Structure and Function of Hedgehog Acyltransferase
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Loss of the PTCH1 Tumor Suppressor Defines a New
Banerjee et al. J Transl Med (2019) 17:246 https://doi.org/10.1186/s12967-019-1995-z Journal of Translational Medicine RESEARCH Open Access Loss of the PTCH1 tumor suppressor defnes a new subset of plexiform fbromyxoma Sudeep Banerjee1,2, Christopher L. Corless3, Markku M. Miettinen4, Sangkyu Noh1, Rowan Ustoy1, Jessica L. Davis3, Chih‑Min Tang1, Mayra Yebra1, Adam M. Burgoyne5 and Jason K. Sicklick1* Abstract Background: Plexiform fbromyxoma (PF) is a rare gastric tumor often confused with gastrointestinal stromal tumor. These so‑called “benign” tumors often present with upper GI bleeding and gastric outlet obstruction. It was recently demonstrated that approximately one‑third of PF have activation of the GLI1 oncogene, a transcription factor in the hedgehog (Hh) pathway, via a MALAT1‑GLI1 fusion protein or GLI1 up‑regulation. Despite this discovery, the biology of most PFs remains unknown. Methods: Next generation sequencing (NGS) was performed on formalin‑fxed parafn‑embedded (FFPE) samples of PF specimens collected from three institutions (UCSD, NCI and OHSU). Fresh frozen tissue from one tumor was utilized for in vitro assays, including quantitative RT‑PCR and cell viability assays following drug treatment. Results: Eight patients with PF were identifed and 5 patients’ tumors were analyzed by NGS. An index case had a mono‑allelic PTCH1 deletion of exons 15–24 and a second case, identifed in a validation cohort, also had a PTCH1 gene loss associated with a suspected long‑range chromosome 9 deletion. Building on the role of Hh signaling in PF, PTCH1, a tumor suppressor protein, functions upstream of GLI1. Loss of PTCH1 induces GLI1 activation and down‑ stream gene transcription. -
Material and Method
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Spiral - Imperial College Digital Repository Attenuation of Hedgehog acyltransferase-catalyzed Sonic hedgehog palmitoylation causes reduced signaling, proliferation and invasiveness of human carcinoma cells Shu-Chun Chang 1, #, Antonio D Konitsiotis 1, Biljana Jovanović 1, *, Paulina Ciepla 2, 3, Naoko Masumoto 2, 3, Christopher P. Palmer 4, Edward W. Tate 2, 3, John R. Couchman 5 and Anthony I. Magee 1, 3 1 Molecular Medicine Section, National Heart & Lung Institute Imperial College London, Sir Alexander Fleming Building, South Kensington London SW7 2AZ, UK 2 Department of Chemistry, Imperial College London, South Kensington London SW7 2AZ, UK 3 Institute of Chemical Biology, Imperial College London 4 Institute for Health Research and Policy, London Metropolitan University London N7 8DB, UK 5 Department of Biomedical Sciences, University of Copenhagen, Biocenter, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark # Current address: Department of Biological Sciences, National University of Singapore 14 Science Drive 4, S1A-05-11, Singapore 117543 * Current address: Department of Biosciences and Nutrition, Karolinska Institutet SE-141 57 Huddinge, Sweden Running title: Carcinoma dependence on Hhat Key words: sonic hedgehog; Hedgehog acyltransferase; MBOAT; carcinoma; pancreatic; lung Corresponding author: Anthony I. Magee, Molecular Medicine Section, National Heart & Lung Institute Imperial College London, South Kensington Campus, London SW7 2AZ, UK. Tel: +44 (0)20 7594 3135 E-mail: [email protected] Abbreviations: PDAC, pancreatic ductal adenocarcinoma; NSCLC, non-small cell lung cancer; Shh, Sonic hedgehog; Hhat, Hedgehog acyltransferase; KD, knockdown; siRNA, small interfering RNA; CFSE, 5(6)-Carboxyfluorescein diacetate N-succinimidyl ester; ALP, alkaline phosphatase 1 ABSTRACT Overexpression of Hedgehog family proteins contributes to the aetiology of many cancers. -
The Role of Gli3 in Inflammation
