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Regulation of the Retinoblastoma Tumor Suppressor by the Novel Ras Effector NORE1A. Thibaut François Barnoud University of Louisville

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Regulation of the Retinoblastoma Tumor Suppressor by the Novel Ras Effector NORE1A. Thibaut François Barnoud University of Louisville University of Louisville ThinkIR: The University of Louisville's Institutional Repository Electronic Theses and Dissertations 12-2015 Regulation of the retinoblastoma tumor suppressor by the novel Ras effector NORE1A. Thibaut François Barnoud University of Louisville Follow this and additional works at: https://ir.library.louisville.edu/etd Part of the Cancer Biology Commons Recommended Citation Barnoud, Thibaut François, "Regulation of the retinoblastoma tumor suppressor by the novel Ras effector NORE1A." (2015). Electronic Theses and Dissertations. Paper 2320. https://doi.org/10.18297/etd/2320 This Doctoral Dissertation is brought to you for free and open access by ThinkIR: The nivU ersity of Louisville's Institutional Repository. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of ThinkIR: The nivU ersity of Louisville's Institutional Repository. This title appears here courtesy of the author, who has retained all other copyrights. For more information, please contact [email protected]. REGULATION OF THE RETINOBLASTOMA TUMOR SUPPRESSOR BY THE NOVEL RAS EFFECTOR NORE1A By Thibaut François Barnoud B.A., University of Louisville, 2009 M.S., University of Louisville, 2013 A Dissertation Submitted to the Faculty of the School of Medicine of the University of Louisville in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Biochemistry and Molecular Genetics Department of Biochemistry and Molecular Genetics University of Louisville Louisville, KY December, 2015 Copyright 2015 by Thibaut François Barnoud All Rights Reserved REGULATION OF THE RETINOBLASTOMA TUMOR SUPPRESSOR BY THE NOVEL RAS EFFECTOR NORE1A By Thibaut François Barnoud B.A., University of Louisville, 2009 M.S., University of Louisville, 2013 A Dissertation Approved on November 9, 2015 by the following Dissertation Committee: ________________________________________ Dr. Geoffrey J. Clark, Dissertation Director ________________________________________ Dr. Howard Donninger, Committee Member ________________________________________ Dr. Marsha P. Cole, Committee Member ________________________________________ Dr. Christine Schaner Tooley, Committee Member ________________________________________ Dr. David Samuelson, Committee Member ii DEDICATION This dissertation is dedicated to my mother, Laurence Chanu Barnoud, the most beautiful person the world has seen. I love you, forever and always. iii ACKNOWLEDGEMENTS I would like to take this opportunity to thank all of those who played a role in the progression of this project as well as my growth and improvement as a scientist. First and foremost, I want to thank Dr. Geoffrey Clark for his efforts and perseverance throughout my entire graduate career. More importantly, I cannot thank him enough for his persistent efforts in helping me achieve my ultimate goal of obtaining a high caliber post-doctoral position. This was something I refused to compromise on, and Dr. Clark was pivotal in making that happen. I want to thank Dr. Howard Donninger, whose list for reasons why I am so grateful would most likely exceed the size of this dissertation. It must be noted that it was because of his vigorous drive and perseverance that I have developed the work ethic that I have today. In addition, he has engraved in me the valuable moral of always being humble, and that will be something that I carry with me throughout my scientific career. I must thank Dr. David Samuelson, Dr. Marcie Cole, and Dr. Christine Schaner Tooley for their support and encouragement, especially in 2015. I can honestly say that if it were not for these five people, I would have quit graduate school. It is only because of them that I was able to survive during the darkest days of my life, and come out on the other side a better, stronger man. I must thank all of the current lab members of the Geoffrey Clark lab, including Dr. Lee Schmidt and Jessica Mezzanotte Sharpe. Dr. Schmidt provided much needed guidance from the start of my graduate studies, but more importantly continuously iv provided guidance throughout the preparation of this dissertation, which allowed me to spend additional time in the laboratory, trying to accomplish my goal of publishing my work in a high impact factor journal. To Jessica: thank you for playing a pivotal role in maintaining laboratory homeostasis. More importantly, you have allowed me to enjoy one of the greatest rock and roll bands of all time, Queen. I must also thank my family for everything that they have instilled in me and for making me the person who I am today. To my brother, Benoit Barnoud, who taught me that