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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. -
Iron Depletion Reduces Abce1 Transcripts While Inducing The
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 22 October 2019 doi:10.20944/preprints201910.0252.v1 1 Research Article 2 Iron depletion Reduces Abce1 Transcripts While 3 Inducing the Mitophagy Factors Pink1 and Parkin 4 Jana Key 1,2, Nesli Ece Sen 1, Aleksandar Arsovic 1, Stella Krämer 1, Robert Hülse 1, Suzana 5 Gispert-Sanchez 1 and Georg Auburger 1,* 6 1 Experimental Neurology, Goethe University Medical School, 60590 Frankfurt am Main; 7 2 Faculty of Biosciences, Goethe-University Frankfurt am Main, Germany 8 * Correspondence: [email protected] 9 10 Abstract: Lifespan extension was recently achieved in Caenorhabditis elegans nematodes by 11 mitochondrial stress and mitophagy, triggered via iron depletion. Conversely in man, deficient 12 mitophagy due to Pink1/Parkin mutations triggers iron accumulation in patient brain and limits 13 survival. We now aimed to identify murine fibroblast factors, which adapt their mRNA expression 14 to acute iron manipulation, relate to mitochondrial dysfunction and may influence survival. After 15 iron depletion, expression of the plasma membrane receptor Tfrc with its activator Ireb2, the 16 mitochondrial membrane transporter Abcb10, the heme-release factor Pgrmc1, the heme- 17 degradation enzyme Hmox1, the heme-binding cholesterol metabolizer Cyp46a1, as well as the 18 mitophagy regulators Pink1 and Parkin showed a negative correlation to iron levels. After iron 19 overload, these factors did not change expression. Conversely, a positive correlation of mRNA levels 20 with both conditions of iron availability was observed for the endosomal factors Slc11a2 and Steap2, 21 as well as for the iron-sulfur-cluster (ISC)-containing factors Ppat, Bdh2 and Nthl1. -
Primary and Secondary Thyroid Hormone Transporters Anita Kinne, Ralf Schülein, Gerd Krause*
Kinne et al. Thyroid Research 2011, 4(Suppl 1):S7 http://www.thyroidresearchjournal.com/content/4/S1/S7 REVIEW Open Access Primary and secondary thyroid hormone transporters Anita Kinne, Ralf Schülein, Gerd Krause* Abstract Thyroid hormones (TH) are essential for the development of the human brain, growth and cellular metabolism. Investigation of TH transporters became one of the emerging fields in thyroid research after the discovery of inactivating mutations in the Monocarboxylate transporter 8 (MCT8), which was found to be highly specific for TH transport. However, additional transmembrane transporters are also very important for TH uptake and efflux in different cell types. They transport TH as secondary substrates and include the aromatic amino acid transporting MCT10, the organic anion transporting polypeptides (e.g. OATP1C1, OATP1A2, OPTP1A4) and the large neutral amino acid transporters (LAT1 and LAT2). These TH transporters characteristically possess 12 transmembrane spanners but due to the strong differing sequences between the three transporter families we assume an identical conformation is not very likely. In contrast to the others, the LAT family members form a heterodimer with the escort protein 4F2hc/CD98. A comparison of sequence proportions, locations and types of functional sensitive features for TH transport discovered by mutations, revealed that transport sensitive charged residues occur as conserved amino acids only within each family of the transporter types but not in all putative TH transporters. Based on the lack of highly conserved sensitive charged residues throughout the three transporter families as a common counterpart for the amino acid moiety of the substrates, we conclude that the molecular transport mechanism is likely organized either a) by different molecular determinants in the divergent transporter types or b) the counterparts for the substrates` amino acid moiety at the transporter are not any charged side chains but other proton acceptors or donators. -
ABCG1 (ABC8), the Human Homolog of the Drosophila White Gene, Is a Regulator of Macrophage Cholesterol and Phospholipid Transport
ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport Jochen Klucken*, Christa Bu¨ chler*, Evelyn Orso´ *, Wolfgang E. Kaminski*, Mustafa Porsch-Ozcu¨ ¨ ru¨ mez*, Gerhard Liebisch*, Michael Kapinsky*, Wendy Diederich*, Wolfgang Drobnik*, Michael Dean†, Rando Allikmets‡, and Gerd Schmitz*§ *Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, 93042 Regensburg, Germany; †National Cancer Institute, Laboratory of Genomic Diversity, Frederick, MD 21702-1201; and ‡Departments of Ophthalmology and Pathology, Columbia University, Eye Research Addition, New York, NY 10032 Edited by Jan L. Breslow, The Rockefeller University, New York, NY, and approved November 3, 1999 (received for review June 14, 1999) Excessive uptake of atherogenic lipoproteins such as modified low- lesterol transport. Although several effector molecules have been density lipoprotein complexes by vascular macrophages leads to proposed to participate in macrophage cholesterol efflux (6, 9), foam cell formation, a critical step in atherogenesis. Cholesterol efflux including endogenous apolipoprotein E (10) and the cholesteryl mediated by high-density lipoproteins (HDL) constitutes a protective ester transfer protein (11), the detailed molecular mechanisms mechanism against macrophage lipid overloading. The molecular underlying cholesterol export in these cells have not yet been mechanisms underlying this reverse cholesterol transport process are characterized. currently not fully understood. To identify effector proteins that are Recently, mutations of the ATP-binding cassette (ABC) trans- involved in macrophage lipid uptake and release, we searched for porter ABCA1 gene have been causatively linked to familial HDL genes that are regulated during lipid influx and efflux in human deficiency and Tangier disease (12–14). -
Effects of Silencing the ATP-Binding Cassette Protein E1 Gene by Electroporation on the Proliferation and Migration of EC109 Human Esophageal Cancer Cells
MOLECULAR MEDICINE REPORTS 12: 837-842, 2015 Effects of silencing the ATP-binding cassette protein E1 gene by electroporation on the proliferation and migration of EC109 human esophageal cancer cells XIAO-RUI LI, LIU-ZHONG YANG, XIAO-QING HUO, YING WANG, QING-HUI YANG and QING-QIN ZHANG Department of Oncology, The First Affiliated Hospital of Xinxiang Medical College, Weihui, Henan 453100, P.R. China Received February 17, 2014; Accepted November 19, 2014 DOI: 10.3892/mmr.2015.3512 Abstract. In the present study, the gene expression of invasion and migration in esophageal cancer and silencing the ATP-binding cassette protein E1 (ABCE1) in the EC109 ABCE1 gene by electroporation can significantly reduce the human esophageal cancer cell line was silenced using elec- proliferation, invasion and migration capacity of EC109 cells troporation to examine the effect if the ABCE1 gene on the in vitro. growth migration and cell cycle of cancer cells. The small interference (si)RNA sequence of ABCE1 was designed and Introduction synthesized to transfect the EC109 cells by electroporation. The mRNA and protein expression levels of ABCE1 were Esophageal cancer is one of most common types of gastro- then detected by reverse transcription quantitative polymerase intestinal malignant tumor in humans. The incidence of the chain reaction (RT-qPCR) and western blot analysis. The disease is higher in developing countries and the majority of analysis of the cell cycle and apoptosis was performed using tumors are squamous carcinoma (1). Although chemotherapy flow cytometry. The effect of silencing the ABCE1 gene on and adjuvant chemotherapy are widely used the treatment of the proliferation, migration and invasive ability of the EC109 esophageal cancer, the prognosis remains poor, particularly human esophageal cancer cells were assessed using a Cell in patients with clinical migration and tumor recurrence (2,3). -
Alternating Hypoglycemia and Hyperglycemia in a Toddler with a Homozygous P.R1419H ABCC8 Mutation: an Unusual Clinical Picture
