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Characterization of a Tumour Suppressor Function of Ranbpm Western University Scholarship@Western Electronic Thesis and Dissertation Repository 11-22-2012 12:00 AM Characterization of a tumour suppressor function of RanBPM Elnaz Atabakhsh The University of Western Ontario Supervisor Dr. Caroline Schild-Poulter The University of Western Ontario Graduate Program in Biochemistry A thesis submitted in partial fulfillment of the equirr ements for the degree in Doctor of Philosophy © Elnaz Atabakhsh 2012 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Biochemistry Commons, Cancer Biology Commons, and the Molecular Biology Commons Recommended Citation Atabakhsh, Elnaz, "Characterization of a tumour suppressor function of RanBPM" (2012). Electronic Thesis and Dissertation Repository. 958. https://ir.lib.uwo.ca/etd/958 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. CHARACTERIZATION OF A TUMOUR SUPPRESSOR FUNCTION OF RANBPM (Spine Title: Characterization of a tumour suppressor function of RanBPM) (Thesis Format: Integrated Article) by Elnaz Atabakhsh Graduate Program in Biochemistry A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy The School of Graduate and Postdoctoral Studies The University of Western Ontario London, Ontario, Canada © Elnaz Atabakhsh 2012 THE UNIVERSITY OF WESTERN ONTARIO School of Graduate and Postdoctoral Studies CERTIFICATE OF EXAMINATION Supervisor Examiners ____________________________________________ ____________________________________________ Dr. Caroline Schild-Poulter Dr. Liliana Attisano Supervisory Committee ____________________________________________ Dr. Gabriel DiMattia ___________________________________________ Dr. Sean Cregan ____________________________________________ Dr. David Rodenhiser ____________________________________________ Dr. Fred Dick ____________________________________________ Dr. Lina Dagnino The thesis by Elnaz Atabakhsh entitled: Characterization of a tumour suppressor function of RanBPM is accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy _____________________________________ __________________________________________________ Date Chair of the Thesis Examination Board ii Abstract Ran-binding protein M (RanBPM) is an evolutionarily conserved nucleocytosolic protein that has been proposed to regulate various cellular processes, including protein stability, gene expression, receptor-mediated signalling pathways, cell adhesion, development, and apoptosis. Despite the multitude of functions attributed to RanBPM however, little is known regarding the precise mechanisms by which RanBPM executes these cellular roles. In this work, we seek to address this matter by describing functions for RanBPM in the regulation of apoptotic and pro-survival signalling pathways, and in cellular transformation. We first identify RanBPM as a pro-apoptotic protein that regulates the activation of the intrinsic apoptotic signalling pathway in response to DNA damage. We show that RanBPM executes its pro-apoptotic functions by modulating the expression and localization of Bcl-2 family proteins. Next, we demonstrate that RanBPM functions as a novel inhibitor of the ERK1/2 signalling cascade, and that RanBPM regulates the expression of Bcl-2 factors through repression of this pathway. We also extend these analyses to show that RanBPM forms a complex with c-Raf, and that it prevents aberrant ERK1/2 signalling by destabilizing the c-Raf-Hsp90 complex, thus maintaining low cellular c-Raf expression. Our studies also implicate an important function for RanBPM in the regulation of gene expression programs. We find that disruption of RanBPM expression affects transcriptional networks involved in the regulation of organism development and tumourigenesis, and that decreased RanBPM levels alter the expression of factors involved in signal transduction through the Notch, Wnt, PI3K, and ERK1/2 pathways. Importantly, our work also reveals that the down-regulation of RanBPM expression is associated with the acquisition of markers of cellular transformation, specifically evasion from apoptosis, sustained proliferative signalling, and increased cellular migration and invasion, suggesting a novel tumour suppressor function for RanBPM. Taken together, our studies provide insight into the molecular mechanisms by which may RanBPM mediate its diverse biological functions, and reveal that altered RanBPM expression may have important ramifications in the regulation of organism development and disease pathogenesis. iii Keywords: RanBPM, Bcl-2, ERK1/2, c-Raf, development, apoptosis, signalling, gene expression, cellular transformation, tumour suppression iv