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Role of Ets-2 Phosphorylation in Inflammation, Development and Cancer

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Role of Ets-2 Phosphorylation in Inflammation, Development and Cancer ROLE OF ETS-2 PHOSPHORYLATION IN INFLAMMATION, DEVELOPMENT AND CANCER DISSERTATION Presented in Partial Fulfillment of the Requirement for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Guo Wei, M.S. * * * * * The Ohio State University 2003 Dissertation Committee: Approved by: Dr. Michael C. Ostrowski, Adviser Dr. Lee F. Johnson ___________________________________ Adviser Dr. Gustavo Leone Department of Molecular Genetics Dr. Michael Weinstein ABSTRACT Ets family transcription factors are regulated by signal transduction pathways. Phosphorylation of the Ets-1 and Ets-2 at a single conserved threonine residue (T38 and T72, respectively) by ras-MAPK pathways leads to their activation and persistent target genes expression. The phosphorylation of Ets-2 affected its activity, as well as its protein partnership. Ets-2 interacted with Brg-1 or BS69 co-repressors in a phosphorylation dependent manner, and repressed target gene expression. Ets-2 knockout mice are embryonic lethal due to an extra-embryonic defect, whereas ets-2T72A/T72A mice are viable and fertile, with no obvious abnormality. Ets-2 is constitutively phosphorylated in macrophages derived from motheaten-viable (mev) mice, while its phosphorylation is tightly regulated in wt cells. The aberrant Ets-2 phosphorylation correlated with increased target gene expression and cell survival. To directly test the role of Ets-2 phosphorylation in inflammation, the ets-2T72A allele was introduced into mev mice. In contrast to ets2+/+, mev/mev mice, ets-2T72A/T72A, mev/mev mice were fertile, had increased life span and body weight, elevated macrophage apoptosis in the absence of CSF-1, but reduced inflammation and expression of inflammatory genes, including cytokines (TNFα), chemokines (MIP1α, β), extracellular matrix proteases (MMP9), cell adhesion molecule (integrin αM) in lungs and macrophages. ii Both ets-1-/- mice and Ets-2 T72A/T72A mice are viable and fertile. To reveal Ets-2 function possibly masked by gene redundancy, we mated ets-2T72A/T72A mice with Ets-1 knockout mice. Ets-1-/-, Ets-2T72A/T72A mice died between embryonic day 11.5 to 14.5, with dramatic angiogenesis and cardiovascular defects. Compared to control embryos, the double mutant embryos expressed lower levels of Ets target genes, such as Ang1, Tie2, MMP3, MMP9, and Fli-1, but elevated levels of VEGF. Therefore, Ets-2 phosphorylation is important in immune response, angiogenesis and cancer. To further explore the in vivo function of Ets-2, an ets-2 conditional knockout allele was developed. This allele is useful to address the cell antonymous function of Ets-2 in inflammation, angiogenesis and tumorgenesis (in tumor cells or stromal cells, including fibroblasts, macrophages and vessel cells) and other human diseases. Understanding how Ets-2 works these diseases may have important clinical implications, both for early diagnosis and developing of novel, effective therapy methods. iii DEDICATION This work is dedicated to my parents, to my wife Jianping Guo, and to my daughter Hope and son Abraham iv ACKNOWLEDGMENTS I wish to thank my adviser, Dr. Michael C. Ostrowski, for his guidance, support, advice, encouragement, patience and generosity throughout my graduate studies in OSU. I would like to thank the members of my committee, Dr. Lee F. Johnson, Dr. Gustavo Leone and Dr. Michael Weinstein, for their time, support, guidance and advice. I would also like to thank Dr. Thomas Rosol, Dr. Donna Kusewitt, Dr. Natarajan Muthusamy, Dr. Michael Robinson, Dr. Andrea Doseff, Dr. Nicanor Moldovan and Dr. Christoph Plass (The Ohio State University), Dr. Robert Oshima (The Burnham Institute) and Dave Hume (The University of Queensland) for their advice and help. I would also like to acknowledge the members of the Ostrowski lab, Department of Molecular Genetics for their friendship and stimulating discussions. This Research was supported by a grant from the National Institute of Health. I am grateful to my family and friends for their continuous understanding, encouragement and support. v VITA 1993 ………………………………………B.S. Biology, Shandong University 1996 ……………….………………..…….M.S. Plant Physiology, Chinese Academy of Sciences 1996-1998 ………………………………..Graduate Teaching Associate, Ohio University 1998-present …………………………….. Graduate Fellow, Teaching and Research Associate, The Ohio State University PUBLICATIONS 1. Wei, G., Schaffner, A. E., Baker, K. M., Mansky, K. C. and Ostrowski, M. C. (2003). "Ets-2 interacts with co-repressor BS69 to repress target gene expression." Anticancer Res 23(3A): 2173-8. 2. Baker, K. M.*, Wei, G.