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The Roles of Atf3 in Stress-Regulated Signal Transduction

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The Roles of Atf3 in Stress-Regulated Signal Transduction THE ROLES OF ATF3 IN STRESS-REGULATED SIGNAL TRANSDUCTION AND CELL DEATH IN PANCREATIC BETA-CELLS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Matthew G. Hartman, B.S. * * * * * The Ohio State University 2005 Dissertation Committee: Approved by Dr. Tsonwin Hai, Advisor Dr. Gary Kociba Advisor Dr. James DeWille Molecular, Cellular and Developmental Biology Program Dr. John Oberdick ABSTRACT Currently there are 20 million people diagnosed with diabetes in the United States and the incidence is expected to increase by 42% over the next twenty years. Type 1, or insulin-dependent diabetes, is an autoimmune disorder characterized by infiltration of activated T-lymphocytes into the pancreas. Auto- reactive immune cells initiate β-cell destruction by several mechanisms including secretion of soluble factors (cytokines), direct cell-cell contact, and activation of osmotic lysis signals. Type 2, or insulin-independent diabetes, is characterized by insulin resistance in the peripheral tissues such as the liver, fat, and skeletal muscle. Phosphorylation of key substrates involved in the insulin signal transduction pathway by stress-activated protein kinases contributes to the insulin resistance and prevents the uptake of glucose from the blood. Recent reports suggest that type 2 diabetes is a slower progressing form of type 1 and that β-cell apoptosis contributes to the pathogenesis of both forms. Activating Transcription Factor 3 (ATF3) is a member of the ATF/CREB family of transcription factors which regulate gene expression through their ability to bind a common DNA sequence motif (TGACGTCA). Levels of endogenous ATF3 are extremely low in most tissues or cell types; however, ATF3 has been characterized as an immediate-early gene whose expression is ii up-regulated during the stress response. Prior to this work and during its undertaking several reports were published which describe the physiological outcomes of ATF3 expression during the stress response. These reports demonstrate a variety roles for ATF3 including protection from stress-induced apoptosis in neurons, promotion of apoptosis in endothelial cells, and enhancement of metastatic potential in colon cancer cells. In addition, transgenic mice which ectopically express ATF3 in endocrine precursor cells during development showed defects in pancreatic islet formation. Based on this information, we set out to investigate a potential role for ATF3 in the pathogenesis of diabetes by examining ATF3 expression and function in pancreatic β-cells. In chapter 2 we tested the hypothesis that ATF3 could be induced in pancreatic β-cells by stress signals relevant to type 1 or type 2 diabetes. Pro- inflammatory cytokines are secreted by infiltrating lymphocytes and act to promote β-cell apoptosis through their ability to up-regulate pro-apoptotic genes (iNOS) and down-regulate pro-survival genes (Bcl-2). We found that treatment of β-cell lines with IL-1β alone resulted in transient ATF3 induction, whereas treatment with IL-1β+TNF-α+IFN-γ showed sustained ATF3 expression. ATF3 expression was also found to be up-regulated in β-cell lines following exposure to free fatty acids, high glucose concentrations, or oxidative stress, which are relevant to type 2 diabetes. Investigation of signal transduction pathways involved in the induction of ATF3 by IL-1β revealed that both the JNK and NFκBpathways are required for optimal expression. Finally, we observed in iii vivo ATF3 expression in insulin-positive cells from a type 1 diabetic mouse model (NOD), as well as type 1 and 2 human patient pancreatic sections. In chapter 3, both gain-of-function and loss-of-function strategies were employed in order to test the functional significance of ATF3 expression in β- cells. Transgenic mice were generated using a PDX1 enhancer region that specifically targeted ATF3 expression to pancreatic β-cells. Ectopic ATF3 expression in insulin precursor cells during development resulted in decreased islet area at postnatal day 1 (P1), abnormal distribution of hormone-producing cells, and decreased body weight. ATF3 transgenic mice displayed several diabetic symptoms including low serum insulin levels, high glucagon levels, high blood glucose levels, and elevated ketone bodies. In order to test whether ATF3 expression is required for β-cell death following stress treatment, primary islets were purified from either ATF3+/+ or ATF3-/- mice. Partial protection from two cytokine (IL-1β+IFN-γ)-induced apoptosis was observed using ATF3-/- islets, suggesting that ATF3 induction is required for optimal cell death. In addition, ATF3 induction by nitric oxide (NO) is required