University of New Hampshire University of New Hampshire Scholars' Repository Doctoral Dissertations Student Scholarship Winter 2020 THE ROLE OF GLI3 IN INFLAMMATION Stephan Josef Matissek University of New Hampshire, Durham Follow this and additional works at: https://scholars.unh.edu/dissertation Recommended Citation Matissek, Stephan Josef, "THE ROLE OF GLI3 IN INFLAMMATION" (2020). Doctoral Dissertations. 2552. https://scholars.unh.edu/dissertation/2552 This Dissertation is brought to you for free and open access by the Student Scholarship at University of New Hampshire Scholars' Repository. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of University of New Hampshire Scholars' Repository. For more information, please contact [email protected]. THE ROLE OF GLI3 IN INFLAMMATION BY STEPHAN JOSEF MATISSEK B.S. in Pharmaceutical Biotechnology, Biberach University of Applied Sciences, Germany, 2014 DISSERTATION Submitted to the University of New Hampshire in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy In Biochemistry December 2020 This dissertation was examined and approved in partial fulfillment of the requirement for the degree of Doctor of Philosophy in Biochemistry by: Dissertation Director, Sherine F. Elsawa, Associate Professor Linda S. Yasui, Associate Professor, Northern Illinois University Paul Tsang, Professor Xuanmao Chen, Assistant Professor Don Wojchowski, Professor On October 14th, 2020 ii ACKNOWLEDGEMENTS First, I want to express my absolute gratitude to my advisor Dr. Sherine Elsawa. Without her help, incredible scientific knowledge and amazing guidance I would not have been able to achieve what I did. It was her encouragement and believe in me that made me overcome any scientific struggles and strengthened my self-esteem as a human being and as a scientist. -
Dissertation V2.2 XR
UCLA UCLA Electronic Theses and Dissertations Title Lysophosphatidylcholine acyltransferase 3-dependent phospholipid remodeling regulates lipid homeostasis and inflammation Permalink https://escholarship.org/uc/item/93c9r39k Author Rong, Xin Publication Date 2015 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA Los Angeles Lysophosphatidylcholine acyltransferase 3-dependent phospholipid remodeling regulates lipid homeostasis and inflammation A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Cellular and Molecular Pathology by Xin Rong 2015 © Copyright by Xin Rong 2015 ABSTRACT OF THE DISSERTATION Lysophosphatidylcholine acyltransferase 3-dependent phospholipid remodeling regulates lipid homeostasis and inflammation by Xin Rong Doctor of Philosophy in Cellular and Molecular Pathology University of California, Los Angeles 2015 Professor Peter John Tontonoz, Chair Phospholipids (PLs) are important structural components of biological membranes and precursors of numerous signaling molecules. The fatty acyl composition of PLs determines the biophysical characteristics of membranes. Multiple lines of evidence demonstrated that changes in fatty acyl composition could potentially affect the properties of proteins associated with membranes and influence the biological processes that occur on membranes. However, there is little understanding of how regulatory pathways control PL fatty acyl composition in vivo or how such regulation dictates physiological responses. In this work, we investigated the regulation of membrane fatty acyl composition by the Liver X Receptor (LXR)-Lysophosphatidylcholine Acyltranferase 3 (Lpcat3) pathway and its physiological or pathological relevance in lipid homeostasis and metabolic diseases. ii In chapter 2, we define a nuclear receptor pathway for the dynamic modulation of membrane composition in response to changes in cellular lipid metabolism. -
Hedgehog Interacting Protein (HHIP) Represses Airway Remodeling And
www.nature.com/scientificreports OPEN Hedgehog interacting protein (HHIP) represses airway remodeling and metabolic reprogramming in COPD‑derived airway smooth muscle cells Yan Li1,2,7*, Li Zhang2,3, Francesca Polverino4, Feng Guo2, Yuan Hao2, Taotao Lao5, Shuang Xu2, Lijia Li2, Betty Pham2, Caroline A. Owen6 & Xiaobo Zhou2,6* Although HHIP locus has been consistently associated with the susceptibility to COPD including airway remodeling and emphysema in genome‑wide association studies, the molecular mechanism underlying this genetic association remains incompletely understood. By utilizing Hhip+/- mice and primary human airway smooth muscle cells (ASMCs), here we aim to determine whether HHIP haploinsufciency increases airway smooth muscle mass by reprogramming glucose metabolism, thus contributing to airway remodeling in COPD pathogenesis. The mRNA levels of HHIP were compared in normal and COPD‑derived ASMCs. Mitochondrial oxygen consumption rate and lactate levels in the medium were measured in COPD‑derived ASMCs with or without HHIP overexpression as readouts of