The Soluble Form of HFE Protein Regulates Hephaestin Mrna Expression in the Duodenum Through an Endocytosis-Dependent Mechanism
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Iron Regulation by Hepcidin
Iron regulation by hepcidin Ningning Zhao, … , An-Sheng Zhang, Caroline A. Enns J Clin Invest. 2013;123(6):2337-2343. https://doi.org/10.1172/JCI67225. Science in Medicine Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body. Physiologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone morphogenetic protein 6 (BMP6), hereditary hemochromatosis protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and transferrin. Misregulation of hepcidin is found in many disease states, such as the anemia of chronic disease, iron refractory iron deficiency anemia, cancer, hereditary hemochromatosis, and ineffective erythropoiesis, such as β- thalassemia. Thus, the regulation of hepcidin is the subject of interest for the amelioration of the detrimental effects of either iron deficiency or overload. Find the latest version: https://jci.me/67225/pdf Science in medicine Iron regulation by hepcidin Ningning Zhao, An-Sheng Zhang, and Caroline A. Enns Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon, USA. Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body. Physi- ologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone morphogenetic protein 6 (BMP6), hereditary hemochromatosis protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and transferrin. Misregulation of hepcidin is found in many disease states, such as the anemia of chronic disease, iron refractory iron deficiency anemia, cancer, hereditary hemochromatosis, and ineffective erythropoiesis, such as β-thalassemia. -
Iron Transport Proteins: Gateways of Cellular and Systemic Iron Homeostasis
Iron transport proteins: Gateways of cellular and systemic iron homeostasis Mitchell D. Knutson, PhD University of Florida Essential Vocabulary Fe Heme Membrane Transport DMT1 FLVCR Ferroportin HRG1 Mitoferrin Nramp1 ZIP14 Serum Transport Transferrin Transferrin receptor 1 Cytosolic Transport PCBP1, PCBP2 Timeline of identification in mammalian iron transport Year Protein Original Publications 1947 Transferrin Laurell and Ingelman, Acta Chem Scand 1959 Transferrin receptor 1 Jandl et al., J Clin Invest 1997 DMT1 Gunshin et al., Nature; Fleming et al. Nature Genet. 1999 Nramp1 Barton et al., J Leukocyt Biol 2000 Ferroportin Donovan et al., Nature; McKie et al., Cell; Abboud et al. J. Biol Chem 2004 FLVCR Quigley et al., Cell 2006 Mitoferrin Shaw et al., Nature 2006 ZIP14 Liuzzi et al., Proc Natl Acad Sci USA 2008 PCBP1, PCBP2 Shi et al., Science 2013 HRG1 White et al., Cell Metab DMT1 (SLC11A2) • Divalent metal-ion transporter-1 • Former names: Nramp2, DCT1 Fleming et al. Nat Genet, 1997; Gunshin et al., Nature 1997 • Mediates uptake of Fe2+, Mn2+, Cd2+ • H+ coupled transporter (cotransporter, symporter) • Main roles: • intestinal iron absorption Illing et al. JBC, 2012 • iron assimilation by erythroid cells DMT1 (SLC11A2) Yanatori et al. BMC Cell Biology 2010 • 4 different isoforms: 557 – 590 a.a. (hDMT1) Hubert & Hentze, PNAS, 2002 • Function similarly in iron transport • Differ in tissue/subcellular distribution and regulation • Regulated by iron: transcriptionally (via HIF2α) post-transcriptionally (via IRE) IRE = Iron-Responsive Element Enterocyte Lumen DMT1 Fe2+ Fe2+ Portal blood Enterocyte Lumen DMT1 Fe2+ Fe2+ Fe2+ Fe2+ Ferroportin Portal blood Ferroportin (SLC40A1) • Only known mammalian iron exporter Donovan et al., Nature 2000; McKie et al., Cell 2000; Abboud et al. -
Molecular Mechanisms Involved Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis
Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2010 Molecular Mechanisms Involved Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis Ryan Fassnacht Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Physiology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/2246 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. Ryan C. Fassnacht 2010 All Rights Reserved Molecular Mechanisms Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. by Ryan Christopher Fassnacht, B.S. Hampden Sydney University, 2005 M.S. Virginia Commonwealth University, 2010 Director: Valeria Mas, Ph.D., Associate Professor of Surgery and Pathology Division of Transplant Department of Surgery Virginia Commonwealth University Richmond, Virginia July 9, 2010 Acknowledgement The Author wishes to thank his family and close friends for their support. He would also like to thank the members of the molecular transplant team for their help and advice. This project would not have been possible with out the help of Dr. Valeria Mas and her endearing -