the most important thing in life is family. To my father, Philippe Barnoud, who has told me over and over again that we must never, never give up. To my uncle, François Chanu, and my cousins Pauline, Alexandre, and Hadrien, who have provided me the courage and strength to fight the toughest battles life brings. And to the most important person of all, my mother, Laurence Chanu Barnoud, the most genuine, selfless, giving, loving, and caring person in my life. May everyone realize that the world is better place because of you. Mom, it’s never goodbye…it’s see you later. I must also thank in his own section the living legend Rex Ecarma, head coach of the University of Louisville Men’s Tennis team. Without a doubt, Coach Ecarma played the most pivotal role in molding me into the man that I have become today. He taught me the importance of respect, honesty, trust, perseverance, integrity, patience, courage, and loyalty. Coach became a father to me and words cannot describe how important he was in my growth as a tennis player and as a person. Don’t wish for it, work for it. Last but not least, I must thank the amazing Dr. Bill Dean. If it wasn’t for him, I would have never started graduate school. Though I have the tendency to fall off the face of the earth, I will never forget that my career as scientist started thanks to you. v ABSTRACT REGULATION OF THE RETINOBLASTOMA TUMOR SUPPRESSOR BY THE NOVEL RAS EFFECTOR NORE1A Thibaut François Barnoud November 9, 2015 Ras is the most frequently mutated oncogene in human cancers. It acts as a critical branch point in signal transduction, regulating numerous downstream effectors involved in cell growth and differentiation. While Ras has the capacity to activate many growth promoting pathways, it can paradoxically regulate growth inhibitory pathways leading to apoptosis and cell cycle arrest. One of the ways Ras can inhibit the growth of cells is via a family of effectors called the RASSF proteins. One of the members of this family, RASSF5, also known as Novel Ras Effector 1A (NORE1A), is a tumor suppressor that is frequently inactivated in human tumors by epigenetic mechanisms. NORE1A binds directly to Ras, and it promotes the growth inhibitory properties of Ras by activating a tumor suppressive function called oncogene induced senescence. We have recently shown in the laboratory that NORE1A serves as a senescence effector of Ras by activating the p53 tumor suppressor. However, knockdown of p53 using siRNA technology did not completely abrogate the ability of NORE1A to induce senescence, vi suggesting that there may be additional mechanisms by which NORE1A promotes senescence. The other well characterized pathway involved in Ras-induced senescence is the Rb pathway. Using immunoprecipitation techniques, we show that NORE1A forms an endogenous, Ras regulated complex with the Rb phosphatase PP1A, and that Ras/NORE1A promote the stability of the PP1A protein. Furthermore, our results show that NORE1A scaffolds PP1A to Rb in a Ras dependent manner, in turn promoting the dephosphorylation of Rb, a pro-senescent event. Using western blot analysis, we found that NORE1A can also regulate non-phosphorylation post-translational modifications of Rb, including its acetylation and SUMOylation. Using commercially available senescence detection kits, we found that loss of Rb significantly suppressed the ability of NORE1A to induce senescence in both murine and human systems. Collectively, our work strongly suggests that NORE1A is a double barreled Ras senescence node, explaining why Ras driven tumors often show loss of NORE1A expression. vii TABLE OF CONTENTS PAGE DEDICATION........................................................................................................... iii ACKNOWLEDGEMENTS....................................................................................... iv ABSTRACT............................................................................................................... vi LIST OF FIGURES................................................................................................... x CHAPTER I. BACKGROUND AND INTRODUCTION.................................................. 1 1.1. Overview............................................................................................ 1 1.2. The Ras Oncogene............................................................................. 5 1.2.1 The Discovery of Ras.............................................................5 1.2.2 Ras and Cancer...................................................................... 7 1.2.3 Regulation of Ras Activation................................................. 8 1.2.4 Post-Translational Modifications of Ras............................... 11 1.2.5 Growth Promoting Pathways of Ras...................................... 12 1.2.5.1 Raf/MEK/Erk Pathway.............................................
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