Epigenetic, Metabolic and Signal Transduction Pathways Involved in Radiation Response of Normal and Transformed Thyrocytes
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ei involved in radiation response of normal and transformed response in radiation involved transduction and signal pathways metabolic, Epigenetic, Epigenetic, metabolic and signal transduction pathways involved in radiation response of normal and transformed thyrocytes Khalil Abouelaradat Khalil Abouelaradat ISBN 978-90-5989-484-6 2011 9 789059 894846 "Once something actually happens somewhere as wildly complicated as the Universe, Kevin knows where it will all end up – where 'Kevin' is any random entity that doesn't know nothin' about nothin'" Douglas Adams, 'Mostly Harmless' Book 5 of the Trilogy of Five ii Promoters: Prof. Dr. Ir. Wim VAN CRIEKINGE Department of Mathematical Modeling, Statistics and Bioinformatics Faculty of Bioscience Engineering Ghent University Prof. Dr. Sarah BAATOUT Radiobiology Unit Belgian Nuclear Research Center (SCK•CEN) & Department of Molecular Biotechnology Faculty of Bioscience Engineering Ghent University Prof. Dr. Ir. Tim DE MEYER Department of Mathematical Modeling, Statistics and Bio-informatics /Department of Molecular Biotechnology Faculty of Bioscience Engineering Ghent University Dr. Ir. Sofie BEKAERT Clinical Research Center Faculty for Medicine and Health Sciences Ghent University Dean: Prof. Dr. Ir. Guido VAN HUYLENBROECK Rector: Prof. Dr. Paul VAN CAUWENBERGE iii Epigenetic, metabolic, and signal transduction pathways involved in radiation response of normal and transformed thyrocytes Khalil Abouelaradat Thesis submitted in fulfillment of the requirements for the degree of Doctor (PhD) in Applied Biological Sciences iv "Epigenetische, metabole en signaaloverdrachtmechanismen betrokken bij de stralingsrespons van normale en getransformeerde schildkliercellen" Cover Illustration: Colored gamma scan (scintigram) of a healthy human thyroid gland, in front view (Centre Jean Perrin/Science Photo Library). A radioactive tracer (Tc-99m) highlights areas of activity in the thyroid where blue represents areas of low activity and green/red areas of high activity. Gamma scans involve injecting a radioactive tracer and then measuring the gamma rays emitted using a gamma camera. Picture was converted to ASCII art using Ascgen2 (http://sourceforge.net/projects/ascgen2). The ASCII picture is made out of repeats of the word RET/PTC. The gamma scan picture is overlayed with an image of a monarch butterfly (Danaus plexippus) (© 2009, Encyclopaedia Britannica). Cover art design by Khalil Abouelaradat Abouelaradat Khalil (2011). Epigenetic, metabolic, and signal transduction pathways involved in radiation response of normal and transformed thyrocytes. PhD Thesis. Ghent University. ISBN: 978-90-5989-484-6 The author and the promoters give the authorization to consult and to copy parts of this work for personal use only. Any other use is limited by the Laws of Copyright. Permission to reproduce any material contained in this work should be obtained from the author. v Members of the Examination Committee Prof. Dr. Ir. Wim Van Criekinge (Promoter) Department of Mathematical Modeling, Statistics and Bioinformatics, Faculty of Bioscience Engineering, Ghent University Prof. Dr. Sarah Baatout (Co-promoter) Radiobiology Unit, Belgian Nuclear Research Center (SCK•CEN) Department of Molecular Biotechnology, Faculty of Bioscience Engineering, Ghent University Prof. Dr. Ir. Sofie Bekaert (Co-promoter) Clinical Research Center, Faculty of Medicine and Health Sciences, Ghent University Prof. Dr. Ir. Tim De Meyer (Co-promoter) Department of Molecular Biotechnology/Department of Mathematical Modeling, Statistics and Bioinformatics, Faculty of Bioscience Engineering, Ghent University Prof. Dr. Ir. Dirk Reheul (Chairman) Department of Plant Production, Faculty of Bioscience Engineering, Ghent University Prof. Dr. Ir. Guy Smagghe (Secretary) Department of Crop Production, Faculty of Bioscience Engineering , Ghent University Dr. Anne-Catherine Gérard Morphology Group, Institute of Fundamental and Clinical Research, Catholic University of Louvain (UCL) Prof. Dr. Hubert Thierens Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University Em. Prof. Dr. Patrick Van Oostveldt Department of Molecular Biotechnology, Faculty of Bioscience Engineering, Ghent University Prof. Dr. Jan Philippé Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University vi vii Table of Contents List of Figures ......................................................................................................................................... xiv List of Tables .......................................................................................................................................... xvi List of Abbreviations ............................................................................................................................ xviii Chapter 1: General Introduction 1. The Nuclear Conundrum ..................................................................................................................... 3 1.1 TMI and Chernobyl: Compare and Contrast .................................................................................. 3 1.2 Nuclear Weapons Testing .............................................................................................................. 5 1.3 Fukushima: Lessons from the Past ................................................................................................ 6 1.4 External Irradiation ........................................................................................................................ 7 2. The Thyroid .......................................................................................................................................... 9 2.1 Iodine Metabolism and Hormone Synthesis ................................................................................. 9 2.2 Thyroid Homeostasis ................................................................................................................... 13 3. Thyroid Cancer................................................................................................................................... 15 3.1 Thyroid Cancer Types .................................................................................................................. 15 3.2 Mutations in PTC ......................................................................................................................... 17 3.2.1 RAF ........................................................................................................................................ 17 3.2.2 RET/PTC ................................................................................................................................ 17 3.2.2.1 Prominance of RET/PTC Translocations in Radiation-induced PTCs .................................. 19 3.2.3 NTRK Rearrangments ........................................................................................................... 21 3.2.4 Ras ........................................................................................................................................ 21 4. Low Dose Radiation Introduction ...................................................................................................... 23 4.1 The Linear Non-Threshold Model (LNT) ...................................................................................... 23 4.2 The LNT: Pros and Cons, Epidemiology ....................................................................................... 25 4.3 Health Risk Estimates: Molecular ................................................................................................ 26 4.3.1 γH2AX ................................................................................................................................... 26 4.3.2 Cell Survival .......................................................................................................................... 27 4.4 Deviations from the LNT .............................................................................................................. 28 4.4.1 HRS/IRR ................................................................................................................................. 28 4.4.2 The Bystander Effect ............................................................................................................ 29 4.4.3 Adaptive Response ............................................................................................................... 30 viii 4.4.4 Hormesis ............................................................................................................................... 30 4.5 Interindividual Sensitivity ............................................................................................................ 31 4.6 Risk to the Thyroid ....................................................................................................................... 31 4.7 Conclusion ................................................................................................................................... 32 5. Senescence Introduction: To Divide or Not To Divide....................................................................... 33 5.1 The Hayflick Mosaic ..................................................................................................................... 34 5.2 Hitting the Breaks: Premature Senescence ................................................................................. 36