Ferroportin Mutation in Autosomal Dominant Hemochromatosis: Loss of Function, Gain in Understanding
Ferroportin mutation in autosomal dominant hemochromatosis: loss of function, gain in understanding Robert E. Fleming, William S. Sly J Clin Invest. 2001;108(4):521-522. https://doi.org/10.1172/JCI13739. Commentary Normal iron homeostasis requires close matching of dietary iron absorption with body iron needs (1). Hereditary hemochromatosis (HH), a common abnormality of iron metabolism, is characterized by excess absorption of dietary iron despite elevated stores, and secondary damage to the liver, pancreas, and other organs (2). Classic HH is caused by mutation of the HFE gene and is inherited as an autosomal recessive trait. However, a substantial percentage of individuals with hemochromatosis, especially in non–Northern European populations, have no mutations in HFE (3). Many such cases differ from classic HH in the relative distribution of iron between the plasma, hepatocytes, and reticuloendothelial (RE) cells (4). Pietrangelo et al. recently reported a pedigree with atypical hemochromatosis inherited as an autosomal dominant trait (5). In this issue of the JCI, Montosi et al. report the surprising finding that the gene mutated in these patients (SLC11A3) encodes the iron export protein ferroportin1 (also known as IREG1, or MTP1) (6). They conclude that the identified mutation (A77D) probably results in loss of ferroportin1 function, suggesting that the affected individuals are haploinsufficient for this gene product. In a nearly simultaneous report, Njajou et al. (7) describe a similar pedigree with autosomal dominant hemochromatosis and a different missense mutation (N144H) in the same gene. Njajou et al., however, conclude that the iron overload phenotype was likely […] Find the latest version: https://jci.me/13739/pdf Ferroportin mutation in autosomal Commentary dominant hemochromatosis: loss See related article, pages 619–623. -
Mitochondrial Iron Homeostasis and Beyond
cells Review Down the Iron Path: Mitochondrial Iron Homeostasis and Beyond Jonathan V. Dietz 1, Jennifer L. Fox 2 and Oleh Khalimonchuk 1,3,4,* 1 Department of Biochemistry, University of Nebraska, Lincoln, NE 68588, USA; [email protected] 2 Department of Chemistry and Biochemistry, College of Charleston, Charleston, SC 29424, USA; [email protected] 3 Nebraska Redox Biology Center, University of Nebraska, Lincoln, NE 68588, USA 4 Fred and Pamela Buffett Cancer Center, Omaha, NE 68198, USA * Correspondence: [email protected] Abstract: Cellular iron homeostasis and mitochondrial iron homeostasis are interdependent. Mito- chondria must import iron to form iron–sulfur clusters and heme, and to incorporate these cofactors along with iron ions into mitochondrial proteins that support essential functions, including cellular respiration. In turn, mitochondria supply the cell with heme and enable the biogenesis of cytosolic and nuclear proteins containing iron–sulfur clusters. Impairment in cellular or mitochondrial iron homeostasis is deleterious and can result in numerous human diseases. Due to its reactivity, iron is stored and trafficked through the body, intracellularly, and within mitochondria via carefully orchestrated processes. Here, we focus on describing the processes of and components involved in mitochondrial iron trafficking and storage, as well as mitochondrial iron–sulfur cluster biogenesis and heme biosynthesis. Recent findings and the most pressing topics for future research are highlighted. Keywords: iron homeostasis; mitochondrial iron–sulfur clusters; heme biosynthesis; iron trafficking Citation: Dietz, J.V.; Fox, J.L.; Khalimonchuk, O. Down the Iron Path: Mitochondrial Iron Homeostasis and Beyond. Cells 2021, 1. Introduction 10, 2198. https://doi.org/10.3390/ Most iron in vertebrates is used to make heme b cofactors for hemoglobin in red blood cells10092198 cells; however, the essential nature of iron derives from more than this role in oxygen transport through the bloodstream. -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