glucose oxidative phosphorylation and aerobic glycolysis rates. The proliferation rate was measured in healthy and COPD‑derived ASMCs treated with or without 2‑DG. Smooth muscle mass around airways was measured by immunofuorescence staining for α‑smooth muscle actin (α‑SMA) in lung sections from Hhip+/- mice and their wild type littermates, Hhip+/+ mice. Airway remodeling was assessed in Hhip+/- and Hhip+/- mice exposed to 6 months of cigarette smoke. Our results show HHIP inhibited aerobic glycolysis and represses cell proliferation in COPD‑derived ASMCs. Notably, knockdown of HHIP in normal ASMCs increased PKM2 activity. Importantly, Hhip+/- mice demonstrated increased airway remodeling and increased intensity of α‑SMA staining around airways compared to Hhip+/+ mice. -
MBOAT5 (D-19): Sc-161831
SAN TA C RUZ BI OTEC HNOL OG Y, INC . MBOAT5 (D-19): sc-161831 BACKGROUND APPLICATIONS MBOAT5 (membrane-bound O-acyltransferase domain-containing protein 5), MBOAT5 (D-19) is recommended for detection of MBOAT5 of mouse, rat and also known as lysophosphatidylcholine acyltransferase 3 (LPCAT3), lysophos - human origin by Western Blotting (starting dilution 1:200, dilution range 1:100- pholipid acyltransferase 5 (LPLAT 5), 1-acylglycerophosphocholine O-acyl - 1:1000), immunoprecipitation [1-2 µg per 100-500 µg of total protein (1 ml of transferase, C3F, OACT5 or nessy, is a 487 amino acid multi-pass membrane cell lysate)], immunofluorescence (starting dilution 1:50, dilution range 1:50- protein of the endoplasmic reticulum that belongs to the membrane-bound 1:500) and solid phase ELISA (starting dilution 1:30, dilution range 1:30- acyltransferase family. As an acyltransferase, MBOAT5 aids in the conversion 1:3000); non cross-reactive with MBOAT1, MBOAT2 or MBOAT4. of lysophosphatidylcholine into phosphatidylcholine, lysophosphatidylserine MBOAT5 (D-19) is also recommended for detection of MBOAT5 in additional into phosphatidylserine, and participates in the Lands cycle by catalyzing species, including equine, canine and porcine. reacylation of phospholipid remodeling. Encoded by a gene located on human chromosome 12, MBOAT5 is highly expressed in liver, adipose tissue and Suitable for use as control antibody for MBOAT5 siRNA (h): sc-95749, pancreas, with lower levels found in skeletal muscle and heart. MBOAT5 siRNA (m): sc-149310, MBOAT5 shRNA Plasmid (h): sc-95749-SH, MBOAT5 shRNA Plasmid (m): sc-149310-SH, MBOAT5 shRNA (h) Lentiviral REFERENCES Particles: sc-95749-V and MBOAT5 shRNA (m) Lentiviral Particles: sc- 149310-V. -
Highly Conserved C-Terminal Region of Indian Hedgehog N-Fragment Contributes to Its Auto-Processing and Multimer Formation
biomolecules Article Highly Conserved C-Terminal Region of Indian Hedgehog N-Fragment Contributes to Its Auto-Processing and Multimer Formation Xiaoqing Wang 1,2 , Hao Liu 3 , Yanfang Liu 2, Gefei Han 2, Yushu Wang 2 , Haifeng Chen 3,*, Lin He 2,* and Gang Ma 1,2,* 1 Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China; [email protected] 2 Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China; [email protected] (Y.L.); [email protected] (G.H.); [email protected] (Y.W.) 3 State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, National Experimental Teaching Center for Life Sciences and Biotechnology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China; [email protected] * Correspondence: [email protected] (H.C.); [email protected] (L.H.); [email protected] (G.M.) Abstract: Hedgehog (HH) is a highly conserved secretory signalling protein family mainly involved in embryonic development, homeostasis, and tumorigenesis. HH is generally synthesised as a precursor, which subsequently undergoes autoproteolytic cleavage to generate an amino-terminal fragment (HH-N), mediating signalling, and a carboxyl-terminal fragment (HH-C), catalysing the Citation: Wang, X.; Liu, H.; Liu, Y.; auto-processing reaction. The N-terminal region of HH-N is required for HH multimer formation Han, G.; Wang, Y.; Chen, H.; He, L.; to promote signal transduction, whilst the functions of the C-terminal region of HH-N remain Ma, G. -
Participation of HHIP Gene Variants in COPD Susceptibility, Lung Function, and Serum and Sputum Protein Levels in Women Exposed to Biomass-Burning Smoke
