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UC San Francisco Electronic Theses and Dissertations UCSF UC San Francisco Electronic Theses and Dissertations Title New Paradigms for eIF4E in Translating the Genome of Normal and Cancer Cells Permalink https://escholarship.org/uc/item/3b57j6f1 Author Truitt, Morgan Lee Publication Date 2014 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California New Paradigms for eIF4E in Translating the Genome of Normal and Canter Ceils ov Morgan Lee Train. DISSERTATION Subjoined in partial satisfaction of the requirements for the degree DOCTOR OF PHILOSOPHY ?n so the Copyright 2015 By Morgan Lee Truitt Page ii Acknowledgements First and foremost, I would like to thank my graduate advisor Dr. Davide Ruggero for his excellent support and guidance over the years. I joined Davide’s lab during my third year of graduate school after my original graduate advisor, Dough Hanahan, announced he would be taking a director position in Switzerland. Davide saw immense potential in me the first time we met and his enthusiasm and support has never wavered over the years. He has given me innumerable opportunities to grow and succeed as a scientist and any claims to future success in science I may have will be in no small part due to the time I spent under his guidance. Davide may not be aware of this but he has also been, along with Dr. Maria Barna, a great example that a relationship between two successful scientists cannot only survive the pressures of the scientific world but also help to drive each individual to even greater success. In that regard, I must add that it has been an immense pleasure getting to work with Dr. Maria Barna, a tremendous scientist who has been invaluable in helping to shape and direct my graduate project over the years. Although your graduate advisor is your primary scientific mentor, if you’re in the right environment, just as much of your mentoring comes from the people you are surrounded by in the lab, and I have been fortunate enough to be surrounded by a fantastic group of people in the Ruggero lab. They are all scientists of the highest caliber and have been my scientific sounding board throughout my graduate career. In particular I would like to acknowledge, Tom Cunningham and Craig Stumpf, who have always taken time out from their own scientific endeavors to give me feedback and guidance. In addition, I am grateful for the opportunities I have had to collaborate with Andrew Hsieh, Michael Pourdehnad, and Crystal Conn, each of whom has been incredibly rewarding to work with. Finally, I would like to thank the entire Ruggero lab, but in particular Adrian Contreras and Mary McMahon, for making the lab a fun place to be- there is no better cure than laughter for a failed experiment or generally crappy lab day. Page iii Graduate school has been a long and trying process, but as my original graduate advisor, Doug Hanahan, once told me- struggle is an inevitable part of doing science and it is important to learn how to deal with and overcome adversities if one wishes to become a successful scientist. Although the time I got to work with Doug was limited, I have the deepest respect for him as both a scientist and a mentor. He has steered an ever increasing and impressive list of people towards their own successful careers. I was very fortunate to work closely with one of those scientists, Dr. Neta Erez, a terrific colleague and an even better friend. She is an amazingly strong woman, who juggled a successful science career while basically single-handedly raising two beautiful children. I hope that one day I can be even half as efficient as she is and more importantly that I can always count her as one of my cherished friends. I must also thank the members of my thesis committee, Dr. William Weiss and Dr. Kevan Shokat, who have given me excellent feedback and scientific support over the years but must be somewhat relieved that I am finally graduating. I should also acknowledge the wonderful support crew that the BMS program has provided us, in particular Lisa Magargal and Monique Piazza who have been there for most of my graduate career to answer any question I may have and help fix any issue that arises. Although most of my time in graduate school may have been spent in the lab, some of the most memorable and important moments of the past years have occurred nowhere near a pipette. Indeed, I have always believed that in order to do your best science, sometimes you need to walk away from the bench and clear your head, and I have had a great group of friends in town to help me do just that. Whether skiing or backpacking with Kelley and Roko Kruze, surfing with David DeNardo, kayaking with my old roommate Ekuike