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B21167564.Pdf Abstract Abstract The high mobility group protein HMGB1 is the most abundant non-histone chromosomal protein in mammals and has counterparts in all eukaryotes. It has long been known as an architectural transcription factor involved in gene activation as well as in other nuclear processes. More recently, HMGB1 has been found to have extra-cellular functions as a late mediator in immune response and also as a cytokine. We have been interested in how the human HMGB1 gene is regulated as well as how HMGB1 regulates other genes in the cell. In this study, an anti-sense strategy was used to suppress the HMGB1 expression level in the human breast cancer MCF-7 cell line. An MCF-7 cell line that expresses HMGB1 at only half the level of the original cell line was established. The expression profiles of these two cell lines were compared using cDNA microarray and the genes differentially expressed at a significant level were identified in these two cell lines. Among these genes, 96 were down regulated and 76 were up regulated in the HMGB1 suppressed MCF-7 cells. Real-time RT-PCR was also used to check the expression levels of some of the differentially expressed genes. Furthermore, these genes were classified into 11 functional groups including transcription factors, cell cycle related factors, apoptosis regulators, kinases and metabolism-related proteins, etc. The potential regulatory roles of HMGB1 on some of these groups were then discussed. In addition, to find out the possible interactions among these differentially expressed genes, Pathwayassist Software was used for analysis. It was found that the products of 16 of these differentially expressed genes fall into a complex network with p53 as the key node. The expression levels of the p53 and MDM2 genes were found to be II Abstract significantly lower in the HMGB1 down-regulated MCF-7 cells. This indicates the importance of HMGB1 in p53 expression and cell cycle checkpoint control. Based on the possible role of HMGB1 in the p53 network, investigattion on whether HMGB1 could regulate some potential downstream genes at the transcriptional level was carried out. An HMGB1 expression plasmid together with the p53, the MDM2 or the E2F1 promoter-containing reporter plasmid were co-transfected into the MCF-7, the HMGB1 suppressed MCF-7 and the p53-null human osteosarcoma Saos-2 cell lines to examine the transcriptional effects of exogenous HMGB1 on these promoters. In a parallel experiment, a p53 expression plasmid was also included to find out if the p53 protein may influence the regulatory effect of HMGB1 on these promoters. The luciferase assay results demonstrated that HMGB1 does not regulate the p53 promoter directly but may affect the expression of p53 via its regulation on the MDM2 and the E2F1 promoters. The action of HMGB1 on the MDM2 promoter is in a p53-dependent manner whereas its activation of the E2F1 promoter is p53-independent. Therefore, HMGB1 is an important regulatory factor in the p53-MDM2-E2F1 network. III Acknowledgments Acknowledgements I would like to take this chance to express my sincere gratitude to the following people for their invaluable support during my research and study in these three years. Firstly, I owe numerous thanks to my chief supervisor Dr. Kam-len Daniel Lee, for his patient guidance, invaluable advices and consistent encouragement throughout the entire project. As my supervisor, he has not only guided me on the rough but magnificent research way, but also supported me to explore my own thinking and trials during the whole time. My accomplishment of the Ph.D degree is directly attributed to his guidance. Moreover, his enthusiasm and devotion to science will guide me in my future research career. Then I would like to thank Dr. Tat-kan Robbie Chan, my co-supervisor, for his kind support to the experiments. I would also like to thank Dr. Pei Li for her important advice on the project. I wish to give special thanks to Dr. Meng-Su Yang for his generous support during the microarray experiments. I would also like to thank his research team, especially Chi-Hung Tzang and Qi Zhang, for their technical assistance. I also wish to thank Prof. Dr. A. K. Bosserhoff (University of Regensburg) for his kind gifts (the plasmids pAshmg1 and pcDNA3) and helpful advice and discussions on the stable cell line as well as Dr. J. M. Shohet (Baylor College of Medicine), Dr. W. D. Cress (University of South Florida), Dr. R. Fukunaga (Osaka University) and Dr. B. Vogelstein (Johns Hopkins University School of Medicine) IV Acknowledgments for their generous gifts (the plasmids MDM2-luc, E2F1-luc, p53-luc, PG13 and MG15, respectively) and helpful information. I would like to thank Dr. Hon-Kei Lum for his useful discussions during the project, the technicians of our department, especially Ms. Sarah Yeung, for their support in coordinating and facilitating the use of different equipments, my teammates, especially Dr. Lijun Li and Miss Yuen-Shan Siu, for their help in this project and all my friends for their assistance, encouragement and support throughout this project. I am very glad to have the chance to work with all my colleagues during these three years. I would also like to thank the Hong Kong Polytechnic University for granting me the research studentship for these three years and the American Society for Biochemistry and Molecular Biology for awarding me the Travel Award to present the results in the Experimental Biology 2006 meeting in San Francisco, April 2006. Finally, I would like to thank my family, especially my husband Ting Shao for their constant support and encouragement during my study. I would like to dedicate my thesis to them. V Contents Contents Certification of Originality........................................................................................ I Abstract ....................................................................................................................II Acknowledgements................................................................................................ IV Contents ................................................................................................................. VI List of Figures .......................................................................................................XII List of Tables....................................................................................................... XIV List of Appendices ................................................................................................XV List of Abbreviations........................................................................................... XVI Chapter 1 Introduction ............................................................................................. 1 1.1 The HMG Family .......................................................................................... 1 1.1.1 History of the HMG Proteins................................................................. 1 1.1.2 The HMG Proteins Classified by the Functional Motifs ....................... 1 1.2 The HMGB1 Protein ..................................................................................... 3 1.2.1 History of the HMGB1 Protein.............................................................. 3 1.2.2 The Human HMGB1 Gene.................................................................... 4 1.2.3 Structure of the HMGB1 Protein........................................................... 5 1.3 The Expression and Localization of HMGB1 ............................................... 7 1.3.1 Regulation of HMGB1 Expression........................................................ 7 1.3.2 Localization of HMGB1 ........................................................................ 9 1.4 Intracellular Functions of the HMGB1 Protein........................................... 10 1.4.1 Binding to DNA................................................................................... 10 1.4.2 Facilitating Nucleosome Remodeling.................................................. 13 1.4.3 Interacting with Other Transcription Factors....................................... 15 1.4.4 Promoting Enhanceosome Assembly .................................................. 18 VI Contents 1.4.5 Stimulating V(D)J Recombination ...................................................... 19 1.5 Extracellular Functions of the HMGB1 Protein.......................................... 20 1.5.1 Extracellular Release of HMGB1........................................................ 20 1.5.2 Multiple Receptors of HMGB1 ........................................................... 23 1.5.3 HMGB1 as a Cytokine......................................................................... 25 1.5.4 HMGB1 in Inflammation and Sepsis .................................................. 27 1.5.5 HMGB1 in Cell Proliferation and Migration....................................... 29 1.5.6 HMGB1 in Cell Differentiation........................................................... 30 1.5.7 HMGB1 in Tissue Repair .................................................................... 32 1.5.8 HMGB1 in Cancer............................................................................... 33 1.6 Outline of This Project ................................................................................ 34 Chapter 2 Establishment of an HMGB1 Down-Regulated MCF-7 Cell line......... 36 2.1 Introduction ................................................................................................. 36 2.2 Materials and Methodologies
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