diagnostics Article Participation of HHIP Gene Variants in COPD Susceptibility, Lung Function, and Serum and Sputum Protein Levels in Women Exposed to Biomass-Burning Smoke Alejandro Ortega-Martínez 1,2 , Gloria Pérez-Rubio 1 , Alejandra Ramírez-Venegas 3, María Elena Ramírez-Díaz 4, Filiberto Cruz-Vicente 5, María de Lourdes Martínez-Gómez 6, Espiridión Ramos-Martínez 7 , Edgar Abarca-Rojano 2,* and Ramcés Falfán-Valencia 1,* 1 HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico; [email protected] (A.O.-M.); [email protected] (G.P.-R.) 2 Sección de Estudios de Posgrado e Investigación. Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomas, Mexico City 11340, Mexico 3 Tobacco Smoking and COPD Research Department, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico; [email protected] 4 Coordinación de Vigilancia Epidemiológica, Jurisdicción 06 Sierra, Tlacolula de Matamoros Oaxaca, Servicios de Salud de Oaxaca, Oaxaca 70400, Mexico; [email protected] 5 Internal Medicine Department. Hospital Civil Aurelio Valdivieso, Servicios de Salud de Oaxaca, Oaxaca 68050, Mexico; fi[email protected] 6 Hospital Regional de Alta Especialidad de Oaxaca, Oaxaca 71256, Mexico; [email protected] 7 Experimental Medicine Research Unit, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 06720, Mexico; [email protected] * Correspondence: [email protected] (E.A.-R.); [email protected] (R.F.-V.); Tel.: +52-55-5729-6000 (ext. 62718) (E.A.-R.); +52-55-5487-1700 (ext. 5152) (R.F.-V.) Received: 6 August 2020; Accepted: 16 September 2020; Published: 23 September 2020 Abstract: Background: A variety of organic materials (biomass) are burned for cooking and heating purposes in poorly ventilated houses; smoke from biomass combustion is considered an environmental risk factor for chronic obstructive pulmonary disease COPD. -
( 12 ) United States Patent
US010127346B2 (12 ) United States Patent (10 ) Patent No. : US 10 , 127 ,346 B2 Dewey et al . (45 ) Date of Patent: Nov . 13 , 2018 (54 ) SYSTEMS AND METHODS FOR Fan et al. Noninvasive diagnosis of fetal aneuploidy by shotgun INTERPRETING A HUMAN GENOME USING sequencing DNA from maternal blood Proceedings of the National A SYNTHETIC REFERENCE SEQUENCE Academy of Sciences USA vol. 16266 - 16271 (2008 ) . * Chen et al. -717A > G polymorphism of human C - reactive protein ( 75 ) Inventors: Frederick Dewey , Redwood City , CA gene associated with coronary heart disease in ethnic Han Chinese : (US ) ; Euan A . Ashley , Menlo Park , CA the Beijing atherosclerosis study Journal of Molecular Medicine (US ) ; Matthew Wheeler, Sunnyvale , vol. 83 , pp . 72 -78 ( 2005 ). * CA (US ) ; Michael Snyder , Stanford , Wheeler et al. The complete genome of an individual by massively CA (US ) ; Carlos Bustamante , Emerald parallel DNA sequencing Nature vol. 452 , j pp . 872 -877 ( 2008 ). * Hills , CA (US ) Candore et al . Pharmacogenomics : A Tool to Prevent and Cure Coronary Heart Disease Current Pharmaceutical Design vol. 13 pp . ( 73 ) Assignee : The Board of Trustees of the Leland 3726 - 3734 ( 2007 ) . * Stanford Junior University , Stanford , Dewey et al . Phase Whole -Genome Genetic Risk in a Family CA (US ) Quartet Using a Major Allele Reference Sequence PLoS Genetics vol. 7 , article e1002280 ( 2011 ) . * ( * ) Notice : Subject to any disclaimer , the term of this Abecasis et al. , “ Merlin — rapid analysis of dense genetic maps patent is extended or adjusted under 35 using sparse gene flow trees ” , Nature Genetics , Jan . 2002 , vol. 30 , U . S . C . 154 ( b ) by 978 days . pp . -
Metabolic Regulation by Lipid Activated Receptors by Maxwell A
Metabolic Regulation by Lipid Activated Receptors By Maxwell A Ruby A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy In Molecular & Biochemical Nutrition In the Graduate Division Of the University of California, Berkeley Committee in charge: Professor Marc K. Hellerstein, Chair Professor Ronald M. Krauss Professor George A. Brooks Professor Andreas Stahl Fall 2010 Abstract Metabolic Regulation by Lipid Activated Receptors By Maxwell Alexander Ruby Doctor of Philosophy in Molecular & Biochemical Nutrition University of California, Berkeley Professor Marc K. Hellerstein, Chair Obesity and related metabolic disorders have reached epidemic levels with dire public health consequences. Efforts to stem the tide focus on behavioral and pharmacological interventions. Several hypolipidemic pharmaceutical agents target endogenous lipid receptors, including the