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The Role of Stanniocalcin-1 in Vascular Cell Function

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The Role of Stanniocalcin-1 in Vascular Cell Function The Role of Stanniocalcin-1 in Vascular Cell Function Rudina Tahiri University College London 2013 A thesis submitted for the degree of Doctor of Philosophy 1 Declaration I, Rudina Tahiri, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract Stanniocalcin-1 (STC-1) is a 56kDa disulphide-linked homodimeric glycoprotein in vertebrates, with the capacity to regulate the extracellular ionised calcium (Ca2+) concentration. Specifically, in fish, Stanniocalcin (STC) is released into bloodstream in response to rising serum calcium levels by acting on calcium sensitive receptors on both gill and intestine epithelial cells to reduce the calcium uptake. Initially, STC was identified as a secreted hormone having an inhibitory effect on whole body Ca2+ influx that prevents hypercalcemia. However the function of this protein in mammals is still unclear. During angiogenesis, essential angiogenic factors such as Vascular Endothelial Growth Factor (VEGF) and Platelet-derived Growth Factor (PDGF), initiate cellular responses, intracellular signaling events that drive proliferation, migration and survival of vascular endothelial and smooth muscle cells (SMCs), respectively. Thus, it is important to understand the physiology of the molecular mechanism through which VEGF and/or PDGF exerts its biological activities as well as its role in malignancies in order to develop anti-angiogenic strategies for therapeutic intervention. In the first part of this thesis, the role of STC-1 in endothelial cell function was characteristed using varirous approaches. Analysis of VEGF-stimulated migration showed that STC-1 can modulate endothelial cell motility but has no effect on endothelial cell signalling. Here, I identified for the first time that PDGF-BB but not PDGF-AA, strongly upregulates expression of STC-1 in vascular smooth muscle cells. PDGF-BB-induced STC-1 expression is at least partially mediated via PDGFR and possibly PDGFR/ heterodimers, but there appears to be compensation between the two receptors. However, the partial inhibition of STC-1 expression by siRNA-mediated knockdown of both PDGFRs raises the possibility that an unconventional pathway is also involved not mediated by known PDGFRs, or by a non-Receptor Tyrosine Kinase (RTK) pathway. Furthermore, a novel synergistic effect of STC-1 and PDGF-BB in SMCs on phosphorylation of Akt/PBK protein that leads to GSK3 inhibition was observed. As 3 a PDGF-induced protein, STC-1 is implicated in modulating PDGF-mediated cell motility, and is a potential modulator of PI3K-Akt pathway activation. Akt enhanced phosphorylation might indicate a role for STC-1 in regulating SMC survival. 4 Acknowledgements Praise and Gratitude belongs to Our Lord, Lord of Universe. My sincere gratitude for my supervisors Professor Ian Zachary, Dr. Ian Evans and my past supervisor Dr. David Homes is so great that I hardly could find any excellent way of describing it. Their guidance, patience, continuous support, and above all their inspiring motivation during my PhD research in this laboratory is endlessly appreciated. I could not have imagined a better supervision for my PhD study. I would like to thank you the British Heart Foundation for funding the work in this project. Thank you also to all members of our laboratory and Ark Therapeutics Ltd., each and every one repeatedly helping me and kindly providing support and reagents for this work; Dr. Paul Frankel, Dr. Lily Cheng, Dr. Hayian Jia and Dr. Berger Herzog for their encouragement, comments and continuous support and guidance. I am genuinely grateful to them for helping with setting up my experiments and sharing their molecular biology knowledge with me and for useful discussions. I would like to thank Dr. Caroline Pellet-Many for her invaluable teaching of smooth muscle cells characteristics and constant help and guidance with technical support. I am grateful to my fellow labmate Dr. Maiko Yamaji for her generous help with PCR techniques and constant availability for an open scientific discussion. I also I would like to thank Dr. Vedanta Mehta and Miss Angela Barrett for being so kind to me and creating a helpful and friendly environment for me in the lab. Many thanks to all members of the Centre for Cardiovascular Biology and Medicine for helping in many areas of my research. Finally, to my family, thank you so greatly for being so loving and compassionate to me and for bearing my stress, my struggle, my passion. I realise that without your 5 tender love, and as my youngest son would describe, your gigantic patience and understanding I could not be here today, fulfilling a dream. 6 Table of Contents Declaration............................................................................................................................... 2 Abstract .................................................................................................................................... 3 Acknowledgements ................................................................................................................. 5 Table of Contents .................................................................................................................... 7 List of Figures ........................................................................................................................ 12 List of Tables ......................................................................................................................... 15 Abbreviations ........................................................................................................................ 16 1 Introduction .................................................................................................................... 19 1.1 Stanniocalcin ............................................................................................................. 20 1.1.1 Stanniocalcin in mammals .................................................................................. 23 1.1.2 Structure of STC-1 gene ..................................................................................... 24 1.1.2.1 Fish STC ...................................................................................................... 24 1.1.2.2 Mammalian STC-1 gene .............................................................................. 25 1.2 Mammalian STC-1 ..................................................................................................... 25 1.2.1 Human STC-1 protein ........................................................................................ 26 1.2.2 STC-1 receptors .................................................................................................. 29 1.3 Role of STC-1 in development ................................................................................... 31 1.4 Physiological roles of STC-1 ..................................................................................... 32 1.4.1 Protection from oxidative stress ......................................................................... 34 1.4.1.1 Induction of UCP2 ....................................................................................... 36 7 1.4.2 Cell survival ........................................................................................................ 36 1.5 STC-1, cancer and angiogenesis ............................................................................... 38 1.5.1 STC in cancer ..................................................................................................... 38 1.5.2 STC and angiogenesis ........................................................................................ 38 1.6 Vascular development ................................................................................................ 39 1.6.1 Vasculogenesis ................................................................................................... 40 1.6.2 Angiogenesis ...................................................................................................... 40 1.6.2.1 The endothelium .......................................................................................... 43 1.6.3 Vascular-derived angiogenic factors and signalling ........................................... 43 1.6.3.1 VEGF ........................................................................................................... 44 1.6.3.2 The VEGF family ........................................................................................ 44 1.6.3.3 Regulation of VEGF gene expression ......................................................... 46 1.6.4 VEGF receptors .................................................................................................. 48 1.6.4.1 VEGFR1 & VEGFR2 .................................................................................. 48 1.6.4.2 VEGFR3 ...................................................................................................... 52 1.6.4.3 Neuropilin-1 & -2 ........................................................................................ 52 1.7 Vascular Smooth Muscle Cell physiology ................................................................. 55 1.7.1 SMC in disease ................................................................................................... 58 1.7.2 Platelet Derived Growth Factors ........................................................................ 59 1.7.2.1 PDGF family ..............................................................................................
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