Co-authorship Statement The chapters of this thesis were written by Elnaz Atabakhsh and edited by Dr. Caroline Schild-Poulter. The data presented in chapter 2 contains portions of the published manuscript: RanBPM has pro-apoptotic activities that regulate cell death pathways in response to DNA damage. Elnaz Atabakhsh, Dawn M. Bryce, Karen J. Lefebvre, and Caroline Schild-Poulter. Mol Cancer Res (2009). In this chapter, the experiments in Figures 2.1 and 2.2 were performed by DMB and CSP. EA and CSP performed the experiments in Figure 2.3, and EA and DMB performed the experiments in Figure 2.4. The experiments presented in Figure 2.5 were performed by EA. The manuscript was written and edited by CSP. The data presented in chapter 3 have been published in the manuscript: RanBPM is a novel inhibitor of ERK signalling. Elnaz Atabakhsh and Caroline Schild-Poulter. PLoS One (2012). All experiments in this chapter were performed by EA. The manuscript was written and edited by EA and CSP. The data presented in chapter 4 have been published in the manuscript: RanBPM expression regulates transcriptional pathways involved in development and tumourigenesis. Elnaz Atabakhsh, Jean H. Wang, Xu Wang, David E. Carter, and Caroline Schild-Poulter. Am J Cancer Res (2012). In this chapter the probe preparation and GeneChip hybridization was performed by DEC at the London Regional Genomic Centre, and the experiments presented in Figure 4.2 were performed by JHW and XW. All other experiments, and data and bioinformatics analyses were performed by EA. The original draft of this manuscript was written by EA and edited by CSP. Revisions to the manuscript were made by EA based upon suggestions by CSP. v For Mamanie, Mahsheed, Dai Bahman and My grandparents Sakineh and Yadola vi "Twenty years from now you will be more disappointed by the things you didn’t do than by the ones you did do. So…explore, dream, discover." – Mark Twain vii Acknowledgements I want to start by thanking my supervisor, Dr. Caroline Schild-Poulter, for your support and guidance during the course of my degree. Your door has always been open to discuss any idea or problem, whether it was science-related or otherwise. Thank you for your advice, mentorship, and for helping me to become a keen and independent scientist. I am honoured to have trained under your supervision. To my advisory committee members, Dr. Sean Cregan and Dr. Fred Dick, thank you for your many helpful discussions regarding my research, and for your support and encouragement throughout the last five years. I sincerely appreciate everything that you have done for me. To past and present members of the Schild-Poulter Lab: Vicki, Louisa, Wesley, Sarah, Xu, Dawn, Jean, and our numerous undergrad students. Thank you for making our lab a great place to work. To Vicki and Louisa, especially: whether we were brainstorming science, laughing at one of my many "isms", or dealing with "ops" and "codes", everyday in the lab with you was great. I would also like to express my gratitude to Mrs. Marilynne Fuller for your continued and generous support of me and this project. As well, a major thank you to Jeff and Jeremy at Robarts IT for the countless times you helped me out of a computer disaster before I lost my mind, and the immense patience you've shown while helping me deal with my aversion to technology. On a personal note, I would like to first thank the most important people in my life, my loving family, for supporting me in everything that I do. To my mother Farzaneh, my sister Mahsheed, and my uncle Bahman: Your incredible strength, unwavering love, and constant encouragement have allowed me to always dream big and to become the person I am today. I cannot put into words how much you mean to me- thank you from the bottom of my heart! And finally, to the group of people who have made my time in grad school truly wonderful: Piya, Brad, Jake, Jess, Lazar, Chris, and Joey. The times spent with you laughing, talking about everything and nothing, celebrating the small victories, or ranting about the trials of science have meant more to me than I could ever express. You are the best friends anyone could ask for. viii List of Abbreviations AD Alzheimer's disease AP-1 Activating protein 1 APAF1 Apoptotic protease-activating factor 1 AR Androgen receptor ATM Ataxia telangiectasia mutated ATR ATM-related Aβ Amyloid β BAG1 Bcl-2 associated athanogene 1 Bcl-2 B-cell lymphoma 2 BH Bcl-2 homology CBF1 C promoter-binding factor 1 CDC37 Cell division cycle 37 (also called p50) CDK11p46 Cyclin-dependent kinase 11 p46 fragment CHIP Carboxy terminal of Hsp70-interacting protein CK1 Casein kinase
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