Falorca, drinking great wine and beer with Dan Diephouse, venting to my classmate Michelle (Tofty) Graham, hanging out with my old friends from Medarex, or playing card games with Ali’s classmates, I have had an amazing support network outside of the lab that has helped to keep me grounded and motivated. Page iv I really must also thank my parents, Anne and Barry Truitt. In more ways than one, I wouldn’t be here without them. They have been excellent role models and fantastic parents. By exposing me to the natural beauty of the landscape where I grew up on the Eastern Shore of Virginia, they helped instill a scientific curiosity in me from an early age. They’ve also helped to nurture that curiosity throughout the years, supporting me in college and putting up with my prolonged graduate career on the opposite side of the country. I truly believe I get some of my best scientific attributes from them: my work ethic and persistence from my mom and my analytical and inquisitive nature from my dad. I hope that when I start my own family, which they are eagerly anticipating, I can live up to the example they have provided in raising me. Finally, I would like to thank my wife Alison Coady. Although I met her prior to this, the first time we really talked was at a New Year’s party. For two hours straight, while ignoring everyone else around us, I had one of the best conversations of my life. We’ve been together for seven years now and thankfully she’s still interested in talking to me. She is a great scientist in her own right and has just finished her PhD studies. It’s been amazing watching her grow as a scientist, while simultaneously helping me to grow both as a scientist and as a human being. I’m excited for the next steps of our careers and lives together and I can honestly say that I couldn’t ask for a more supportive, caring, and loving partner. Page v Contributions The Abstract, Chapter 2, and Chapter 4 are in part taken from a manuscript published in the Proceedings of the National Academy of Sciences of the United States of America. M. Pourdehnad and M.L. Truitt contributed equally to this work. M. Pourdehnad and M.L. Truitt designed and performed research, analyzed data, and wrote the manuscript. I.N. Siddiqi performed research, contributed new reagents/analytic tools, and analyzed the data. G.S. Ducker contributed new reagents/analytic tools. KM Shokat contributed new reagents/analytic tools and analyzed the data. D. Ruggero designed research, analyzed data, and wrote the manuscript. Pourdehnad M1, Truitt ML1, Siddiqi IN, Ducker GS, Shokat KM, Ruggero D. 2013. Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc Natl Acad Sci U S A. Chapter 1 is adapted from a review I co-authored with A.C. Hsieh and D. Ruggero published in the British Journal of Cancer. Hsieh AC, Truitt ML, Ruggero D. 2011. Oncogenic AKTivation of translation as a therapeutic target. Br J Cancer 105: 329–36. The Abstract, Chapter 3, and Chapter 4 are in part taken from a manuscript currently submitted for publication entitled “eIF4E dose is critical for the oncogenic translation program but not mammalian development and protein synthesis”. M.L. Truitt designed and performed research, analyzed data, and wrote the manuscript. C.S. Conn designed and performed research and analyzed data. Z. Shi analyzed data. X. pang designed new reagents. T. Tokuyasu analyzed data. M. Barna designed and performed research, analyzed data, and wrote the manuscript. D. Ruggero designed research, analyzed data, and wrote the manuscript. Truitt, ML, Conn CS, Shi Z, Pang X, Tokuyasu T, Barna M, Ruggero D. eIF4E dose is critical for the oncogenic translation program but not mammalian development and protein synthesis. (In submission). Page vi Abstract Although it was first observed nearly a century ago that transformed cells are marked by enlarged nucleoli, where ribosomal RNA synthesis and ribosome assembly occur, it has only recently become clear that deregulated protein synthesis plays a causal role in the development and progression of cancer. Indeed, aberrant mRNA translation has emerged as a hallmark of oncogenic transformation, underlying many cellular functions critical for tumorigenesis. Oncogenic signaling has been shown to enhance and alter the protein synthesis capacity of cancer cells to directly contribute to their survival, proliferation, metastasis, and genome instability. Therefore, inhibiting enhanced protein synthesis may represent a highly relevant strategy for the treatment of human cancers. For example, Myc is one of the most commonly deregulated oncogenes in human cancer, yet therapies directly targeting Myc hyperactivation are not presently available in the clinic.
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