J Pediatr Endocr Met 2015; 28(3-4): 345–351 Patient report Open Access Shira Harel, Ana S.A. Cohen, Khalid Hussain, Sarah E. Flanagan, Kamilla Schlade-Bartusiak, Millan Patel, Jaques Courtade, Jenny B.W. Li, Clara Van Karnebeek, Harley Kurata, Sian Ellard, Jean-Pierre Chanoine and William T. Gibson* Alternating hypoglycemia and hyperglycemia in a toddler with a homozygous p.R1419H ABCC8 mutation: an unusual clinical picture Abstract Results: A 16-month-old girl of consanguineous descent manifested hypoglycemia. She had dysregulation of Background: Inheritance of two pathogenic ABCC8 alleles insulin secretion, with postprandial hyperglycemia fol- typically causes severe congenital hyperinsulinism. We lowed by hypoglycemia. Microarray revealed homozygo- describe a girl and her father, both homozygous for the sity for the regions encompassing KCNJ11 and ABCC8. Her same ABCC8 mutation, who presented with unusual father had developed diabetes at 28 years of age. Sequenc- phenotypes. ing of ABCC8 identified a homozygous missense mutation, Methods: Single nucleotide polymorphism microarray p.R1419H, in both individuals. Functional studies showed and Sanger sequencing were performed. Western blot, absence of working KATP channels. rubidium efflux, and patch clamp recordings interrogated Conclusion: This is the first description of a homozygous the expression and activity of the mutant protein. p.R1419H mutation. Our findings highlight that homozy- gous loss-of-function mutations of ABCC8 do not neces- sarily translate into early-onset severe hyperinsulinemia. *Corresponding author: William T. Gibson, Child and Family Research Institute, Department of Medical Genetics, British Keywords: ABCC8; diabetes; hyperglycemia; hyperinsu- Columbia Children’s Hospital, 950 West 28th Avenue, Vancouver, linism; hypoglycemia. BC, V5Z 4H4, Canada, Phone: +1-604-875-2000 ext. -
Differential Expression of Hydroxyurea Transporters in Normal and Polycythemia Vera Hematopoietic Stem and Progenitor Cell Subpopulations
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2021 Differential expression of hydroxyurea transporters in normal and polycythemia vera hematopoietic stem and progenitor cell subpopulations Tan, Ge ; Meier-Abt, Fabienne Abstract: Polycythemia vera (PV) is a myeloproliferative neoplasm marked by hyperproliferation of the myeloid lineages and the presence of an activating JAK2 mutation. Hydroxyurea (HU) is a standard treat- ment for high-risk patients with PV. Because disease-driving mechanisms are thought to arise in PV stem cells, effective treatments should target primarily the stem cell compartment. We tested for theantipro- liferative effect of patient treatment with HU in fluorescence-activated cell sorting-isolated hematopoietic stem/multipotent progenitor cells (HSC/MPPs) and more committed erythroid progenitors (common myeloid/megakaryocyte-erythrocyte progenitors [CMP/MEPs]) in PV using RNA-sequencing and gene set enrichment analysis. HU treatment led to significant downregulation of gene sets associated with cell proliferation in PV HSCs/MPPs, but not in PV CMP/MEPs. To explore the mechanism underlying this finding, we assessed for expression of solute carrier membrane transporters, which mediate trans- membrane movement of drugs such as HU into target cells. The active HU uptake transporter OCTN1 was upregulated in HSC/MPPs compared with CMP/MEPs of untreated patients with PV, and the HU diffusion facilitator urea transporter B (UTB) was downregulated in HSC/MPPs compared withCM- P/MEPs in all patient and control groups tested. These findings indicate a higher accumulation ofHU within PV HSC/MPPs compared with PV CMP/MEPs and provide an explanation for the differential effects of HU in HSC/MPPs and CMP/MEPs of patients with PV. -
Invited Review Ion Transport in Chondrocytes: Membrane
