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Role and Regulation of Autophagy During Developmental Cell Death in Drosophila Melanogaster: a Dissertation Kirsten M University of Massachusetts eM dical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 4-6-2015 Role and Regulation of Autophagy During Developmental Cell Death in Drosophila Melanogaster: A Dissertation Kirsten M. Tracy University of Massachusetts eM dical School Follow this and additional works at: http://escholarship.umassmed.edu/gsbs_diss Part of the Cancer Biology Commons, Cell Biology Commons, and the Cellular and Molecular Physiology Commons Recommended Citation Tracy, KM. Role and Regulation of Autophagy During Developmental Cell Death in Drosophila Melanogaster: A Dissertation. (2015). University of Massachusetts eM dical School. GSBS Dissertations and Theses. Paper 769. DOI: 10.13028/M2160H. http://escholarship.umassmed.edu/gsbs_diss/769 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. ROLE AND REGULATION OF AUTOPHAGY DURING DEVELOPMENTAL CELL DEATH IN DROSOPHILA MELANOGASTER A Dissertation Presented By Kirsten Mary Tracy Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY April 6, 2015 Cancer Biology ii ROLE AND REGULATION OF AUTOPHAGY DURING DEVELOPMENTAL CELL DEATH IN DROSOPHILA MELANOGASTER A Dissertation Presented By Kirsten Mary Tracy The signatures of the Dissertation Defense Committee signifies completion and approval as to the style and content of the Dissertation _______________________________________ Eric Baehrecke, Ph.D., Thesis Advisor _______________________________________ Marc Freeman, Ph.D., Member of Committee _______________________________________ Kimberly McCall, Ph.D., Member of Committee _______________________________________ Arthur Mercurio, Ph.D., Member of Committee _______________________________________ Mary Munson, Ph.D., Member of Committee The signature of the Chair of the Committee signifies that the written dissertation meets the requirements of the Dissertation Committee _______________________________________ Leslie Shaw, Ph.D., Chair of Committee The signature of the Dean of the Graduate School of Biomedical Sciences signifies that the student has met all graduation requirements of the school. _______________________________________ Anthony Carruthers, Ph.D. Dean of the Graduate School of Biomedical Sciences Cancer Biology April 6, 2015 iii Dedication This work is dedicated to Janice Nowak. iv Acknowledgements I would like to thank my mentor, Eric Baehrecke, for your guidance and encouragement throughout the years. Thank you for teaching me the importance of the big picture and how to focus on the critical questions. Thank you for your optimism and for always reminding me that science is fun. I would also like to thank my committee members, Leslie Shaw, Marc Freeman, Arthur Mercurio, and Mary Munson for challenging me and providing me with valuable insights and mentoring. Thank you to the past and present members of the Baehrecke lab. A special thank you to Christina Kary for your friendship and mentorship. Our coffee chats always help sort out problems in and out of the lab. Thank you to Gautam Das for your enthusiasm and positivity, Bhupendra Shravage for your advice, and Rachel Simin for teaching me the all-important histological sectioning. Thank you to Yakup Batlevi and Sudeshna Dutta for your knowledge. Thank you to Charles Nelson for your input, energy and beer knowledge, Kevin Chang for your advice and calming nature, and Lin Lin for your optimism and honesty. Thank you to Allyson Anding for your friendliness and advice, Johnna Doherty for your knowledge and sense of humor, Panos Velentzas for your help, and Shaowei Zhao for your input. Thank you to Chris Powers for your EM expertise. Julie Agapite, thank you for your kindness and laughter. Finally, thank you Tina Fortier for keeping the lab in order, baking all the delicious desserts, and being thoughtful and caring. Thank you to my friends for all the support you have provided and the fun times that we have shared. To the UMass crew, especially Leanne, Dan, Jeremy, Justine, and v Jeannette, we have grown together as scientists and people, and I am proud to call you colleagues and friends. To my soccer friends, thank you for making my time spent in Worcester more enjoyable and for reminding me that there is a world outside of science. Thank you to my family for your love and support. To my parents for raising me to be independent and for fostering my curiosity. To Dad for your endless optimism and always believing that the finish line would be about two and half years away. To Mom for everything you have done for us and for still being the first person I go