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Inflammation-Associated Gene Regulation in Primary Astrocytes Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2008 Inflammation-associated gene egulationr in primary astrocytes, glial tumors and cellular differentiation Katarzyna Marta Wilczynska Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Biochemistry, Biophysics, and Structural Biology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/1113 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. © Katarzyna Marta Wilczynska 2008 All Rights Reserved INFLAMMATION-ASSOCIATED GENE REGULATION IN PRIMARY ASTROCYTES, GLIAL TUMORS AND CELLULAR DIFFERENTIATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. by KATARZYNA MARTA WILCZYNSKA M.Sc., Jagiellonian University, Poland, 2003 Director: TOMASZ KORDULA, Ph.D. Associate Professor, Department of Biochemistry and Molecular Biology Virginia Commonwealth University Richmond, Virginia May, 2008 ii Acknowledgements I would like to express my greatest gratitude to those whom I was lucky to meet on my path through life, and who have undeniably contributed to this huge endeavor for a doctoral degree. First of all, I would like to thank Dr. Aneta Kasza, my Master’s thesis mentor, who has encouraged me to pursue a scientific career towards a doctoral degree by showing me with her own example that one can have it all. It will be difficult for me to find the words to thank Tomek, my mentor and friend, who has guided me patiently throughout my graduate study to teach me everything he could about science and life, and who showed me how to enjoy one’s work and believe in oneself. It is him who has nurtured my need for scientific independence and has awakened my desire to discover. My special thank you goes to Sunita, Lauren and Magda for being awesome and supportive friends and creating an unforgettable atmosphere in the lab day by day. I would like to also thank my labmates: Sandeep, Silvina, Weilli, and Basia for collaborative work environment and help in demanding situations. I would like to also express my gratitude and owe for Dr. Sarah Spiegel, who has been a real inspiration and a role model in all aspects of life, and whom I will remember for ever. iii I would like to thank my graduate student committee members: Dr. Lloyd, Dr. Gil, and Dr. Rao, for their time and involvement to refine my scientific qualifications, and for being helpful and understanding in difficult situations. Especially, I feel deeply thankful to Carmen, who has been extremely supportive and motivating and whom I have always admired for the idealistic approach to life and science. Last, but not least I would like to thank cordially my dearest husband for his love and trust, without whom I would not be even writing this thesis, who has been extremely supportive, helpful and always there. I would like to also thank my dearest grandma, the most incredible woman I have ever met, who has loved me unconditionally, has always believed in me and encouraged me to take the challenges which I thought were beyond my reach. “Where There Is a Will There Is a Way” -grandma iv Table of Contents Page Acknowledgements............................................................................................................. ii List of Figures ................................................................................................................... ix List of Abbreviations ......................................................................................................... xi Abstract............................................................................................................................ xix Chapter 1 INTRODUCTION............................................................................................1 1.1. Inflammation in the brain.......................................................................1 1.2. Metalloproteinases and their inhibitors (MMPs/TIMPs). ......................2 1.3. TIMP-1 ...................................................................................................4 1.4. Alpha-1-antichymotrypsin (ACT)..........................................................8 1.5. Inteurleukin 1 (IL-1).............................................................................10 1.6. MAPK pathway....................................................................................12 1.7. Oncostatin M (OSM)............................................................................13 1.8. JAK/STAT pathway.............................................................................14 1.9. Inflammation in cancer.........................................................................16 1.10. Classification of neurological tumors.................................................17 1.11. Glioblastoma ......................................................................................19 1.12. STAT3 in GBM..................................................................................20 1.13. Oligodendroglioma.............................................................................21 v 1.14. Gliomagenesis ....................................................................................22 1.15. Differentiation of astrocytes...............................................................24 1.16. Nuclear Factor I..................................................................................26 2 A NOVEL MECHANISM OF TISSUE INHIBITOR OF METALLOPROTEINASES-1 ACTIVATION BY INTERLEUKIN-1 IN PRIMARY HUMAN ASTROCYTES................................................31 2.1. Abstract ................................................................................................31 2.2. Introduction ..........................................................................................33 2.3. Materials and Methods .........................................................................35 2.3.1. Cell culture. .................................................................................35 2.3.2. Cytokines and Cell Stimulation...................................................35 2.3.3 RNA Preparation and Northern Blot Analysis.............................36 2.3.4. Quantitative PCR.........................................................................36 2.3.5. Synthetic Oligonucleotides..........................................................36 2.3.6. Plasmid Construction ..................................................................38 2.3.7. Transient Transfections ...............................................................39 2.3.8. Down-regulation with siRNA .....................................................40 2.3.9. Nuclear Extract Preparation and EMSA .....................................40 2.3.10. Western Blotting........................................................................40 2.4. Results ..................................................................................................42 vi 2.4.1. Activation of TIMP-1 expression by IL-1 requires ongoing transcription and is mediated by multiple signaling cascades...............42 2.4.2. Identification of the IL-1 regulatory elements of the TIMP-1 gene. ......................................................................................................47 2.4.3. Identification of regulatory elements binding IL-1-induced factors. ...................................................................................................50 2.4.4. Critical role of p65 in regulating TIMP-1 gene expression.........54 2.4.5. TIMP-1 expression is not activated by IL-1 in many gliomas due to the aberrant activation of either NF-κB or ATF-2. ........................59 2.5. Discussion ............................................................................................64 3 CONSTITUTIVELY ACTIVE STAT3 PROMOTES THE GROWTH OF OLIGODENDROGLIOMA TUMORS............................................72 3.1. Abstract ................................................................................................72 3.2. Introduction ..........................................................................................74 3.3. Materials and Methods .........................................................................77 3.3.1. Cell Culture .................................................................................77 3.3.2. Clinical Samples..........................................................................77 3.3.3. Cytokines and Cell Stimulation...................................................78 3.3.4. RNA Preparation and Quantitative PCR.....................................78 3.3. 5. Plasmids and Transient or Stable Transfections.........................78 3.3.6. Western Blotting..........................................................................79 vii 3.3.7. Gene Knock-down by si RNA.....................................................80 3.3.8. Cell Proliferation Assay ..............................................................80 3.3.9. Lentiviral transductions of HOG cells.........................................81 3.4. Results ..................................................................................................83 3.4.1. Pro-inflammatory cytokines
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