*, Schaffner, A. E. and Ostrowski, M. C. (2003). "Ets-2 and Components of Mammalian SWI/SNF Form a Repressor Complex That Negatively Regulates the BRCA1 Promoter." J. Biol. Chem. 278(20): 17876-17884. *Equal contribution. 3. Smith, J. L., Schaffner, A. E., Hofmeister, J. K., Hartman, M., Wei, G., Forsthoefel, D., Hume, D. A. and Ostrowski, M. C. (2000). Ets-2 Is a Target for an Akt (Protein Kinase B)/Jun N-Terminal Kinase Signaling Pathway in Macrophages of motheaten-viable Mutant Mice." Mol. Cell. Biol. 20(21): 8026-8034. vi 4. Wei, G., Shan, X., Ding, Q., Liu, B. and Jing, Y.: Transgenic rice plants with Parasponia haemoglobin gene and its expression. In KA Malik, MS Mirza and JK Ladha (eds.), Nitrogen Fixation with Non-Legumes. Kluwer Academic Publishers, Dordrecht, Netherlands,1998, pp. 125-131. 5. Zhao, S., Su,Y., Wei, G.: High Efficient Transformation of Escherichia coli by Electroporation. In Scientific Research Progress in Shandong Province. Science and technology Press of China, Beijing, 1993 pp. 839-845. FIELDS OF STUDY Major Field: Molecular Genetics vii TABLE OF CONTENTS Page ABSTRACT....................................................................................................................... ii DEDICATION.................................................................................................................. iv ACKNOWLEDGMENTS ................................................................................................ v VITA.................................................................................................................................. vi LIST OF FIGURES ........................................................................................................ xii LIST OF TABLES ......................................................................................................... xiv LIST OF ABBREVIATIONS ........................................................................................ xv CHAPTER 1 INTRODUCTION..................................................................................... 1 1.1. ETS FAMILY TRANSCRIPTION FACTORS...................................................................... 3 1.1.1. The Ets domain. ................................................................................................ 6 1.1.2. The Pointed domain. ....................................................................................... 11 1.2. BIOLOGICAL ROLES OF ETS PROTEINS. .................................................................... 16 1.2.1 Ets factors in embryonic development............................................................. 16 1.2.2. Ets proteins and cancer. .................................................................................. 22 1.2.3. Ets Target Genes............................................................................................. 24 1.3. REGULATIONS OF ETS PROTEINS ACTIVITY AND SPECIFICITY. ................................. 27 1.3.1 Tissue specific expression of Ets family members.......................................... 27 1.3.2. DNA binding................................................................................................... 35 1.3.3.Protein partners of Ets family members........................................................... 37 1.3.4. Signal transduction and post-translational modification of Ets family members.................................................................................................................... 39 1.4 ETS-2 AND RAS SIGNALING...................................................................................... 41 1.4.1 Ras and Ras signaling. ..................................................................................... 41 1.4.2 Persistent activation of Ets-1 and Ets-2 through phosphorylation by Ras- MAPK pathway. ....................................................................................................... 43 CHAPTER 2 MATERIALS AND METHODS............................................................ 49 2.1 PLASMIDS AND DNA MANIPULATIONS. ................................................................... 49 2.1.1 Plasmids. .......................................................................................................... 49 2.1.2. Plasmid miniprep and maxiprep. .................................................................... 50 2.1.3. Colony lifts...................................................................................................... 51 2.1.4. DNA cloning................................................................................................... 52 2.1.5. High molecular weight genomic DNA isolation and purification.................. 54 viii 2.1.6. ES cell DNA extraction. ................................................................................. 54 2.1.7. Polymerase chain reaction (PCR) ..................................................................
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