DOCSLIB.ORG

The Regulation and Application of Sodium Iodide Symporter

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Regulation and Application of Sodium Iodide Symporter REGULATION OF SODIUM IODIDE SYMPORTER EXPRESSION/FUNCTION AND TISSUE-TARGETED GENE TRANSFER OF SODIUM IODIDE SYMPORTER DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University by Xiaoqin Lin * * * * * The Ohio State University 2003 Dissertation Committee: Approved by Professor Sissy M. Jhiang, Advisor Professor Lee F. Johnson _______________________________ Advisor Professor Patrick L. Green Ohio State Biochemistry Program Professor Thomas J. Sferra ABSTRACT The Sodium/Iodide Symporter (NIS) is an intrinsic membrane glycoprotein that mediates active iodide transport into thyroid follicular cells. Active iodide uptake is the basis for the use of radioiodine in diagnosis and treatment of follicular-cell-derived differentiated thyroid cancers (FDTC). However, approximately one third of patients with FDTC have decreased NIS expression on cell surface and cannot benefit from radioiodine therapy. Thus, it is clinically important to study the regulatory mechanisms underlying NIS expression and cell surface trafficking. In Chapter 2, I demonstrate that untranslated regions (UTRs) of human NIS (hNIS) regulate hNIS expression and/or cell surface trafficking. The 5’UTR of hNIS, 362 nt in length, increases hNIS function by facilitating cell surface trafficking, despite decreasing total protein expression levels. Deletion studies reveal that the proximal 9 nt of the 5’UTR are sufficient to increase hNIS function by facilitating cell surface trafficking, with no effect on hNIS total protein expression levels. Moreover, the proximal 58 nt of the 3’UTR greatly increase hNIS mRNA expression, yet only modestly increase total hNIS protein levels. These studies provide new insight into the roles of UTRs in the regulation of hNIS expression and function. In Chapter 3, I clone and characterize a 3.2 kb 5’-flanking region of mouse NIS gene (mNIS). I have identified the mNIS Upstream Enhancer (mNUE), which enhances mNIS transcription in a thyroid-specific and thyroid stimulating hormone (TSH)- ii responsive manner. Based on the degree of homology, I propose that mouse and rat NIS share similar mechanisms for transcriptional regulation. Finally, in Chapter 4, I investigate the efficacy of Cre/loxP system to enhance thyroid-targeted hNIS expression driven by thyroglobulin (Tg) promoter in a variety of thyroid cells. Three recombinant adenoviruses were constructed: rAd-Tg-hNIS (hNIS expression driven by Tg promoter), rAd-Tg-Cre (Cre expression driven by Tg promoter), and rAd-CMV-loxP-hNIS (CMV promoter and hNIS cDNA separated by loxP-GFP-Zeo-loxP). In cells with weak Tg promoter activity, co-infection of rAd-Tg-Cre and rAd-CMV-loxP-hNIS induce higher hNIS expression than single infection of rAd-Tg-hNIS. Thus, the relative promoter activity of Tg versus CMV is critical for the efficacy of Cre/loxP system. iii Dedicated to my parents iv ACKNOWLEDGMENTS I would like to thank my advisor, Dr. Sissy M. Jhiang, for her encouragement, support and guidance, throughout this research. I am grateful to the members of my dissertation committee, for their guidance and assistance: Dr. Lee F. Johnson, Dr. Patrick L. Green and Dr. Thomas J. Sferra. I also wish to thank Dr. Richard T. Kloos for his helpful advice. I would like to thank the current and former members of Dr. Jhiang’s lab, for providing advice and assistance with this work and for their friendship: Dr. Tara L.F. Buckwalter, Dr. Je-Yoel Cho, Dr. Kwon-Yul Ryu, Dr. Krista M.D.La Perle, Dr. Daniel H.Y. Shen, Anjli Venkateswaran, Derek Marsee, Douangsone Vadysirisack, Dr. Katie Knostman, Zhaoxia Zhang, Marc S. Lavender, and Danielle E. Westfall. Most of all, I would like to thank my grandmother and my parents for their love and support in my life. v VITA November 3, 1973..........................................Born – Fuzhou, Fujian, P.R.China 1996................................................................B.S. Biochemistry, Xiamen University, P.R.China 1996-1998…………………………………...Research Assistant, Fujian Institute of Research on the Structure of Matter, P.R.China 1998 -present .................................................Graduate Research Associate, The Ohio State University FIELDS OF STUDY Major Field: Biochemistry Molecular Biology vi TABLE OF CONTENTS Page Abstract.............................................................................................................................ii Dedication......................................................................................................................... v Acknowledgments............................................................................................................vi Vita..................................................................................................................................vii List of Tables .................................................................................................................... x List of Figures..................................................................................................................xi Chapters: 1. Introduction........................................................................................................... 