Histol Histopathol (1998) 13: 893-910 Histology and 001: 10.14670/HH-13.893 Histopathology http://www.hh.um.es From Cell Biology to Tissue Engineering Invited Review Ion transport in chondrocytes: membrane transporters involved in intracellular ion homeostasis and the regulation of cell volume, free [Ca2+] and pH A. MobasherP, R. Mobasherl2, M.J.O. Francis3, E. Trujillo4, D. Alvarez de la Rosa4 and P. Martin-Vasallo4 1 University Laboratory of Physiology, University of Oxford, and Department of Biomedical Sciences, School of Biosciences, University of Westminster, London, 2United Medical and Dental Schools of Guy's and St Thomas's Hospitals, London, 3Nuffield Department of Orthopaedic Surgery, Nuffield Orthopaedic Centre, Headington, UK and 4Laboratory of Developmental Biology, Department of Biochemistry and Molecular Biology, University of La Laguna, La Laguna, Tenerife, Spain Summary. Chondrocytes exist in an unusual and their patterns of isoform expression underscore the variable ionic and osmotic environment in the extra subtlety of ion homeostasis and pH regulation in normal cellular matrix of cartilage and are responsible for cartilage. Perturbations in these mechanisms may affect maintaining the delicate equilibrium between extra the physiological turnover of cartilage and thus increase cellular matrix synthesis and degradation. The the susceptibility to degenerative joint disease. mechanical performance of cartilage relies on the biochemical properties of the matrix. Alterations to the Key words: Chondrocyte, Cartilage, Ion transport, £H ionic and osmotic extracellular environment of chondro regulation, Na+, K+-ATPase, Na+/H+ exchange, Ca + cytes have been shown to influence the volume, ATPase intracellular pH and ionic content of the cells, which in turn modify the synthesis and degradation of extra cellular matrix macromolecules. -
A Comprehensive Mapping of the Structure and Gene Organisation in the Sheep MHC Class I Region N
Siva Subramaniam et al. BMC Genomics (2015) 16:810 DOI 10.1186/s12864-015-1992-4 RESEARCH ARTICLE Open Access A comprehensive mapping of the structure and gene organisation in the sheep MHC class I region N. Siva Subramaniam1, EF Morgan1, JD Wetherall1, MJ Stear2,3* and DM Groth1 Abstract Background: The major histocompatibility complex (MHC) is a chromosomal region that regulates immune responsiveness in vertebrates. This region is one of the most important for disease resistance because it has been associated with resistance or susceptibility to a wide variety of diseases and because the MHC often accounts for more of the variance than other loci. Selective breeding for disease resistance is becoming increasingly common in livestock industries, and it is important to determine how this will influence MHC polymorphism and resistance to diseases that are not targeted for selection. However, in sheep the order and sequence of the protein coding genes is controversial. Yet this information is needed to determine precisely how the MHC influences resistance and susceptibility to disease. Methods: CHORI bacterial artificial chromosomes (BACs) known to contain sequences from the sheep MHC class I region were sub-cloned, and the clones partially sequenced. The resulting sequences were analysed and re-assembled to identify gene content and organisation within each BAC. The low resolution MHC class I physical map was then compared to the cattle reference genome, the Chinese Merino sheep MHC map published by Gao, et al. (2010) and the recently available sheep reference genome. Results: Immune related class I genes are clustered into 3 blocks; beta, kappa and a novel block not previously identified in other organisms. -
Serum Albumin OS=Homo Sapiens
Protein Name Cluster of Glial fibrillary acidic protein OS=Homo sapiens GN=GFAP PE=1 SV=1 (P14136) Serum albumin OS=Homo sapiens GN=ALB PE=1 SV=2 Cluster of Isoform 3 of Plectin OS=Homo sapiens GN=PLEC (Q15149-3) Cluster of Hemoglobin subunit beta OS=Homo sapiens GN=HBB PE=1 SV=2 (P68871) Vimentin OS=Homo sapiens GN=VIM PE=1 SV=4 Cluster of Tubulin beta-3 chain OS=Homo sapiens GN=TUBB3 PE=1 SV=2 (Q13509) Cluster of Actin, cytoplasmic 1 OS=Homo sapiens GN=ACTB PE=1 SV=1 (P60709) Cluster of Tubulin alpha-1B chain OS=Homo sapiens GN=TUBA1B PE=1 SV=1 (P68363) Cluster of Isoform 2 of Spectrin alpha chain, non-erythrocytic 1 OS=Homo sapiens GN=SPTAN1 (Q13813-2) Hemoglobin subunit alpha OS=Homo sapiens GN=HBA1 PE=1 SV=2 Cluster of Spectrin beta chain, non-erythrocytic 1 OS=Homo sapiens GN=SPTBN1 PE=1 SV=2 (Q01082) Cluster of Pyruvate kinase isozymes M1/M2 OS=Homo sapiens GN=PKM PE=1 SV=4 (P14618) Glyceraldehyde-3-phosphate dehydrogenase OS=Homo sapiens GN=GAPDH PE=1 SV=3 Clathrin heavy chain 1 OS=Homo sapiens GN=CLTC PE=1 SV=5 Filamin-A OS=Homo sapiens GN=FLNA PE=1 SV=4 Cytoplasmic dynein 1 heavy chain 1 OS=Homo sapiens GN=DYNC1H1 PE=1 SV=5 Cluster of ATPase, Na+/K+ transporting, alpha 2 (+) polypeptide OS=Homo sapiens GN=ATP1A2 PE=3 SV=1 (B1AKY9) Fibrinogen beta chain OS=Homo sapiens GN=FGB PE=1 SV=2 Fibrinogen alpha chain OS=Homo sapiens GN=FGA PE=1 SV=2 Dihydropyrimidinase-related protein 2 OS=Homo sapiens GN=DPYSL2 PE=1 SV=1 Cluster of Alpha-actinin-1 OS=Homo sapiens GN=ACTN1 PE=1 SV=2 (P12814) 60 kDa heat shock protein, mitochondrial OS=Homo -
