory only. -
Coe Elizabeth 1100772730 BIO Phd Thesis
University of Bath PHD Identification and characterisation of MITF-regulated long non-coding RNA candidate regulators of melanoma Coe, Elizabeth Award date: 2020 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public 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 the public 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. Download date: 05. Oct. 2021 Identification and characterisation of MITF- regulated long non-coding RNA candidate regulators of melanoma Elizabeth Anne Coe A thesis submitted for the degree of Doctor of Philosophy University of Bath Department of Biology & Biochemistry September 2019 COPYRIGHT Attention is drawn to the fact that copyright of this thesis rests with the author. A copy of this thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and that they must not copy it or use material from it except as permitted by law or with the consent of the author. -
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 ........................................................................................ -
CR011, a Fully Human Monoclonal Antibody-Auristatin E Conjugate, for the Treatment of Melanoma Kam Fai Tse,1 Michael Jeffers,1 Vincent A
Cancer Therapy: Preclinical CR011, a Fully Human Monoclonal Antibody-Auristatin E Conjugate, for the Treatment of Melanoma Kam Fai Tse,1 Michael Jeffers,1 Vincent A. Pollack,1 Denise A. McCabe,1 Melanie L. Shadish,1 Nikolai V. Khramtsov,1Craig S. Hackett,1Suresh G. Shenoy,1Bing Kuang,1Ferenc L. Boldog,1 John R. MacDougall,1Luca Rastelli,1John Herrmann,1Michael Gallo,2 Gadi Gazit-Bornstein,2 Peter D. Senter,3 Damon L. Meyer,3 Henri S. Lichenstein,1and William J. LaRochelle1 Abstract Purpose: Advanced melanoma is a highly drug-refractory neoplasm representing a significant unmet medical need. We sought to identify melanoma-associated cell surface molecules and to develop as well as preclinically test immunotherapeutic reagents designed to exploit such targets. Experimental Design and Results: By transcript profiling, we identified glycoprotein NMB (GPNMB) as a gene that is expressed by most metastatic melanoma samples examined. GPNMB is predicted to be a transmembrane protein, thus making it a potential immunotherapeutic target in the treatment of this disease. A fully human monoclonal antibody, designated CR011, was generated to the extracellular domain of GPNMB and characterized for growth-inhibitory activity against melanoma. The CR011monoclonal antibody showed surface staining of most melanoma cell lines by flow cytometry and reacted with a majority of metastatic melanoma specimens by immunohistochemistry. CR011alone did not inhibit the growth of melanoma cells. However, when linked to the cytotoxic agent monomethylauristatin E (MMAE) to generate the CR011-vcMMAE antibody-drug conjugate, this reagent now potently and specifically inhibited the growth of GPNMB-positive melanoma cellsin vitro. Ectopic overexpression and small interfering RNA trans- fection studies showed that GPNMB expression is both necessary and sufficient for sensitivity to low concentrations of CR011-vcMMAE. -
Biomarkers in Triple-Negative Breast Cancer: State-Of-The-Art and Future Perspectives
International Journal of Molecular Sciences Review Biomarkers in Triple-Negative Breast Cancer: State-of-the-Art and Future Perspectives Stefania Cocco , Michela Piezzo , Alessandra Calabrese, Daniela Cianniello, Roberta Caputo, Vincenzo Di Lauro, Giuseppina Fusco, Germira di Gioia, Marina Licenziato and Michelino de Laurentiis * Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Mariano Semmola, 53, 80131 Napoli NA, Italy; [email protected] (S.C.); [email protected] (M.P.); [email protected] (A.C.); [email protected] (D.C.); [email protected] (R.C.); [email protected] (V.D.L.); [email protected] (G.F.); [email protected] (G.d.G.); [email protected] (M.L.) * Correspondence: [email protected]; Tel.: +39-081-5903-535 Received: 31 May 2020; Accepted: 25 June 2020; Published: 27 June 2020 Abstract: Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors characterized by aggressive behavior, high risk of distant recurrence, and poor survival. Chemotherapy is still the main therapeutic approach for this subgroup of patients, therefore, progress in the treatment of TNBC remains an important challenge. Data derived from molecular technologies have identified TNBCs with different gene expression and mutation profiles that may help developing targeted therapies. So far, however, only a few of these have shown to improve the prognosis and outcomes of TNBC patients. Robust predictive biomarkers to accelerate clinical progress are needed. Herein, we review prognostic and predictive biomarkers in TNBC, discuss the current evidence supporting their use, and look at the future of this research field. Keywords: TNBC; BRCA1/2; HRR; PDL1; TILs; PI3KCA; PTEN; CTCs; CSC 1. -
The Transcription Factor MITF Is a Critical Regulator of GPNMB
Gutknecht et al. Cell Communication and Signaling (2015) 13:19 DOI 10.1186/s12964-015-0099-5 RESEARCH Open Access The transcription factor MITF is a critical regulator of GPNMB expression in dendritic cells Michael Gutknecht, Julian Geiger, Simone Joas, Daniela Dörfel, Helmut R Salih, Martin R Müller, Frank Grünebach* and Susanne M Rittig Abstract Background: Dendritic cells (DC) are the most potent antigen-presenting cells (APC) with the unique ability to activate naïve T cells and to initiate and maintain primary immune responses. Immunosuppressive and anti-inflammatory stimuli on DC such as the cytokine IL-10 suppress the activity of the transcription factor NF-κB what results in downregulation of costimulatory molecules, MHC and cytokine production. Glycoprotein NMB (GPNMB) is a transmembrane protein, which acts as a coinhibitory molecule strongly inhibiting T cell responses if present on APC. Interestingly, its expression on human monocyte-derived dendritic cells (moDC) is dramatically upregulated upon treatment with IL-10 but also by the BCR-ABL tyrosine kinase inhibitors (TKI) imatinib, nilotinib or dasatinib used for the treatment of chronic myeloid leukemia (CML). However, the molecular mechanisms responsible for GPNMB overexpression are yet unknown. Results: The immunosuppressive cytokine IL-10 and the BCR-ABL TKI imatinib or nilotinib, that were examined here, concordantly inhibit the PI3K/Akt signaling pathway, thereby activating the downstream serine/threonine protein kinase GSK3ß, and subsequently the microphthalmia-associated transcription factor (MITF) that is phosphorylated and translocated into the nucleus. Treatment of moDC with a small molecule inhibitor of MITF activity reduced the expression of GPNMB at the level of mRNA and protein, indicating that GPNMB expression is in fact facilitated by MITF activation.