1 Thyroid physiology......................................................................................... 1 Molecular Cloning of NIS .............................................................................. 2 Structure of NIS ..............................................................................................2 Function of NIS...............................................................................................3 Tissue distribution of NIS............................................................................... 4 Regulation of NIS ........................................................................................... 5 Transcriptional regulation of NIS .................................................................. 9 NIS mutations in congenital ITD.................................................................. 11 NIS in thyroid cancer.................................................................................... 12 NIS gene therapy........................................................................................... 14 2. The roles of 5’ untranslated region in the protein expression and cell surface trafficking of human sodium/iodide symporter (hNIS) ...................................... 23 Introduction............................................................................................. 23 Materials and Methods............................................................................ 25 Results..................................................................................................... 32 Discussion............................................................................................... 38 vii 3. Cloning and characterization of mouse sodium iodide symporter promoter and a thyroid-specific and TSH-responsive enhancer ............................................. 57 Introduction............................................................................................. 57 Materials and Methods............................................................................ 59 Results..................................................................................................... 62 Discussion............................................................................................... 65 4. Application of the Cre-loxP system to enhance thyroid-targeted expression of sodium/iodide symporter (NIS) .......................................................................... 81 Introduction............................................................................................. 81 Materials and Methods............................................................................ 83 Results..................................................................................................... 87 Discussion............................................................................................... 92 5. Conclusions and future research directions ...................................................... 104 List of References ......................................................................................................... 109 viii LIST OF TABLES Table Page 1.1 The molecular characterization of NIS mutations identified in ITD .......... ……18 2.1 Primers used for PCR amplification ................................................................... 44 2.2 Quantification of the hNIS protein expression on cell surface, total hNIS protein expression, and the steady-state level of hNIS mRNA in cells transfected with ORF-hNIS, (-362)-hNIS, hNIS-(1989) and (-362)-hNIS-(1989) ....................... 45 3.1 The potential transcription binding sites shared by both mouse and rat NIS promoters ............................................................................................................ 69 ix LIST OF FIGURES Figure Page 1.1 Schematic representation of the biosynthetic pathway of thyroid hormones in the thyroid follicular cell................................................................................. 19 1.2 NIS cDNA and protein sequence identity in four species: human, pig, rat and mouse ........................................................................................................... 20 1.3 Secondary structure model of human sodium/iodide symporter
