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The Roles of JAB1 and NOTCH1 in the Development of Cardiovascular Disease

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The Roles of JAB1 and NOTCH1 in the Development of Cardiovascular Disease The Roles of JAB1 and NOTCH1 in the Development of Cardiovascular Disease A S Karountzos Doctor of Philosophy 2019 The Roles of JAB1 and NOTCH1 in the Development of Cardiovascular Disease Anastasios Stylianos Karountzos, BSc, MSc, MSc, MRSB A thesis submitted in partial fulfilment of the requirements of the University of Lincoln for the degree of Doctor of Philosophy This research programme was carried out in collaboration with the King’s College London, UK June 2019 The Roles of JAB1 and NOTCH1 in the Development of Cardiovascular Disease Anastasios Stylianos Karountzos ABSTRACT Background Pulmonary arterial hypertension (PAH) and Adams-Oliver syndrome (AOS) are rare vascular disorders, characterised by severe late-onset and developmental cardiac abnormalities respectively. Both of them are clinically associated in a proportion of cases. PAH is a progressive condition that is clinically characterized by sustained elevation in mean pulmonary artery pressure, through vascular remodelling with luminal obliteration of small vessels and increased vascular resistance, while AOS is characterized by congenital limb defects and scalp cutis aplasia. In a proportion of AOS-cases, notable cardiac development is also apparent. PAH may be hereditary (HPAH), idiopathic (IPAH) or associated with other conditions, for example AOS. Most of HPAH and 25% of IPAH cases are associated with heterozygous mutations of a TGF-β superfamily member transmembrane receptor type-II, known as BMPR2. The majority of mutations suggest haploinsufficiency as the molecular mechanism of disease. In addition, monoclonal proliferation and uncontrolled growth in pulmonary artery endothelial (PAEC) and smooth muscle (PASMC) cells result in perturbation and muscularization of the arterial tone. This study aims to identify the cause of a further loss of BMPR-II expression in previous immunohistochemical studies of patient’s lung sections, that cannot be explained by haploinsufficiency. The defective BMP/TGF-β signalling in PAH will be addressed as well. This study also aims to identify novel genetic determinants of AOS, along with the hitherto unresolved underlying molecular defects, for the majority of affected subjects. Methods and Results Protein-protein interaction experimentation revealed a BMPR-II novel interacting partner, namely JAB1 protein, which through association with the kinase domain of the receptor, functions as the first identified proteasomal-associated inhibitor of BMPR-II. In addition, the linked experimental data of this study are indicative of BMPR-II degradation via the proteasomal pathway in the normal circulation. In addition, transient transfection studies demonstrated that JAB1 down-regulates BMPR-II in a dose-dependent manner. It is also confirmed that JAB1 is over- expressed during PAH progression, and proliferation studies revealed that JAB1 promotes uncontrolled cell proliferation and survival. Furthermore, functional studies supported the hypothesis that JAB1 appears to be a key regulator of BMP and TFG-β signalling pathways in PASMC cells, regulating differentially all stages of the pathways’ cascades in SMAD-dependant and SMAD-independent manners. Apart its up-stream action of promoting the proteolytic degradation of BMPR-II, RT-qPCR experimentation and further functional studies proved that it II also acts down-stream, by suppressing ID1 transcription factor or by promoting ID expression via up-regulation of SMAD-dependant and SMAD-independent signalling pathways, via activation of TAK1 and p38 MAPK mitogenic cascades, thus enhancing the pro-proliferative state of healthy and/or BMPR2 mutated PASMC cells. Knock-down of JAB1 in healthy and BMPR2 mutant PASMC cells resulted in control of their proliferation, an outcome which is indicative of the essential role of JAB1 in positively regulating the cell proliferation. The anti- proliferative effect of BMP4-ligand stimulation on hyper-proliferating BMPR2 mutant PASMC cells was also established, highlighting the suppressive regulatory role of BMP signalling on cell proliferation and differentiation. Regarding AOS disease, NOTCH1 mutations were found as the primary cause of AOS, in a proportion of cases of a cohort study (17%) with further cardiovascular complications. Novel identification of 10 mutations [3 frameshifts, 6 missense (EGF-like domain) and 1 nonsense] of the NOTCH1 gene in AOS- patients, along with a significant reduction of NOTCH1 expression in leukocyte- derived RNA from subjects, suggested that NOTCH1 plays a key role in the AOS pathogenesis. Transient transfections of mutagenized NOTCH1 missense constructs also revealed significant reduction in gene