Low Affinity Uniporter Carrier Proteins Can Increase Net Substrate Uptake
www.nature.com/scientificreports OPEN Low afnity uniporter carrier proteins can increase net substrate uptake rate by reducing efux Received: 10 November 2017 Evert Bosdriesz 1,3, Meike T. Wortel 1,4, Jurgen R. Haanstra 1, Marijke J. Wagner1, Accepted: 9 March 2018 Pilar de la Torre Cortés2 & Bas Teusink 1 Published: xx xx xxxx Many organisms have several similar transporters with diferent afnities for the same substrate. Typically, high-afnity transporters are expressed when substrate is scarce and low-afnity ones when it is abundant. The beneft of using low instead of high-afnity transporters remains unclear, especially when additional nutrient sensors are present. Here, we investigate two hypotheses. It was previously hypothesized that there is a trade-of between the afnity and the catalytic efciency of transporters, and we fnd some but no defnitive support for it. Additionally, we propose that for uptake by facilitated difusion, at saturating substrate concentrations, lowering the afnity enhances the net uptake rate by reducing substrate efux. As a consequence, there exists an optimal, external-substrate- concentration dependent transporter afnity. A computational model of Saccharomyces cerevisiae glycolysis shows that using the low afnity HXT3 transporter instead of the high afnity HXT6 enhances the steady-state fux by 36%. We tried to test this hypothesis with yeast strains expressing a single glucose transporter modifed to have either a high or a low afnity. However, due to the intimate link between glucose perception and metabolism, direct experimental proof for this hypothesis remained inconclusive. Still, our theoretical results provide a novel reason for the presence of low-afnity transport systems. -
ABCG2, ABCC2, ABCC1, ABCC3 and Multiple Myeloma Risk: a Case--Control Study in the Context of the International Multiple Myeloma Research (Immense) Consortium
Letters to the Editor 1419 Program, The Japanese Cord Blood Bank Network and The Japanese Society of myeloid leukemia or myelodysplastic syndrome who have chromosome 5 Pediatric Hematology. We also thank Ms Takako Sakai, data manager of the Japan and/or 7 abnormalities. Haematologica 2005; 90: 1339 -- 1345. Society for Hematopoietic Cell Transplantation Data Registry, for their excellent 2 Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A assistance. et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern K Ishiyama1,2, A Takami1,13, Y Kanda3,13, S Nakao1, M Hidaka4, Cooperative Oncology Group Study. Blood 2000; 96: 4075 -- 4083. T Maeda5, T Naoe6, S Taniguchi7, K Kawa8, T Nagamura9, 3 Kurosawa S, Yamaguchi T, Miyawaki S, Uchida N, Kanamori H, Usuki K et al. K Tabuchi10, Y Atsuta11 and H Sakamaki12 A Markov decision analysis of allogeneic hematopoietic cell transplantation 1Department of Cellular Transplantation Biology, versus chemotherapy in patients with acute myeloid leukemia in first remission. Kanazawa University Graduate School of Medical Sciences, Blood 2011; 117: 2113 -- 2120. 4 Slovak ML, Gundacker H, Bloomfield CD, Dewald G, Appelbaum FR, Larson RA Kanazawa, Ishikawa, Japan; 2 et al. A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes Department of Hematology, Tokyo Metropolitan the need for a prospective, multicenter initiative for rare ‘poor prognosis’ myeloid Ohtsuka Hospital, Toshima, Tokyo, Japan; malignancies. Leukemia 2006; 20: 1295 -- 1297. 3 Division of Hematology, Saitama Medical Center, 5 Ishiyama K, Takami A, Kanda Y, Nakao S, Hidaka M, Maeda T et al.