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The Regulation of Musashi Rna Binding Proteins and the Implications for Cancer Therapy

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The Regulation of Musashi Rna Binding Proteins and the Implications for Cancer Therapy THE REGULATION OF MUSASHI RNA BINDING PROTEINS AND THE IMPLICATIONS FOR CANCER THERAPY By Copyright 2015 Amber Rae Smith Submitted to the Department of Molecular Biosciences and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. ________________________________ Chairperson: Liang Xu, M.D., Ph.D. ________________________________ Kristi L. Neufeld, Ph.D. ________________________________ Roberto De Guzman, Ph.D. ________________________________ Berl Oakley, Ph.D. ________________________________ Yoshi Azuma, Ph.D. ________________________________ Danny Welch, Ph.D. Date Defended: October 8, 2015 The Dissertation Committee for Amber R. Smith certifies that this is the approved version of the following dissertation: THE REGULATION OF MUSASHI RNA BINDING PROTEINS AND THE IMPLICATIONS FOR CANCER THERAPY ________________________________ Chairperson: Liang Xu, M.D., Ph.D. Date approved: October 22, 2015 ii Abstract: RNA-binding protein and stem cell regulator, Musashi-1 (MSI1) is overexpressed in a broad range of human cancers and associated with poor clinical outcome. MSI1 encourages tumorigenesis by promoting Notch and Wnt signaling, along with cell cycle progression. In vitro and in vivo data have demonstrated that MSI1 is an attractive therapeutic target. Accordingly, there is great interest in identifying and exploiting MSI1 regulating mechanisms as anti-cancer therapy. We successfully determined that non-coding RNA, miR-137, acts as a negative regulator of MSI1 by binding to the 3′UTR of MSI1 mRNA. Using numerous in vitro and in vivo studies, we show that miR-137 acts as a tumor suppressive miRNA in colon cancer, in part by inhibiting MSI1. To understand the clinical relevance of our observations, we measured the expression of miR-137 and MSI1 in tissue samples from patients with rectal cancer. miR-137 expression is decreased in approximately 84% of rectal tumor samples as compared to paired normal rectal mucosal samples. Inversely, MSI1 protein was found to be highly expressed in 79% of primary rectal tumors. In addition to this study, we show preliminary data that miR-137 also negatively regulates Musashi-2 (MSI2). We provide a comprehensive review on the expression of MSI1 and MSI2 in human cancers and correlate this expression with clinical outcome and evidence for MSI-induced malignancy. In addition to using noncoding RNAs to inhibit MSI1, we are also identifying small molecules that inhibit the RNA-binding function of MSI1. Our preliminary studies identified (−)-Gossypol, gossypolone and azaphilone-9 as potent MSI1 inhibitors using a fluorescence polarization-based screening of our in-house library of compounds. In this study, we validated and characterized iii the binding event between hit compounds and MSI1 RNA-binding domain 1 (RBD1) using nuclear magnetic resonance. In summary, we discovered two novel means of inhibiting the function of MSI1 in cancer, using miR-137 and small molecule inhibitors. Our study supports the idea of exploiting miRNAs and small molecules as novel cancer therapy targeting the RNA- binding protein, Musashi. iv Dedication I lovingly dedicate this work to my husband Joshua and our son, Ethan. v Acknowledgments To my mentor, Dr. Liang Xu, Thank you for your guidance and patience; for giving me space to think independently and the opportunities and resources to seek answers to my own questions. I appreciate that you constantly challenged me to think beyond the bench. You gave me so many opportunities to develop skills that are necessary for succeeding in this field; from exposure to grant writing to managing undergraduate students. I feel like I’m ready for the next stage in my career and it’s because of you. Also, thank you for encouraging a collaborative and friendly lab environment. I can honestly say that I loved walking into the lab every day. It’s something I will cherish forever. Thank you. To my comrade, friend and mentor, Dr. Rebecca Marquez, You have been my biggest encourager, teacher and supporter during graduate school. I will look back on my graduate school years with only fond memories, the majority spent with you. Thank you for pretending like you had time for my endless questions, for proofing abstracts and lending a hand when I needed help and guidance. I will forever be grateful for your friendship and mentorship. #AACRbuddiesforlife To Dr. Kristi Neufeld, A very wise woman once told me, “Every time you say yes to something, you’re saying no to something else. So choose carefully.” Thank you for always saying yes to me. Thank you for allowing me to spend countless moments in your office. I cherish your scientific, professional and personal advice. You have a way of challenging