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The Function of Zinc Transporters in Human Cells

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The Function of Zinc Transporters in Human Cells THE FUNCTION OF ZINC TRANSPORTERS IN HUMAN CELLS BY LOVELEEN KUMAR, BSc., MSc. Submitted in fulfilment of requirements for the degree of Doctor of Philosophy DEAKIN UNIVERSITY JULY 2014 i Acknowledgements I would sincerely like to thank my supervisor Professor Leigh Ackland for giving me the opportunity to undertake my PhD under her invaluable guidance with continual support, encouragement and infinite enthusiasm. Thank you so much Leigh for having faith in me and being wonderful supervisor one could ever wish for. I would like to thank my co-supervisor Dr Agnes Michalczyk, not only for providing invaluable supervision and encouragement but being a great friend who I could talk to during hard times. Thanks a lot Agnes for being always there to support me. I am grateful to Professor Julian Mercer for allowing me to undertake my PhD candidature in the CCMB. I would also like to thank him for his expert advice at the discussion sessions that made me think in detail. Special thanks to Prof Andy Sinclair for providing me the scholarship and the mentoring sessions we had, it made me concentrate on the main goal. I would like to thank my Lab Manager Mr. Michael Holmes for having faith in my capability and providing me with opportunity to work as a technical officer to financially support my family. I am very grateful to our school manager Marita Reynolds to sanction my study leave to finish off my writting. I would like to extend that thanks to all Technical staff, who gave enormous mental support and friendly environment that helped me come out of my grief. Special thanks to Maria and Linda who were always there to hear my long iv conversations and gave me expert advice. Thank you so much for being great friends. Thanks to everyone from CCMB for being helpful especially David, Lee and Dean for their technical advice. To everyone involved in teaching as I enjoyed demonstrating undergraduate students. I might have forgotten some names to mention but their great wishes have been playing a big role along the journey of PhD. Thanks to them for their well wishes that helped me to fulfil this goal. Finally, I would like to save the biggest thanks to my husband Vivek and kids, Vansh and Lehar for their unconditional love and faith in me. They are the main reason for me to submit this work. I feel really lucky to have best kids who understood the importance of their mums dream and spend days and nights without me. My husband who stood like a strong pillar beside me while, going through the tough times of our lives. Thank you so much. I don’t have words to express my gratitude but would like to say “Love, Affection, Care and Pride, All were there by my side. I bow my Heart with a glitter in my eye, I owe you all Thanks for the rest of my life.” At the end I would like to dedicate this thesis to my Dad and Grandpa, two important members in my life, I lost during my candidature. It’s your upbringing that set my mind to submit this work. v Publications Arising from this Project The data presented in thesis has been submitted or is currently in preparation for publication. Kumar Loveleen, Michalczyk Agnes, McKay Jill, Ford Dianne, Kambe Taiho, Hudek Lee, Varigos George, Taylor Philip, and Ackland M Leigh. “Altered expression of zinc transporters SLC30A5 and 6 (ZnT5 and 6) underlie a mammary gland disorder of reduced zinc secretion into milk” Manuscript submitted to Human Molecular Genetics Kumar Loveleen, Michalczyk Agnes and Ackland M Leigh. “Functional analysis to determine co-dependency of ZnT5 and ZnT6 in neuronal cells” Manuscript in preparation Kumar Loveleen, Michalczyk Agnes, Suphioglu Cenk, Sinclair Andrew and Ackland M Leigh. “Effect of Zinc and DHA on hZnT5 and hZnT6 transporters in neuronal cells” Manuscript in preparation Kumar Loveleen, Michalczyk Agnes and Ackland M Leigh. “In silico molecular characterization of ZnT family members” Manuscript in preparation vi List of Contents Access to Thesis – A .......................................................................................... ii Candidature Declaration ................................................................................... iii Acknowledgements ........................................................................................... iv Publications Arising From This Project ........................................................... vi List of Contents ................................................................................................ vii List of Figures .................................................................................................. xiv List of Tables ................................................................................................... xvii List of Abbreviations ..................................................................................... xviii Abstract ............................................................................................................ xxi Chapter 1 Introduction ....................................................................................... 1 1.1 History of Zinc .................................................................................... 2 1.2 Chemistry of Zinc ............................................................................... 2 1.3 Zinc homeostasis ............................................................................... 3 1.3.1 Zinc absorption ....................................................................... 4 1.3.2 Zinc distribution ...................................................................... 5 1.3.3 Zinc transport ......................................................................... 5 1.3.4 Zinc storage ............................................................................ 6 1.3.5 Zinc excretion ......................................................................... 6 vii 1.4 Biological/physiological roles of zinc .............................................. 7 1.4.1 Zinc and nucleic acids ............................................................ 7 1.4.2 Zinc and Membranes .............................................................. 8 1.4.3 Zinc and Cell signaling ........................................................... 9 1.4.4 Zn and immune system ........................................................ 11 1.4.5 Zn and oxidative stress......................................................... 11 1.4.6 Zn and apoptosis .................................................................. 12 1.5 Zinc Deficiency ................................................................................. 13 1.6 Neonatal requirement of zinc .......................................................... 16 1.7 Zinc supplementation ...................................................................... 17 1.8 Zinc and diseases ............................................................................ 18 1.8.1 Zinc and cancer .................................................................... 18 1.8.2 Zinc and Alzheimer’s disease ............................................... 19 1.8.3 Zn and cardiovascular disease ............................................. 19 1.8.4 Zinc and Wilson disease18 ................................................... 20 1.9 Inherited disorders of zinc deficiency ............................................ 20 1.9.1 Acrodermatitis enteropathica ................................................ 20 1.9.2 Mammary gland disorder of zinc secretion ........................... 21 1.10 Zinc and lipids interactions in the brain ...................................... 22 1.10.1 DHA .................................................................................... 23 1.10.2 DHA and Brain ................................................................... 23 1.10.3 Link between DHA and zinc ............................................... 24 1.11 Cellular zinc transport ................................................................... 25 1.11.1 Bacterial zinc transporters .................................................. 25 1.11.1.1 Cellular zinc import systems ............................... 25 viii 1.11.1.2 Cellular zinc export systems ............................... 27 1.11.2 Eukaryotic zinc transport .................................................... 28 1.11.2.1 Zrt, Irt-like Proteins (ZIP) or SLC39 family .......... 28 1.11.2.2 Cation Diffusion Facilitators (CDF) or SLC30 family .................................................................. 29 1.11.3 Zinc transport in Saccharomyces cerevisiae ...................... 32 1.11.3.1 Cellular zinc uptake ............................................ 32 1.11.3.2 Cellular zinc efflux .............................................. 33 1.11.4 Mammalian zinc transporters ............................................. 34 1.11.4.1 ZIP family ........................................................... 35 1.11.4.2 ZNT family .......................................................... 42 1.11.4.3 NRAMP (Natural Resistance-Associated Macrophage Proteins) or SLC11 family .............. 54 1.12 Project aims .................................................................................... 55 Chapter 2 - Material and Methods ................................................................... 57 2.1 Case history summaries .................................................................. 58 2.2 Sample collection and cell culture ................................................. 58 2.3 Plasmid preparation and cell transfection ....................................
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