for optimal levels of NO-induced β-cell death. Data presented in chapter 4 investigates the potential interaction between Akt activation and ATF3 induction and explores the functional relevance of this cross-talk. In this chapter, Akt activation is shown to block ATF3 induction following IL-1β treatment through its ability to inhibit JNK activation in β-cells. Based on this cross-talk, we hypothesized that one mechanism whereby Akt prevents β-cell death is by inhibiting expression of pro-apoptotic genes, such as iv ATF3. In support of this hypothesis, co-expression of ATF3 in β-cells significantly reversed the phenotype observed in the constitutively active Akt transgenic mice. Insights into the mechanism of ATF3-mediated killing revealed that ATF3 expression was sufficient to induce caspase-9 activation, suggesting that both ATF3 and Akt may affect cell survival at the level of the intrinsic (mitochondrial) cell death pathway. Work presented in this thesis implicates a novel role for ATF3 in stress- induced β-cell death and diabetes. Our lab is currently interested in gaining a mechanistic understanding of ATF3-induced β-cell death, including the identification of target genes and interacting proteins that are involved in this process. In addition, we are interested in investigating the roles of the intrinsic versus the extrinsic apoptotic pathways and the cell death machinery (caspases) in ATF3-dependent β-cell apoptosis. Based on this body of work, ATF3 represents a potential therapeutic target for the generation of inhibitors designed to enhance β-cell survival. v Dedicated to my family: George, Jane, Halea, and Tim vi ACKNOWLEDGMENTS I would like to thank my advisor Dr. Tsonwin Hai for the tireless dedication and encouragement she provided while training me to become a better scientist. I appreciate all those long friday lab meetings in which she challenged me to understand the logic and critical thought processes involved in scientific discovery. I also thank her for giving me the freedom to test my own ideas and hypothesis. I would also like to thank my committee members Dr. Gary Kociba, Dr. James DeWille, and Dr. John Oberdick for discussions and advice on my research. A special thanks to Dr. Kociba for providing pathology expertise in the critical analysis of pancreas tissue sections. I would like to thank current and past members of the Hai lab: Dr. Amy Allen-Jennings, Dr. Yoshida Okamoto, Jingchun Chen, Dan Lu, Dan Li, Xin Yin, Erik Zmuda, and Christopher Wolford. The fun and supportive atmosphere that they provided in the lab was greatly appreciated. I thank them for making me laugh, especially during those difficult lab days. I would like to give a special thanks to Matthew Duer for providing expert assistance in the maintenance, screening, and characterization of transgenic mice. vii I would like to give a special thanks to my parents. Without their unconditional love, support, and guidance my journey to become a scientist would not have been possible. They have provided me with an example of honesty and integrity, and their hard work and sacrifice over the years gives me the motivation to overcome any obstacle. I am extremely proud of my twin sister Halea and younger brother Tim. Their outgoing personalities and passion for living has provided me with many special memories throughout the years and I look forward to many more in the future. Finally, I would like to thank my wife Tiffiney for her love and support. You are my best friend and I look forward to many happy years of marriage in our future. viii VITA September 23, 1974…………………………Born – Princeton, NJ 1997……………………………………...B.S. Biology, University of Maryland 1998-present……………………………Graduate Teaching and Research Associate, The Ohio State University PUBLICATIONS 1. James L. Smith, Alicia E. Schaffner, Joseph K. Hofmeister, Matthew G. Hartman, Guo Wei, David A. Hume, and Michael C. Ostrowski. Ets-2 is a target for an Akt (PKB)/Jun N-terminal Kinase signaling pathway in macrophages of motheaten-viable mutant mice. Mol. Cell Biol. 2000 Nov; 20(21):8026-34. 2. Amy E. Allen-Jennings, Matthew G. Hartman, Gary J. Kociba, and Tsonwin Hai. The roles of ATF3 in glucose homeostasis: A transgenic mouse model with liver dysfunction and defects in endocrine pancreas. J Biol Chem. 2001 Aug 3; 276 (31):29507-14. 3. Matthew G. Hartman and Tsonwin Hai. The molecular biology and nomenclature of the ATF/CREB family of transcription factors: ATF proteins and homeostastis. Gene 2001 Jul 25;273(1):1-11 4. Amy E. Allen-Jennings, Matthew G. Hartman, Gary J. Kociba, and Tsonwin Hai. The roles of ATF3 in liver dysfunction and the regulation of phosphoenolpyruvate carboxykinase gene expression. J Biol Chem. 2002 May 31;277(22):20020-5. ix 5. Matthew G. Hartman, Mi-Lyan Kim, Dan Lu, Gary J. Kociba, Tala
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