Load more

Recommended publications
  • Antibodies Products
    Chapter 2 : Gentaur Products List • Human Signal peptidase complex catalytic subunit • Human Sjoegren syndrome nuclear autoantigen 1 SSNA1 • Human Small proline rich protein 2A SPRR2A ELISA kit SEC11A SEC11A ELISA kit SpeciesHuman ELISA kit SpeciesHuman SpeciesHuman • Human Signal peptidase complex catalytic subunit • Human Sjoegren syndrome scleroderma autoantigen 1 • Human Small proline rich protein 2B SPRR2B ELISA kit SEC11C SEC11C ELISA kit SpeciesHuman SSSCA1 ELISA kit SpeciesHuman SpeciesHuman • Human Signal peptidase complex subunit 1 SPCS1 ELISA • Human Ski oncogene SKI ELISA kit SpeciesHuman • Human Small proline rich protein 2D SPRR2D ELISA kit kit SpeciesHuman • Human Ski like protein SKIL ELISA kit SpeciesHuman SpeciesHuman • Human Signal peptidase complex subunit 2 SPCS2 ELISA • Human Skin specific protein 32 C1orf68 ELISA kit • Human Small proline rich protein 2E SPRR2E ELISA kit kit SpeciesHuman SpeciesHuman SpeciesHuman • Human Signal peptidase complex subunit 3 SPCS3 ELISA • Human SLAIN motif containing protein 1 SLAIN1 ELISA kit • Human Small proline rich protein 2F SPRR2F ELISA kit kit SpeciesHuman SpeciesHuman SpeciesHuman • Human Signal peptide CUB and EGF like domain • Human SLAIN motif containing protein 2 SLAIN2 ELISA kit • Human Small proline rich protein 2G SPRR2G ELISA kit containing protein 2 SCUBE2 ELISA kit SpeciesHuman SpeciesHuman SpeciesHuman • Human Signal peptide CUB and EGF like domain • Human SLAM family member 5 CD84 ELISA kit • Human Small proline rich protein 3 SPRR3 ELISA kit containing protein
    [Show full text]
  • Transporters
    Alexander, S. P. H., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Sharman, J. L., Southan, C., Davies, J. A., & CGTP Collaborators (2019). The Concise Guide to Pharmacology 2019/20: Transporters. British Journal of Pharmacology, 176(S1), S397-S493. https://doi.org/10.1111/bph.14753 Publisher's PDF, also known as Version of record License (if available): CC BY Link to published version (if available): 10.1111/bph.14753 Link to publication record in Explore Bristol Research PDF-document This is the final published version of the article (version of record). It first appeared online via Wiley at https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14753. Please refer to any applicable terms of use of the publisher. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/ S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Transporters. British Journal of Pharmacology (2019) 176, S397–S493 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Transporters Stephen PH Alexander1 , Eamonn Kelly2, Alistair Mathie3 ,JohnAPeters4 , Emma L Veale3 , Jane F Armstrong5 , Elena Faccenda5 ,SimonDHarding5 ,AdamJPawson5 , Joanna L Sharman5 , Christopher Southan5 , Jamie A Davies5 and CGTP Collaborators 1School of Life Sciences,
    [Show full text]
  • Comprehensive Review on Lactate Metabolism in Human Health☆,☆☆
    Mitochondrion 17 (2014) 76–100 Contents lists available at ScienceDirect Mitochondrion journal homepage: www.elsevier.com/locate/mito Review Comprehensive review on lactate metabolism in human health☆,☆☆ M. Adeva-Andany a,⁎, M. López-Ojén b, R. Funcasta-Calderón a,1,E.Ameneiros-Rodrígueza,1, C. Donapetry-García a,1, M. Vila-Altesor a,1, J. Rodríguez-Seijas a,1 a Nephrology Division, Hospital General Juan Cardona, Ave. Pardo Bazán, s/n, 15406 Ferrol, La Coruña, Spain b Internal Medicine Division, Policlínica Assistens, c/Federico García, 4-planta baja, 15009 La Coruña, Spain article info abstract Article history: Metabolic pathways involved in lactate metabolism are important to understand the physiological response to Received 18 October 2013 exercise and the pathogenesis of prevalent diseases such as diabetes and cancer. Monocarboxylate transporters Received in revised form 19 March 2014 are being investigated as potential targets for diagnosis and therapy of these and other disorders. Glucose and al- Accepted 5 May 2014 anine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen Available online 12 June 2014 consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. Pyruvate may be either oxidized to carbon dioxide producing energy or transformed into glucose. Pyruvate oxidation requires Keywords: Glycolysis oxygen supply and the cooperation of pyruvate dehydrogenase, the tricarboxylic acid cycle, and the mitochondri- Tricarboxylic acid cycle al respiratory chain. Enzymes of the gluconeogenesis pathway sequentially convert pyruvate into glucose. Con- Respiratory chain genital or acquired deficiency on gluconeogenesis or pyruvate oxidation, including tissue hypoxia, may induce Gluconeogenesis lactate accumulation.
