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Cprk and Rev-Erbβ THIOL-BASED REDOX MODULATION OF TRANSCRIPTIONAL REGULATORS; CprK AND Rev-erbβ By Nirupama Gupta A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Biological Chemistry) in the University of Michigan 2011 Doctoral Committee: Professor Stephen W. Ragsdale, Chair Professor Ruma V. Banerjee Associate Professor Jeffrey R. Martens Assistant Professor Patrick J. O'Brien Research Assistant Professor Jeanne Stuckey ACKNOWLEDGEMENTS No project can be described as a one-man show. It needs the close co-operation of friends, colleagues and the guidance of experts in the field, to achieve something worthwhile and substantial. In this context, I am privileged to have an opportunity to acknowledge the people who have provided enormous support throughout my graduate school in the last six and half years. I would like to extend my gratitude towards my mentor, my thesis committee, lab members, department administration, and my family. Without their support and encouragement, this dissertation would have not been possible. First and foremost, I would like to express my sincere thanks and gratitude to my advisor, Prof. Stephen Ragsdale, who has been a great mentor for both my professional and personal development. He was my mentor during my master’s program at the University of Nebraska-Lincoln and also my Ph.D program at the University of Michigan-Ann Arbor. The knowledge and experience I have acquired under his mentorship throughout these years is invaluable. His enthusiasm, encouragement and dedication towards science are unavoidable and kept me constantly motivated. His quest for science, endless patience and easily approachable qualities always welcomed an open discussion. He not only gave his precious guidance throughout my graduate studies, but always promoted my ideas and encouraged its pursuit. And this has resulted in my thesis; all of this work would not have been possible without his incredible mentorship and his faith in me. It was an honor for me to be his student.I have been fortunate to have Prof. Ruma Banerjee as one of my ii committee members during my Master’s studies at the University of Nebraska-Lincoln and Ph.D program at the University of Michigan-Ann Arbor. Her strong understanding and love for science is contagious and motivates others. Her faith and passion for science is a great inspiration for me. She never accepted less than my best efforts. Many of her brilliant ideas helped me moving forward smoothly in my research. I would also like to acknowledge and extend my heartfelt gratitude to other committee members, Dr. Jeffrey Martens, Dr. Patrick O’Brien and Dr. Jeanne Stuckey, who provided their support and insightful suggestions during yearly committee meetings or during individual meetings. I greatly appreciate the tremendous help, guidance and encouragement they have provided me over the years. I also would like to take this opportunity to thank Dr. Daniel Bochar who was initially a committee member but is no longer on my committee due to change in his job. He made available his support in a number of ways; He not only shared his expertise in mammalian cell culture but also provided me plasmids, instruments and other tools required to execute the experiments. I would like to thank the past and present members of Dr. Ragsdale’s laboratory, who provided a very friendly environment in the lab to work. Especially I am indebted to many of my colleagues for their selfless support, particularly, Li Yi, Elizabeth Pierce, Dr. Gunesh Bender, Dr. Yuzhen Zhou, Dr. Darek Sliwa, Andrea Morris, Dr. Joseph Darthy, Dr. Xianghui Li, Dr. Ireena Bagai, and Ali Bogart. Their endless support, understanding, cooperation and friendliness are truly appreciated. I would also like to show my gratitude to members of Dr. Banerjee’s lab, who helped me periodically especially Dr. Dominique Padovani, Dr. Carmen Gherasim, and Valentin Cracan. iii I would also like to thank the staff in the Department of Biological Chemistry, especially Beth, Julie and Prasanna. They are not only helpful with administrative work but have always provided their warm friendliness, which is priceless. Many thanks to the faculty members and the students in the Department of Biological Chemistry for providing me such a stimulating research environment. Last but not least, I would like to express my deepest gratitude to my family. Words can not express what I owe them. Their encouragement and patient love has enabled me to complete this dissertation. I dedicate my thesis to my mom who passed away during my Ph.D, but has left behind her love and blessings with me eternally. I would also like to dedicate my thesis to my son Aaryen who came into my family last year. He fills my life with love and joy everyday. Moreover, I am grateful to my father for his everlasting love and unconditional support since the beginning of my career. My acknowledgement would be incomplete without mentioning the unconditional love and unlimited support of my husband, Sanjay Garg. He not only has provided me great companionship at home but also guided and helped me in my research. Finally, I would like to thank each and everyone who has supported me directly or indirectly during my studies and whose best wishes have always seen me through ordeals. iv PREFACE Oxidative stress has been associated with a number of notorious diseases including Parkinson’s disease, cancer, and it exerts its effect on cellular machineries primarily via thiols which are very sensitive to oxidation due to their chemical nature. Thiol-based redox modulation of cellular functions is an emerging field of study and there are numerous examples of proteins whose activity has been shown to be under the control of cellular redox status. Transcriptional regulators are key targets of reactive oxygen species (ROS) under oxidative stress conditions due to the capability of transcription regulators to control the expression of various genes involved in redox processes. The last decade has witnessed the identification of many transcriptional regulators whose activity is controlled by ROS. The aim of this research was to gain knowledge on redox-modulation of two transcriptional regulators; CprK (Section I) and Rev-erbβ (Section II). Recognition of the molecular mechanism underlying the redox regulation and function of these transcriptional regulators is the main focus of this thesis. We focused primarily on the following three issues: 1) The identification of the redox-active cysteines, 2) determination of the type of modifications of the redox-sensitive cysteines upon oxidation and, 3) unraveling the downstream effects of oxidation of redox-active cysteines on the cellular function of these proteins. This thesis is composed of 7 chapters. The general introduction (chapter 1) describes our current understanding of thiol based v redox modulation of transcriptional regulators. Chapter 2 provides an introduction and prior knowledge about a bacterial transcriptional activator, CprK. Chapter 3 is a copy of the publication by Gupta N et al (Gupta N and Ragsdale SW. Dual roles of an essential cysteine residue in activity of a redox-regulated bacterial transcriptional activator. J Biol Chem. 2008 Oct 17;283(42):28721-8). In this chapter, Steve Ragsdale and I designed the experiments, interpreted the results and wrote the manuscript, and I performed the experiments. Chapter 4 is an introduction to the eukaryotic transcription regulator, Rev- erb, which is emerging as a key controller of many cellular functions. The contents of chapter 5 were published in the following paper: Gupta, N., and Ragsdale, SW. 2011. Thiol-disulfide redox dependence of heme binding and heme ligand switching in the nuclear hormone receptor, Rev-erbβ. J. Biol. Chem. 286(6):4392-403. Epub 2010 Dec 1. In this chapter, both authors contributed to the research design, data analysis and writing. I performed the experiments.Chapter 6 reports on the analysis of redox-dependent gas binding to Rev-erbβ. Chapter 7 describes ongoing work and potential future directions for the project. vi TABLE OF CONTENTS ACKOWLEDGEMENTS....................................................................................................ii PREFACE............................................................................................................................v LIST OF FIGURES...........................................................................................................xiii LIST OF TABLES............................................................................................................xvi LIST OF ABBREVIATIONS.........................................................................................xvii ABSTRACT...................................................................................................................xviii Chapter 1: General Introduction: Transcriptional regulators and their redox regulation...........................................................................................................................1 1.1 Transcriptional regulators..........................................................................................1 1.2 Thiol-based redox modulation of transcriptional regulators.................................2 1.2.1 Thiol-based redox-modulation..............................................................................2 1.2.2 Thiol-based redox switches...................................................................................5 1.3 References...................................................................................................................10
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