to for advice. To Grandpa for sharing your fascinating stories and your passion for science. I would also like to thank my extended family and in-laws for your interest and teaching me how to communicate my work to non-scientists. To my son, Henryk, for bringing so much joy and wonder into our lives and for being my constant writing companion. Finally, I would like to thank my husband, Joe for your unwavering belief in my ability to accomplish this goal. Thank you for your remarkable patience and understanding, especially in this past year. I can’t wait to see what the next chapter holds for us. vi Abstract Autophagy is a conserved catabolic process that traffics cellular components to the lysosome for degradation. Autophagy is required for cell survival during nutrient restriction, but it has also been implicated in programmed cell death. It is associated with several diseases, including cancer. Cancer is a disease characterized by aberrant cell growth and proliferation. To support this growth, the tumor cell often deregulates several metabolic processes, including autophagy. Interestingly, autophagy plays paradoxical roles in tumorigenesis. It has been shown to be both tumor suppressive through cell death mechanisms and tumor promoting through its cytoprotective properties. However, the mechanisms regulating the balance between cell death and cell survival, as well as the metabolic consequences of disrupting this balance, are still poorly understood. Autophagy functions in both cell survival and cell death during the development of Drosophila melanogaster, making it an ideal model for studying autophagy in vivo. My research aimed to better understand the regulation and metabolic contribution of autophagy during cell death in Drosophila. I found that the Ral GTPase pathway, important to oncogenesis, regulates autophagy specifically during cell death in Drosophila larval salivary glands. Contrary to previous studies in mammalian cell culture, Ral is dispensable for autophagy induced during nutrient deprivation suggesting that Ral regulates autophagy in a context-dependent manner. This is the first in vivo evidence of Ral regulating autophagy. I found that disrupting autophagy has an extensive impact on an organism’s metabolism. Additionally, I found that autophagy in degrading tissues is crucial for maintaining the fly’s metabolic homeostasis, and that it may be vii important for resource allocation amongst tissues. This research highlights the importance of understanding how pathways regulate autophagy in different cell contexts and the metabolic outcomes of manipulating those pathways. This is especially important as we investigate which pathways to target therapeutically in an effort to harness autophagy to promote cell death rather than cell survival. viii Table of Contents Title i Signature Page ii Dedication iii Acknowledgements iv Abstract vi Table of Contents viii List of Tables x List of Figures x Preface xii Chapter I: Introduction 1 Autophagy 1 Regulatory pathways 3 Autophagosome formation 4 Autophagy and membrane trafficking 6 The Ral/exocyst effector complex and autophagy 7 Drosophila as a model for studying the interface between steroid signaling, nutrition and growth during development 15 Steroid signaling 15 Growth and nutrient utilization 19 Autophagy and Drosophila development 23 Autophagy in growth and nutrient utilization 24 Autophagy and cell death 29 Autophagy, Ral, and cancer 35 Outstanding questions 38 Chapter II: Ral GTPase and the Exocyst Regulate Autophagy in a Tissue- 41 Specific Manner Abstract 41 Introduction 42 ix Results 44 Ral and Rgl are required for salivary gland degradation 44 Ral is required for autophagy in dying salivary gland cells 52 The exocyst is required for autophagy associated with cell death, not 63 starvation-induced autophagy Discussion 74 Materials and Methods 76 Acknowledgements 80 Chapter III: Dying to Grow 81 Abstract 81 Introduction 82 Results 84 atg18-/- mutants have altered metabolite profiles 84 atg18-/- mutants have increased lactate levels 99 Tissue-specific autophagy inhibition affects whole animals lactate levels 105 Discussion 115 Materials and Methods 117 Acknowledgments 122 Chapter IV: Discussion 123 The role of Ral and the exocyst in salivary gland degradation 123 The role of Ral and the exocyst in starvation-induced autophagy 131 Autophagy and metabolism 136 Conclusions 142 Appendix 143 Bibliography 151 x List of Tables Table 3-1. List of significantly altered biochemicals and associated pathways in 87 atg18-/- animals. List of Figures Figure 1-1. Regulation of autophagy. 5 Figure 1-2. Schematic of small GTPases. 8 Figure 1-3.
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