Ncomms4301.Pdf
ARTICLE Received 8 Jul 2013 | Accepted 23 Jan 2014 | Published 13 Feb 2014 DOI: 10.1038/ncomms4301 Genome-wide RNAi ionomics screen reveals new genes and regulation of human trace element metabolism Mikalai Malinouski1,2, Nesrin M. Hasan3, Yan Zhang1,4, Javier Seravalli2, Jie Lin4,5, Andrei Avanesov1, Svetlana Lutsenko3 & Vadim N. Gladyshev1 Trace elements are essential for human metabolism and dysregulation of their homoeostasis is associated with numerous disorders. Here we characterize mechanisms that regulate trace elements in human cells by designing and performing a genome-wide high-throughput siRNA/ionomics screen, and examining top hits in cellular and biochemical assays. The screen reveals high stability of the ionomes, especially the zinc ionome, and yields known regulators and novel candidates. We further uncover fundamental differences in the regulation of different trace elements. Specifically, selenium levels are controlled through the selenocysteine machinery and expression of abundant selenoproteins; copper balance is affected by lipid metabolism and requires machinery involved in protein trafficking and post-translational modifications; and the iron levels are influenced by iron import and expression of the iron/haeme-containing enzymes. Our approach can be applied to a variety of disease models and/or nutritional conditions, and the generated data set opens new directions for studies of human trace element metabolism. 1 Genetics Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. 2 Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, Nebraska 68588, USA. 3 Department of Physiology, Johns Hopkins University, Baltimore, Maryland 21205, USA. 4 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. -
Identification of Potential Key Genes and Pathway Linked with Sporadic Creutzfeldt-Jakob Disease Based on Integrated Bioinformatics Analyses
medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Identification of potential key genes and pathway linked with sporadic Creutzfeldt-Jakob disease based on integrated bioinformatics analyses 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 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Abstract Sporadic Creutzfeldt-Jakob disease (sCJD) is neurodegenerative disease also called prion disease linked with poor prognosis. The aim of the current study was to illuminate the underlying molecular mechanisms of sCJD. The mRNA microarray dataset GSE124571 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened. -
Molecular Pathogenesis of Iron Overload Gut: First Published As 10.1136/Gut.51.2.290 on 1 August 2002
290 REVIEW Molecular pathogenesis of iron overload Gut: first published as 10.1136/gut.51.2.290 on 1 August 2002. Downloaded from D Trinder, C Fox, G Vautier, J K Olynyk ............................................................................................................................. Gut 2002;51:290–295 Our current understanding of iron absorption under deficiency.34Iron is then stored in the enterocyte normal conditions is presented, together with an or transferred out across the basolateral mem- brane by a membrane bound protein called ferro- overview of the clinical disorders of iron overload and portin (also known as IREG1 and MTP1).5–7 the molecular processes that contribute to increased iron Extracellular ferrous iron is oxidised by the multi deposition in iron overload. Recently, a number of new copper oxidase haephestin and bound by plasma transferrin.8 genes involved in iron metabolism have been identified The mechanism of absorption of haem iron has which is allowing the molecular mechanisms of iron yet to be elucidated. Transfer across the brush absorption to be elucidated. border membrane is probably mediated by an unidentified haem receptor. Once inside, entero- .......................................................................... cyte iron is released from haem by haem oxygen- ase and either stored or transferred out of the ron homeostasis is controlled by the absorption enterocyte by a mechanism that is likely to be of iron from the diet. It occurs mainly in the similar to that for ionic iron (fig 1).9 Iduodenum at a rate of approximately 1–2 mg iron per day. When iron levels in the body or the REGULATION OF IRON ABSORPTION diet are low, the rate of iron absorption is Iron absorption is regulated by a number of increased, and when iron levels are replete there factors, including the level of body iron stores, the is a reduction in the rate of iron absorption and rate of erythropoiesis, and hypoxia. -