    [Show full text]
  • The Effects of Genetic Mutations and Drugs on the Activity of the Thiamine Transporter, SLC19A2
    UCSF UC San Francisco Previously Published Works Title The Effects of Genetic Mutations and Drugs on the Activity of the Thiamine Transporter, SLC19A2. Permalink https://escholarship.org/uc/item/0fb7q1fj Journal The AAPS journal, 23(2) ISSN 1550-7416 Authors Enogieru, Osatohanmwen J Koleske, Megan L Vora, Bianca et al. Publication Date 2021-03-01 DOI 10.1208/s12248-021-00562-4 Peer reviewed eScholarship.org Powered by the California Digital Library University of California The AAPS Journal (2021) 23:35 DOI: 10.1208/s12248-021-00562-4 Brief/Technical Note Theme: Celebrating Women in the Pharmaceutical Sciences Guest Editors: Diane Burgess, Marilyn Morris and Meena Subramanyam The Effects of Genetic Mutations and Drugs on the Activity of the Thiamine Transporter, SLC19A2 Osatohanmwen J. Enogieru,1 Megan L. Koleske,1 Bianca Vora,1 Huy Ngo,1 Sook Wah Yee,1 Derrick Chatad,2 Marina Sirota,3,4,5 and Kathleen M. Giacomini1,4 Received 11 November 2020; accepted 26 January 2021 Abstract. A rare cause of megaloblastic anemia (MA) is thiamine-responsive megalo- blastic anemia (TRMA), a genetic disorder caused by mutations in SLC19A2 (encoding THTR1), a thiamine transporter. The study objectives were to (1) functionally characterize selected TRMA-associated SLC19A2 variants and (2) determine whether current prescrip- tion drugs associated with drug-induced MA (DIMA) may act via inhibition of SLC19A2. Functional characterization of selected SLC19A2 variants was performed by confocal microscopy and isotopic uptake studies of [3H]-thiamine in HEK293 cells. Sixty-three drugs associated with DIMA were screened for SLC19A2 inhibition in isotopic uptake studies. Three previously uncharacterized SLC19A2 variants identified in TRMA patients exhibited disrupted localization to the plasma membrane along with near-complete loss-of-function.
    [Show full text]
  • Linking Vitamin B1 with Cancer Cell Metabolism Jason a Zastre*, Rebecca L Sweet, Bradley S Hanberry and Star Ye
    Zastre et al. Cancer & Metabolism 2013, 1:16 http://www.cancerandmetabolism.com/content/1/1/16 Cancer & Metabolism REVIEW Open Access Linking vitamin B1 with cancer cell metabolism Jason A Zastre*, Rebecca L Sweet, Bradley S Hanberry and Star Ye Abstract The resurgence of interest in cancer metabolism has linked alterations in the regulation and exploitation of metabolic pathways with an anabolic phenotype that increases biomass production for the replication of new daughter cells. To support the increase in the metabolic rate of cancer cells, a coordinated increase in the supply of nutrients, such as glucose and micronutrients functioning as enzyme cofactors is required. The majority of co- enzymes are water-soluble vitamins such as niacin, folic acid, pantothenic acid, pyridoxine, biotin, riboflavin and thiamine (Vitamin B1). Continuous dietary intake of these micronutrients is essential for maintaining normal health. How cancer cells adaptively regulate cellular homeostasis of cofactors and how they can regulate expression and function of metabolic enzymes in cancer is underappreciated. Exploitation of cofactor-dependent metabolic pathways with the advent of anti-folates highlights the potential vulnerabilities and importance of vitamins in cancer biology. Vitamin supplementation products are easily accessible and patients often perceive them as safe and beneficial without full knowledge of their effects. Thus, understanding the significance of enzyme cofactors in cancer cell metabolism will provide for important dietary strategies and new molecular targets to reduce disease progression. Recent studies have demonstrated the significance of thiamine-dependent enzymes in cancer cell metabolism. Therefore, this review discusses the current knowledge in the alterations in thiamine availability, homeostasis, and exploitation of thiamine-dependent pathways by cancer cells.
