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Analysis of Post-Translational Modifications of Fat1 Cadherin

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Analysis of Post-Translational Modifications of Fat1 Cadherin ANALYSIS OF POST-TRANSLATIONAL MODIFICATIONS OF FAT1 CADHERIN Elham Sadeqzadeh, MD MSc in Medical Biotechnology Thesis submitted in the fulfilment of the requirements to obtain the degree of Doctor of Philosophy in Medical Biochemistry School of Biomedical Sciences and Pharmacy University of Newcastle August 2013 shown Statement of Originality This thesis contains no material which has been accepted for the award of any other degree or diploma in any University or other tertiary institution and, to the best of my knowledge and belief, contains no material previously published or written by another person, except where due reference has been made in the text. I give consent to the final version of my thesis being made available worldwide when deposited in the University’s Digital Repository** subject to the provisions of the Copyright Act 1968. ** Unless an Embargo has been approved for a determined period. Elham Sadeqzadeh ii Acknowledgements The fulfilment of this project would not be possible without sincere help from a number of people, whom I am utterly grateful for all they have done. Rick (Dr. Rick F Thorne), my supervisor, who entrusted me with some great studies into understanding more about his baby, the FAT1 cadherin project. If it were not for your guidance, advice, encouragements, arguments and dares none of this would have come to exist. I am also grateful for giving me the opportunity to do a PhD project under your supervision, despite a not so good gut feeling at the start. Gordon (Professor Gordon F Burns), my co-supervisor before retirement and a very supportive figure after that. Your presence and support during the first two years of this project and the courage you gave me to challenge things are exemplary. In the last two years I was always fortunate of having your encouraging words to lift my spirits, when things went wrong. Charley (Dr. Charles E deBock), if it were not for your help in molecular biology experiments and your sudden and abrupt decision-making capabilities, the second and third chapters of this thesis might have taken an entirely different turn and not end up in me getting those very interesting results. Xu (Ms. Xu Guang Yan), your help in immunocytochemistry and immunofluorescence microscopy experiments were invaluable and I do appreciate it all. I also thank all my lab- mates in the Cancer Research Unit, who made this journey more appealing, especially when experiments tend to have a mind of their own, which is not such a rare event. Thanks to my parents who through their witty foresight prepared me for this journey in life. Thanks for teaching me how to be a better person, how to care for other people, how to be independent, how to carry my own burden in life and the philosophy of “what goes around comes around”. Last but not least, I thank my beloved better half. You sacrificed all you had to join me here and start everything from scratch again. I was the most fortunate person for having you by my side. Your patience and grace in going through all you endured for the first few years here have been extraordinary. You have always been my best supporter and my solid ground when things went terribly wrong. I am really very grateful. iii Acknowledgement of contribution I hereby certify that the some parts of the work embodied in this thesis has been done in collaboration with other researches, and carried out in other institutions. I have included a statement clearly outlining the extent of collaboration, with whom and under what auspices as follows. Chapter one The Chapter was published as a review article in Medicinal Research Reviews (Appendix 2). I prepared the first draft of the manuscript and some of the original artwork and all of the tables. Thereafter I undertook further editing and corrections with direction provided by my co-supervisor, Dr. Charles E. de Bock and primary supervisor, Dr. Rick F. Thorne. Dr. de Bock prepared the artwork for figures 1.1, 1.3 and 1.4 and edited drafts versions of the manuscript. Dr. Thorne edited the draft manuscripts and approved the final version for submission. Chapter three The work was published in the Journal of Biological Chemistry (Appendix 2). I performed the majority of the experiments for this Chapter and prepared the primary draft of the manuscript including all figures and tables. Dr. de Bock carried out the Northern blotting experiment presented as figure 3.1. My co-supervisor, Professor Gordon F Burns, read the drafts of the manuscript and advised relevant corrections. Professor Andrew Boyd also provided advice on the drafts of the manuscript. Professor Xu Dong Zhang provided melanoma cell lines used and provided advice about the experimental direction of the study. Dr. Camila Salum Oliveira performed the knockdown experiment presented in figure 3.4A. Dr. Thorne edited the drafts and approved the final version for submission. iv Chapter four The work has been published in the Journal of Experimental Cell Research I performed the majority of the experiments for this Chapter and prepared the primary draft of the manuscript including all figures and tables. Dr. Natalie Wojtalewicz carried out blotting experiments to detect the shed ectodomain of FAT1 in furin-overexpressing melanoma cells presented in figure 4.5A. Dr. de Bock assisted me in the production of the stable furin overexpressing cell lines. Dr. Matthew D. Dun and Nathan D. Smith performed mass spectrographic runs on samples I prepared. Dr. Dun also analysed data used to prepare tables in appendix 4 (tables A4.2 – A4.4). Dr. Irmgard Schwarte-Waldhoff supervised Dr. Wojtalewicz as a post-graduate student and provided advice about experimental directions for the study. Dr. Thorne edited the draft manuscripts and approved the final version for submission. v Table of Contents STATEMENT OF ORIGINALITY ........................................................................................................... II ACKNOWLEDGEMENTS ...................................................................................................................III ACKNOWLEDGEMENT OF CONTRIBUTION ..................................................................................... IV TABLE OF CONTENTS ...................................................................................................................... VI LIST OF FIGURES ............................................................................................................................. IX ABSTRACT ...................................................................................................................................... XI CHAPTER ONE - GENERAL INTRODUCTION ....................................................................................... 1 1.1. INTRODUCTION ......................................................................................................................... 2 1.2. THE FAT CADHERIN FAMILY .......................................................................................................... 3 1.2.1. Functions of the Drosophila Fat cadherins ................................................................... 5 1.2.2 The vertebrate Fat cadherins.......................................................................................... 16 1.3. FAT CADHERINS IN DISEASE ....................................................................................................... 35 1.3.1. Roles for FAT cadherins in human genetic disorders .................................................. 35 1.3.2. FAT cadherins in cancer ............................................................................................. 37 1.4. FAT CADHERINS IN THE GENOMIC ERA ......................................................................................... 43 1.5. OVERVIEW AND CONCLUDING REMARKS ....................................................................................... 45 1.6. HYPOTHESIS AND AIMS ............................................................................................................. 46 CHAPTER TWO - GENERAL MATERIALS AND METHODS .................................................................. 48 2.1. CHEMICALS ............................................................................................................................. 49 2.2. CELL LINES AND CULTURE ........................................................................................................... 49 2.1.1. Cryopreservation of cells ............................................................................................ 49 2.1.2. Revival of cryopreserved cells .................................................................................... 50 2.3. MOLECULAR BIOLOGY TECHNIQUES ............................................................................................ 50 2.3.1. Bacterial transformation and isolation of plasmid DNA ............................................ 50 2.3.2. Manipulation of DNA fragments ................................................................................ 51 2.3.3. Ligation of DNA fragments......................................................................................... 51 2.4. BCA PROTEIN ASSAY ................................................................................................................ 52 2.5. ELECTROPHORETIC SEPARATION AND DETECTION OF PROTEINS .......................................................... 52 2.5.1. Preparation of cell lysates .........................................................................................
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