expression. Likewise, assessment of NOTCH1 target genes HEY1 and HES1 expression via RT-qPCR studies, verified the dysregulation of the NOTCH1 canonical signalling pathway in AOS-patients. Lastly, functional studies demonstrated the cross talk of BMP and NOTCH1 signalling as a synergistic effect in AOS pathology, underlined by forms of non-canonical signalling, potentiating the suppressive BMP cell signalling effect in AOS-cases of dysfunctional NOTCH1 signalling and further cardiovascular defects. Conclusions These findings manage to provide further insight into JAB1 mediated BMPR-II down-regulation and degradation via the proteasomal pathway, and determination of JAB1 dysregulation and role in the aggressive mitogenic proliferation potential, through reduction of SMAD signalling and consequently p38 MAPK and TAK1 activation, observed in PAH cells. This study highlights the significance of this molecule in the vasculature and sets it as a potential novel target in PAH therapy, and for drugs against PASMC cells in pro-proliferating state harbouring or not BMPR2 PAH-associated mutations. Finally, it is established that haploinsufficiency of the NOTCH1 receptor is a primary cause of AOS, while solidifies NOTCH1 as an important genetic factor in AOS with associated cardiovascular complications. Further X-ray crystallography studies of the identified NOTCH1 missense mutations of the EGF-like domain will also elucidate the extend of the structural perturbation of the receptor and subsequent impairment of the signalling cascade. III ACKNOWLEDGEMENTS Firstly, I would like to thank to my former supervisors, Dr Rajiv D. Machado and Dr Laura Southgate, for their guidance and support throughout this research project. It was great to have the opportunity to work with you and gain my very first publication. Furthermore, I would like to express my immense gratitude to my supervisor Dr Stephen Bevan, for I have received the best advice possible to conclude and edit my experimental work. Special thanks goes to the Life Sciences department, past and present, especially Dr Timothy Bates, Dr Alan Goddard, Dr Ron Dixon and Dr Timea Palmai-Pallag for the friendly and help-insisted environment that created during the project. Also, thank you Maria, Tammy and James, and all the MSc students for it was great to share the lab with all of you. I am also extremely grateful for being one of the winners of 2014 Primerdesign Ltd. Gold sponsorship, funds that were well utilized for the accomplishment of significant novel results towards Adams-Oliver Syndrome disease. Also, I would like to thank my parents (Vasileios and Margarita), who have always encouraged me to achieve my dreams and been keen listeners to my progress. Nobody has been more important to me in the pursuit of this project than the members of my family, whose love and guidance are with me in whatever I pursue. Equally importantly, I wish to thank Demy, for giving me all the love and wisdom needed to overcome any obstacles during my PhD progress and think of the future’s unlimited perspectives. IV DECLARATION I herewith declare that I autonomously carried out the PhD thesis entitled “The Roles of JAB1 and NOTCH1 in the Development of Cardiovascular Disease”. The following third-party assistance has been enlisted: - • Where stated, work was conducted in King’s College London, as part of collaborative work within the Cardiovascular department of Life Sciences & Medicine at KCL and the School of Life Sciences at the University of Lincoln. I did not receive any assistance in return for payment by consulting agencies or any other person. No-one has received any kind of payment for direct or indirect assistance in correlation to the content of the submitted thesis. I conducted the project in the School of Life Sciences at the University of Lincoln. The thesis has not been submitted elsewhere for an exam, as thesis or for evaluation in a similar context. I hereby affirm the above statements to be complete and true to the best of my knowledge. Signature..................Anastasios S. Karountzos, MSc, MRSB V TABLE OF CONTENTS ABSTRACT ......................................................................................................... II ACKNOWLEDGEMENTS ................................................................................. IV DECLARATION ................................................................................................. V TABLE OF CONTENTS .................................................................................... VI TABLE OF TABLES .......................................................................................... XI TABLE OF FIGURES ........................................................................................ XI LIST OF ABBREVIATIONS ............................................................................ XIV CHAPTER 1: INTRODUCTION
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