peroxisomal proliferator activated receptor α (PPAR α) and cannabinoid receptor 1 (CB1). To further the understanding of these clinically relevant receptors, we elucidated the biochemical basis of PPAR α activation by lipoprotein lipolysis products and the metabolic and transcriptional responses to elevated endocannabinoid signaling. PPAR α is activated by fatty acids and their derivatives in vitro. While several specific pathways have been implicated in the generation of PPAR α ligands, we focused on lipoprotein lipase mediated lipolysis of triglyceride rich lipoproteins. Fatty acids activated PPAR α similarly to VLDL lipolytic products. Unbound fatty acid concentration determined the extent of PPAR α activation. Lipolysis of VLDL, but not physiological unbound fatty acid concentrations, created the fatty acid uptake necessary to stimulate PPAR α. Consistent with a role for vascular lipases in the activation of PPAR α, administration of a lipase inhibitor (p-407) prevented PPAR α dependent induction of target genes in fasted mice. -
1 Expression of Sonic Hedgehog and Pathway Components In
bioRxiv preprint doi: https://doi.org/10.1101/2021.03.30.437697; this version posted March 31, 2021. 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-NC 4.0 International license. Expression of Sonic Hedgehog and Pathway Components in the Embryonic Mouse Head: Anatomical Relationships Between Regulators of Positive and Negative Feedback Crystal L. Sigulinsky1, Xiaodong Li2, and Edward M. Levine1,2,3* 1 Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah 2 Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee 3 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee *Corresponding Author 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.30.437697; this version posted March 31, 2021. 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-NC 4.0 International license. ABSTRACT Objective: The Hedgehog pathway is a fundamental signaling pathway in organogenesis. The expression patterns of the ligand Sonic Hedgehog (Shh) and key pathway components have been studied in many tissues but direct spatial comparisons across tissues with different cell compositions and structural organization are not common and could reveal tissue-specific differences in pathway dynamics. Results: We directly compared the expression characteristics of Shh, and four genes with functional roles in signaling and whose expression levels serve as readouts of pathway activity in multiple tissues of the embryonic mouse head at embryonic day 15.5 by serial in situ hybridization. -
Microrna‑200A Suppresses Epithelial‑To‑Mesenchymal Transition in Rat Hepatic Stellate Cells Via GLI Family Zinc Finger 2
MOLECULAR MEDICINE REPORTS 12: 8121-8128, 2015 MicroRNA‑200a suppresses epithelial‑to‑mesenchymal transition in rat hepatic stellate cells via GLI family zinc finger 2 FUJUN YU1, YIHU ZHENG2, WEILONG HONG3, BICHENG CHEN3, PEIHONG DONG1 and JIANJIAN ZHENG3 Departments of 1Infectious Diseases and 2General Surgery; 3Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China Received December 31, 2014; Accepted September 25, 2015 DOI: 10.3892/mmr.2015.4452 Abstract. Hepatic stellate cells (HSCs) have an important Introduction role in liver fibrosis. Epithelial-to-mesenchymal transition (EMT), which is promoted by the Hedgehog (Hh) signaling Liver fibrosis, characterized by excess production and depo- pathway, is involved in the activation of HSCs. MicroRNAs sition of extracellular matrix (ECM) along with loss of liver (miRNAs/miRs) have been reported to be involved in the function and disruption of liver structure, is a wound-healing progression of liver fibrosis. A previous study indicated response to chronic liver injury (1,2). It is well known that that the activation of HSCs was suppressed by miR-200a hepatic stellate cells (HSCs) have an important role in liver via targeting transforming growth factor-β2 and β-catenin. fibrosis. The activation and proliferation of resident hepatic stel- However, whether miR-200a is able to regulate the EMT in late cells (HSCs) has been considered as a central event in the HSCs has remained elusive. The present study revealed that progression of liver fibrosis. During fibrosis progression, quies- miR-200a was decreased in vitro and in vivo during liver cent (Q)-HSCs become activated and transdifferentiate into fibrosis.