    [Show full text]
  • Disruption of Transport Activity in a D93H Mutant Thiamine Transporter 1, from a Rogers Syndrome Family
    Eur. J. Biochem. 270, 4469–4477 (2003) Ó FEBS2003 doi:10.1046/j.1432-1033.2003.03839.x Disruption of transport activity in a D93H mutant thiamine transporter 1, from a Rogers Syndrome family Dana Baron1, Yehuda G. Assaraf2, Stavit Drori2 and Ami Aronheim1 1Department of Molecular Genetics, The Rappaport Institute for Research in the Medical Sciences and the B. Rappaport Faculty of Medicine, and 2Department of Biology, The Technion-Israel Institute of Technology, Haifa, Israel Rogers syndrome is an autosomal recessive disorder result- transport null cells of a homologous D88H mutation in ing in megaloblastic anemia, diabetes mellitus, and sensori- the hRFC did not result in restoration of MTX trans- neural deafness. The gene associated with this disease port activity, thereby suggesting that D88 is an essential encodes for thiamine transporter 1 (THTR1), a member of residue for MTX transport activity. These results suggest the SLC19 solute carrier family including THTR2 and the that the D93H mutation does not interfere with trans- reduced folate carrier (RFC). Using transient transfections porter expression, glycosylation and plasma membrane into NIH3T3 cells of a D93H mutant THTR1 derived targeting. However, the substitution of this negatively from a Rogers syndrome family, we determined the charged amino acid (Asp93) by a positively charged expression, post-translational modification, plasma mem- residue (His) in an extremely conserved region (the bor- brane targeting and thiamine transport activity. We also der of transmembrane domain 2/intracellular loop 2) in explored the impact on methotrexate (MTX) transport the SLC19 family, presumably inflicts deleterious struc- activity of a homologous missense D88H mutation in the tural alterations that abolish thiamine binding and/or human RFC, a close homologue of THTR1.
    [Show full text]
  • The Concise Guide to PHARMACOLOGY 2015/16: Transporters
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: Transporters. British Journal of Pharmacology (2015) 172, 6110–6202 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: Transporters Stephen PH Alexander1, Eamonn Kelly2, Neil Marrion2, John A Peters3, Helen E Benson4, Elena Faccenda4, Adam J Pawson4, Joanna L Sharman4, Christopher Southan4, Jamie A Davies4 and CGTP Collaborators L 1 School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2 School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK 3 Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK N 4 Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13355/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets.
