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Identification and Characterization of Downstream Effector Protein(S) Regulated by P53 and Prb Miranda B

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Identification and Characterization of Downstream Effector Protein(S) Regulated by P53 and Prb Miranda B Marshall University Marshall Digital Scholar Theses, Dissertations and Capstones 2014 Identification and characterization of downstream effector protein(s) regulated by p53 and pRb Miranda B. Carper [email protected] Follow this and additional works at: http://mds.marshall.edu/etd Part of the Biological Phenomena, Cell Phenomena, and Immunity Commons, and the Medical Cell Biology Commons Recommended Citation Carper, Miranda B., "Identification and characterization of downstream effector protein(s) regulated by p53 and pRb" (2014). Theses, Dissertations and Capstones. Paper 897. This Dissertation is brought to you for free and open access by Marshall Digital Scholar. It has been accepted for inclusion in Theses, Dissertations and Capstones by an authorized administrator of Marshall Digital Scholar. For more information, please contact [email protected]. IDENTIFICATION AND CHARACTERIZATION OF DOWNSTREAM EFFECTOR PROTEIN(S) REGULATED BY p53 AND pRb A dissertation submitted to the Graduate College of Marshall University In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences By Miranda B. Carper Approved by Pier Paolo Claudio, MD, PhD, Committee Chairperson Richard Niles, PhD W. Elaine Hardman, PhD Jagan Valluri, PhD Piyali Dasgupta, PhD Emine Koc, PhD Marshall University December, 2014 DEDICATION My thesis is dedicated to my father, Millard. He is the foundation in my life in which I gather my strength. Without his love, support, and encouraging words none of this would have been possible. ii ACKNOWLEDGMENTS “The mediocre teacher tells. The good teacher explains. The superior teacher demonstrates. The great teacher inspires.” ― William Arthur Ward I would like to first acknowledge my advisor and mentor Dr. Pier Paolo Claudio for his unrelenting faith in me. He is a great teacher who has inspired me with his enthusiasm and dedication to his work and his students. He has provided an inspirational voice or a kick in the behind when I needed it most and aided in the development of the skills I will need to be a successful researcher. I will be eternally grateful for his mentoring. I am fortunate to have the guidance of several faculty members who are great teachers that inspired me to think outside of the box. I want to express my gratitude to my committee members: Dr. Richard Niles, Dr. W. Elaine Hardman, Dr. Jagan Valluri, Dr. Piyali Dasgupta, and Dr. Emine Koc who have all imparted some of their knowledge and aided in my growth as a researcher. Without their guidance, I would still be banging my head against a wall. I would also like to thank the Marshall University Genomic Core members Dr. Don Primerano, Dr. James Denvir, and Dr. Goran Boskovic for their help in performing the RNA expression profiling and data analysis. Without their endeavors my project would not be in existence. I would like to also acknowledge the NASA WV Space Grant Consortium for funding my stipend. Without their support my research would not have been possible. My success would not have been possible without the help and support of fellow lab members and friends. I would like to acknowledge the current and past Claudio lab members: Dr. Flavia DeCarlo, Dr. Allison Wolf, Sarah Mathis, Rounak Nande, Benji Pyles, Colleen Conlon, and Dr. Ilaria Naldi for their support and patience. I want to give a special thanks to Drs. Flavia DeCarlo and Allison Wolf; these two wonderful women are an inspiration. Their inner strength, knowledge, and work ethic have inspired me to push through and overcome many iii hurdles. Without our impromptu problem solving sessions, I would have pulled out all of my hair a long time ago. I want to particularly thank Flavia for her patience in not only working with me but in also having to share a cubicle and an apartment with me. I am fortunate to have forged a strong life-time friendship. I would also like to thank the members of the McKown Translational Genomic Research Institute, Dr. Sarah Miles, Theodore Witte, and Dr. Johannes Fahrmann. These amazing individuals have provided advice, support or materials that I desperately needed. I particularly want to thank Theodore Witte and Dr. Fahrmann, I cannot count the times that I went to their lab seeking either one of their council. I want to send a special thanks to Maragaret McFarland whose hard work is greatly appreciated. Without her my work would have been ten times more difficult. I would also like to thank the biomedical sciences program faculty, staff and students. I would like to particularly acknowledge Dr. Todd Green and Diana Maue for their dedication to helping the students to succeed. And thank you to my fellow students especially Holly Tamski, who provided support or a distraction when needed. I would not be where I am today if it were not for my family. My graduate school journey has been a long, bumpy road, and my family has been the backseat drivers offering advice and support that helped me reach my destination. I particularly want to thank my brother Ryan, who always reminded me that I have a place when I was feeling blue and for finding ways to make me laugh. I am truly lucky to have a big brother like him who always looks out for me. I thank God each day for the time I have with him. I am proud of all that he has accomplished and I thank him for aspiring me to follow my dreams. I also want to thank my father, who has always been and always will be my greatest teacher. I would not have made it where I am today iv without his advice, support, love, and encouraging words. His unwavering faith in me has kept me going through many struggles. I would not be who I am today without him, he has always been my biggest supporter and I am proud to be his daughter. I would also like to thank the three amazing women who have inspired me to be a strong, independent woman. To my mother, I thank her for her encouraging words, love, and faith in me. My love of the life sciences stemmed from her passion and interest in learning. She has always encouraged me to learn and to explore the world around me. I am thankful for all that she has done. I would also like to acknowledge my stepmother Bonny and her family for their support, positive thoughts and prayers. They have truly opened their family to me and accepted me as their own. Their encouraging words and support has meant more than words can express. Lastly, I would like to acknowledge Vicki, who is like a mother to me, for her guidance and support. She has sent many cards, baked many cookies, and provided many hugs over the years to cheer me up while in grad school. I am truly lucky to have her in my life; her advice has been instrumental in keeping me grounded. I am extremely fortunate to have a great support system to help me reach my goals. v TABLE OF CONTENTS Dedication ....................................................................................................................... ii Acknowledgments .......................................................................................................... iii Table of Contents ........................................................................................................... vi List of Tables .................................................................................................................. ix List of Figures ................................................................................................................. x List of Abbreviations ..................................................................................................... xii Abstract ........................................................................................................................ xiv Chapter 1. ............................................................................................................................ 1 Introduction ..................................................................................................................... 1 Section 1.1: p53 and pRb collaborators in the fight against cancer ................................ 1 Background.................................................................................................................. 1 Brief overview of p53 function and regulation ........................................................... 1 Brief overview of pRb function and regulation ........................................................... 3 p53 and pRb cross-talk ................................................................................................ 6 Section 1.2. Pancreatic Cancer ...................................................................................... 12 Epidemiology and characterization ........................................................................... 12 Staging ....................................................................................................................... 13 Diagnosis and Treatment ........................................................................................... 15 Mutations and altered signaling pathways in pancreatic cancer ............................... 17 Epidermal Growth Factor (EGF) Signaling .............................................................. 20 Metastasis .................................................................................................................. 21 Section 1.3. RGS16: Expression, Regulation, and Function ......................................... 24 Background...............................................................................................................
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