students and providing constructive criticism in a kind and positive demeanor. It’s a gift really and I’m grateful I was on the vi receiving end of it. I appreciate your encouragement and faith in me, even when I doubted myself. To Dr. Roberto De Guzman, Because of you, I am graduating with a Ph.D. You took a chance on a small town Kansas girl as an undergraduate student from Baker University. You provided a safe and friendly lab environment for me to test my scientific wings, with only encouragement when I failed. Your positive energy and natural curiosity for all things is contagious. I now love looking at protein structures because of you. Thank you for introducing a new world to me. Also, thank you for serving on my committee and always leaving your office door open for when I needed advice and guidance. To my friend and mentor, Dr. Fernando Estrada, As a graduate student, you mentored my first undergraduate research project over 6 years ago. It was during this time that I fell in love with science! I admire your scientific talents and exceptional ability to teach. Thank you for investing in me as a naïve undergraduate student. I appreciate your patience and willingness to teach a non-biochemistry student and turning her into a protein structure and function loving gal! Thank you for continuing to provide advice and encouragement. I sincerely appreciate your friendship and mentorship. To Dr. Danny Welch, I distinctly remember listening to your lecture for the first time. It was the most inspiring scientific talk I had ever heard. I appreciate your passion for cancer research and for mentoring scientists. I hope to follow in your footsteps someday. Thank you for asking challenging and vii intriguing questions, for always speaking the truth and for offering your opinion even when it’s the unpopular one. I am a better scientist because of you. Thank you for your willingness to help, to listen, to teach, and to encourage; all while managing your crazy schedule. To Dr. Yoshi Azuma, Thank you for serving on my committee and for providing advice and constructive criticism in regards to my project. I truly appreciate your input and admire your scientific ingenuity. To Dr. Berl Oakley, Thank you for always asking the hard questions; for challenging me and encouraging me to think outside of my research interest and knowledge. You are an exceptional scientist. Thank you for serving on my committee and for providing fresh perspective regarding my projects. To Chemical Biology Training Grant mentors; Dr. Audrey Lamb, Dr. Tom Prisinzano, Dr. Paul Hanson, Thank you for welcoming me into the training grant family. Although I was not a funded trainee, you made me feel like an important part of the group. Thank you for investing in my career development and taking an interest in my progress. You provided numerous opportunities to meet with amazing scientists in the field and paid for countless meals. Participating in the training grant activities provided me with valuable knowledge that I will cherish and utilize for the rest of my scientific career. Thank you. To Dr. Xiao-Feng Sun, Thank you for giving me the opportunity to study in your lab. I value the skills and knowledge I viii gained while training in your lab. Additionally, thank you to the Sun lab members for making the “American” feel so welcome. I will forever appreciate your kindness. To Dr. Lan Lan and Dr. Xiaoqing (Sarah) Wu, I feel so grateful to have had the opportunity to work with you in the Xu lab. Thank you for your friendship, for the constant encouragement and for your patience. I appreciate your willingness to offer technical advice and to lend a hand when I needed help. I will miss you both dearly. To the past and present members of the Xu lab, Thank you all for making the lab an enjoyable place to work. It has been my pleasure working with everyone. I will cherish our fun lab outings and the late nights in the lab rocking out to Beyoncé between experiments. We learned together, struggled together, laughed together and celebrated our accomplishments together. I feel as though we’re family. Thank you. To undergraduate students, Alexandria Roy and Bailey Wilkerson, One of the most enjoyable experiences of my graduate career was working with you girls. Thank you for your patience as I was learning how to mentor students. I am so proud of your many accomplishments. Your fresh enthusiasm about science was greatly appreciated and I think I learned just as much from you, as you did from me. Thank you for your hard work and dedication to our research projects. I’m looking forward to watching you both achieve great things! To David and Clara Smith, Thank you for welcoming me into your family and treating me as one of your own. I owe you ix both so much. Thank you for investing in my education, helping with home duties when I needed to study and for your constant voice of confidence in me.
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