    [Show full text]
  • Mirnas Documented to Play a Role in Hematopoietic Cell Lineage. Our
    Table S1: miRNAs documented to play a role in hematopoietic cell lineage. Our review of the literature summarizing miRNAs known to be involved in the development and proliferation of the hematopoietic lineage cells. miRNA Expression/function/target/regulator References miR-150 Elevated during developmental stages of B and T cell maturation. 16-19 Controls B cell differentiation, present in mature, resting T and B cells but decreased upon activation of naïve T or B cells. Plays a role in establishing lymphocyte identity. Very little is known about function in T cells. Regulators: Foxp3 Target: C-Myb miR-146a/b Upregulated in macropgahe inflammatory response. Differentially 17, 20 upregulated in murine Th1 subset but abolished in Th2 subset. Upregulated in response to TCRs stimulation, as well as by IL-1 and TNF. Highly expressed in murine T-regs and could play a role in establishing lymphocyte identity. Modulates activation induced cell death in activated T cells. Negative regulator of TLR and cytokine signaling pathway. Endotoxin tolerance. Antiviral role. Targets: IRAK1, IRAK2, TRAF6, FAF1 miR-16-1 Promote apoptosis by targeting Bcl2 expression, act as tumor 22 cluster suppressor RNAs. May block differentiation of later stage hematopoietic progenitor cells to mature cells. Downregulated in CLL. Target: BCL2. miR-155 Regulator of T and B cell maturation and innate immune response. 23-29 Expressed in primary mediastinal B-cell lymphoma, T and B cells, macrophages and DCs. Upregulated during B cell activation. Involved in T cell differentiation and indicated as a positive regulator of cytokine production. Activated by stimulating TLR3 and INFab receptors in bone derived macrophages (regulation of antimicrobial defense).
    [Show full text]
  • Transporters
    University of Dundee The Concise Guide to PHARMACOLOGY 2015/16 Alexander, Stephen P. H.; Kelly, Eamonn; Marrion, Neil; Peters, John A.; Benson, Helen E.; Faccenda, Elena Published in: British Journal of Pharmacology DOI: 10.1111/bph.13355 Publication date: 2015 Licence: CC BY Document Version Publisher's PDF, also known as Version of record Link to publication in Discovery Research Portal Citation for published version (APA): Alexander, S. P. H., Kelly, E., Marrion, N., Peters, J. A., Benson, H. E., Faccenda, E., Pawson, A. J., Sharman, J. L., Southan, C., Davies, J. A., & CGTP Collaborators (2015). The Concise Guide to PHARMACOLOGY 2015/16: Transporters. British Journal of Pharmacology, 172(24), 6110-6202. https://doi.org/10.1111/bph.13355 General rights Copyright and moral rights for the publications made accessible in Discovery Research 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 Discovery Research 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: 06. Oct. 2021 S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: Transporters.
    [Show full text]
  • The Adaptive Regulation of Thiamine Pyrophosphokinase-1 Facilitates Malignant Growth During Supplemental Thiamine Conditions
    www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 83), pp: 35422-35438 Research Paper The adaptive regulation of thiamine pyrophosphokinase-1 facilitates malignant growth during supplemental thiamine conditions Hunter C. Jonus1, Bradley S. Hanberry2, Shivani Khatu1, Jaeah Kim1, Hendrik Luesch3, Long H. Dang4, Michael G. Bartlett1 and Jason A. Zastre1 1Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, United States of America 2Department of Pediatrics, Emory University, Atlanta, GA, United States of America 3Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, United States of America 4Division of Hematology/Oncology, Department of Internal Medicine, University of Florida Shands Cancer Center, University of Florida, Gainesville, FL, United States of America Correspondence to: Jason A. Zastre, email: [email protected] Keywords: thiamine; cancer; hypoxia-inducible factor-1α; reactive oxygen species; thiamine pyrophosphokinase-1 Received: August 22, 2018 Accepted: October 06, 2018 Published: October 23, 2018 Copyright: Jonus et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Supplemental levels of vitamin B1 (thiamine) have been implicated in tumor progression. Tumor cells adaptively up-regulate thiamine transport during hypoxic stress. Upon uptake, thiamine pyrophosphokinase-1 (TPK1) facilitates the rapid phosphorylation of thiamine into thiamine pyrophosphate (TPP). However, the regulation of TPK1 during hypoxic stress is undefined. Understanding how thiamine homeostasis changes during hypoxia will provide critical insight into the malignant advantage supplemental thiamine may provide cancer cells.