Targeted Mutagenesis of the Murine Transferrin Receptor-2 Gene Produces Hemochromatosis
Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis Robert E. Fleming*†, John R. Ahmann*, Mary C. Migas*, Abdul Waheed†, H. Phillip Koeffler‡, Hiroshi Kawabata‡, Robert S. Britton§, Bruce R. Bacon§, and William S. Sly†¶ *Department of Pediatrics, †Edward A. Doisy Department of Biochemistry and Molecular Biology, and §Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, 1402 South Grand Boulevard, St. Louis, MO 63104; and ‡Department of Medicine, University of California School of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048 Contributed by William S. Sly, June 17, 2002 Hereditary hemochromatosis (HH) is a common genetic disorder (Y250X) had a clinical picture similar to HFE-associated HH, characterized by excess absorption of dietary iron and progressive including hepatic iron loading (6). This form of iron overload was iron deposition in several tissues, particularly liver. The vast ma- designated HH type 3 (Online Mendelian Inheritance in Man jority of individuals with HH are homozygous for mutations in the 604250) to distinguish it from HFE-associated HH (HH type 1) HFE gene. Recently a second transferrin receptor (TFR2) was dis- and juvenile-onset HH (HH type 2). Several additional TFR2 covered, and a previously uncharacterized type of hemochroma- gene mutations have been described since in patients with iron tosis (HH type 3) was identified in humans carrying mutations in overload, suggesting that the iron homeostasis abnormalities are the TFR2 gene. To characterize the role for TFR2 in iron homeosta- caused by functional loss of TFR2 (7, 8). By contrast, functional sis, we generated mice in which a premature stop codon (Y245X) loss of Tfr1 (in knockout mice) produces an embryonic lethal was introduced by targeted mutagenesis in the murine Tfr2 coding phenotype (9). -
Genetical and Clinical Studies in Wilson's Disease
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 246 Genetical and Clinical Studies in Wilson's Disease ERIK WALDENSTRÖM ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 UPPSALA ISBN 978-91-554-6845-3 2007 urn:nbn:se:uu:diva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o my family At vide, hvad man ikke véd, er dog en slags alvidenhed Piet Hein List of publications This thesis is based on the following papers, which will be referred -
Supp Table 6.Pdf
Supplementary Table 6. Processes associated to the 2037 SCL candidate target genes ID Symbol Entrez Gene Name Process NM_178114 AMIGO2 adhesion molecule with Ig-like domain 2 adhesion NM_033474 ARVCF armadillo repeat gene deletes in velocardiofacial syndrome adhesion NM_027060 BTBD9 BTB (POZ) domain containing 9 adhesion NM_001039149 CD226 CD226 molecule adhesion NM_010581 CD47 CD47 molecule adhesion NM_023370 CDH23 cadherin-like 23 adhesion NM_207298 CERCAM cerebral endothelial cell adhesion molecule adhesion NM_021719 CLDN15 claudin 15 adhesion NM_009902 CLDN3 claudin 3 adhesion NM_008779 CNTN3 contactin 3 (plasmacytoma associated) adhesion NM_015734 COL5A1 collagen, type V, alpha 1 adhesion NM_007803 CTTN cortactin adhesion NM_009142 CX3CL1 chemokine (C-X3-C motif) ligand 1 adhesion NM_031174 DSCAM Down syndrome cell adhesion molecule adhesion NM_145158 EMILIN2 elastin microfibril interfacer 2 adhesion NM_001081286 FAT1 FAT tumor suppressor homolog 1 (Drosophila) adhesion NM_001080814 FAT3 FAT tumor suppressor homolog 3 (Drosophila) adhesion NM_153795 FERMT3 fermitin family homolog 3 (Drosophila) adhesion NM_010494 ICAM2 intercellular adhesion molecule 2 adhesion NM_023892 ICAM4 (includes EG:3386) intercellular adhesion molecule 4 (Landsteiner-Wiener blood group)adhesion NM_001001979 MEGF10 multiple EGF-like-domains 10 adhesion NM_172522 MEGF11 multiple EGF-like-domains 11 adhesion NM_010739 MUC13 mucin 13, cell surface associated adhesion NM_013610 NINJ1 ninjurin 1 adhesion NM_016718 NINJ2 ninjurin 2 adhesion NM_172932 NLGN3 neuroligin