    [Show full text]
  • Neurological, Psychiatric, and Biochemical Aspects of Thiamine Deficiency in Children and Adults
    UC Davis UC Davis Previously Published Works Title Neurological, Psychiatric, and Biochemical Aspects of Thiamine Deficiency in Children and Adults. Permalink https://escholarship.org/uc/item/71n066f0 Journal Frontiers in psychiatry, 10(APR) ISSN 1664-0640 Authors Dhir, Shibani Tarasenko, Maya Napoli, Eleonora et al. Publication Date 2019 DOI 10.3389/fpsyt.2019.00207 Peer reviewed eScholarship.org Powered by the California Digital Library University of California MINI REVIEW published: 04 April 2019 doi: 10.3389/fpsyt.2019.00207 Neurological, Psychiatric, and Biochemical Aspects of Thiamine Deficiency in Children and Adults Shibani Dhir 1†, Maya Tarasenko 1†, Eleonora Napoli 1 and Cecilia Giulivi 1,2* 1 Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States, 2 Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, University of California, Davis, Davis, CA, United States Thiamine (vitamin B1) is an essential nutrient that serves as a cofactor for a number of enzymes, mostly with mitochondrial localization. Some thiamine-dependent enzymes are involved in energy metabolism and biosynthesis of nucleic acids whereas others are part of the antioxidant machinery. The brain is highly vulnerable to thiamine deficiency due to its heavy reliance on mitochondrial ATP production. This is more evident during rapid Edited by: growth (i.e., perinatal periods and children) in which thiamine deficiency is commonly Shannon Rose, associated with either malnutrition or genetic defects. Thiamine deficiency contributes University of Arkansas for Medical Sciences, to a number of conditions spanning from mild neurological and psychiatric symptoms United States (confusion, reduced memory, and sleep disturbances) to severe encephalopathy, ataxia, Reviewed by: congestive heart failure, muscle atrophy, and even death.
    [Show full text]
  • A Novel Homozygous SLC19A2 Mutation in a Portuguese Patient with Diabetes Mellitus and Thiamine-Responsive Megaloblastic Anaemia
    Tahir et al. International Journal of Pediatric Endocrinology (2015) 2015:6 DOI 10.1186/s13633-015-0002-6 CASE REPORT Open Access A novel homozygous SLC19A2 mutation in a Portuguese patient with diabetes mellitus and thiamine-responsive megaloblastic anaemia Sophia Tahir1†, Lieve GJ Leijssen1†, Maha Sherif1, Carla Pereira2, Anabela Morais3 and Khalid Hussain1,4* Abstract Thiamine-responsive megaloblastic anaemia (TRMA) is a rare syndrome where patients present with early onset diabetes mellitus, megaloblastic anaemia and sensorineural deafness. This report describes a new case of TRMA syndrome in a female patient of Portuguese descent, born to unrelated parents. The patient was found to have a novel homozygous change R397X in exon 4 of the SLC19A2 gene, leading to a premature stop codon. The patient’s diabetes and anaemia showed a good response to daily thiamine doses, reducing the daily insulin dose requirement. The report further indicates that TRMA is not only limited to consanguineous or ethnically isolated families, and should be considered as a differential diagnosis for patients presenting with suggestive clinical symptoms. Keywords: TRMA, Diabetes mellitus, Sensorineural deafness, Megaloblastic anaemia, SLC19A2 mutation Introduction endocrine function, but neurological manifestations do Thiamine-responsive megaloblastic anaemia (TRMA; not respond as well [1,3]. OMIM 249270), also called Roger’s syndrome, is a very Most of the TRMA patients originated from consan- rare autosomal recessive disorder characterized by early guineous families, which is consistent with autosomal re- onset diabetes mellitus (DM), megaloblastic anaemia and cessive inheritance [4]. TRMA is caused by homozygous sensorineural deafness. The syndrome was first described mutations in the SLC19A2 gene [4], which encodes a high- by Rogers et al.
    [Show full text]