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Characterization of the ING1 Candidate Tumor Suppressor Gene in Breast Cancer Cells

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Characterization of the ING1 Candidate Tumor Suppressor Gene in Breast Cancer Cells University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies Legacy Theses 2001 Characterization of the ING1 candidate tumor suppressor gene in breast cancer cells Nelson, Rebecca Nelson, R. (2001). Characterization of the ING1 candidate tumor suppressor gene in breast cancer cells (Unpublished master's thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/11964 http://hdl.handle.net/1880/41031 master thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca The author of this thesis has granted the University of Calgary a non-exclusive license to reproduce and distribute copies of this thesis to users of the University of Calgary Archives. Copyright remains with the author. Theses and dissertations available in the University of Calgary Institutional Repository are solely for the purpose of private study and research. They may not be copied or reproduced, except as permitted by copyright laws, without written authority of the copyright owner. Any commercial use or publication is strictly prohibited. The original Partial Copyright License attesting to these terms and signed by the author of this thesis may be found in the original print version of the thesis, held by the University of Calgary Archives. The thesis approval page signed by the examining committee may also be found in the original print version of the thesis held in the University of Calgary Archives. Please contact the University of Calgary Archives for further information, E-mail: [email protected] Telephone: (403) 220-7271 Website: http://www.ucalgary.ca/archives/ UNIVERSITY OF CALGARY Characterization of the ING1 Candidate Tumor Suppressor Gene in Breast Cancer Cells by Rebecca Nelson A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE DEPARTMENT OF BIOCHEMISTRY AND MOLECULAR BIOLOGY CALGARY, ALBERTA AUGUST, 2001 © Rebecca Nelson 2001 Abstract The nuclear proteins encoded by the ING1 candidate tumor suppressor gene have been suggested to play a role in apoptosis, cellular growth, DNA repair, chromatin remodeling and senescence. Aberrant expression of specific ING1 proteins has been observed in several different cancers and cancer cell lines, including those from breast, blood, and head and neck. Here, the role of the ING1 gene in breast cancer cells has been examined through cDNA microarray experiments. In response to overexpression of ING1b and ING1c proteins, we observed changes in expression of many other genes, including the downregulation of ribosomal proteins and cell structural proteins, and the upregulation of PCNA, a protein known to interact with ING1b under conditions of UV-induced DNA damage. Taken together, these results propose new mechanisms for ING1 involvement in DNA repair and chromatin remodeling, and suggest that ING1 proteins may participate in a new type of cellular stress response. iii Acknowledgements The work that went into this thesis would not have been possible without the help and guidance of many people. Firstly, I would like to acknowledge my supervisor, Dr. Karl Riabowol, for his patience, advice and support over the past three years. I would especially like to thank Dr. Doug Demetrick, one of my committee members, who not only provided me with wonderful resources and suggestions, but also with insight and guidance. Additionally, I would like to thank the other members of my committee, Dr. Julie Deans, and Dr. Peter Forsyth, for all of their support, helpful comments and suggestions, as well as Dr. Randy Johnston, who provided generous advice and encouragement. Thank you so much to all of the Riabowol lab members, including Michelle Scott, Paul Bonnefin, Phil Berardi, Diego Vierya, Jason Quarrie, Keith Wheaton, Denise Lawless, Paula Hettiaratchi, Parneet Cheema, Kyle Mackenzie, Yasuo Hara, Donna Boland, Vanessa Berezovski, Brad Unryn, Xiao Lan Feng and Lana Pastyryeva, for everything from work to play. Additionally, I would like to thank Dr. Sabita Murthy for her amazing help and patience with all of the microarray experiments, as well as members of the Demetrick and Forsyth labs, for their kindness and assistance. Outside of the lab, many friends have helped me enjoy my time in the city and in the mountains. A special thanks to my girls - Jen, Sue, Milena, Shanlee, Brenda, Tara and Tracy, for keeping me on track! Thanks also to Scott, Kosta, Greg, Eric, Duncan, JB, Tim, Peter, Heather, Carolyn and Knutforall of the ski trips, hikes, crazy parties and coffee breaks. Don't know what I'd have done without you! Last but not least, I would like to thank those other members of the Cancer Biology Research Group at the University of Calgary, who made my work possible. Many people have given me moral support, guidance and insight over the years, and I am grateful for your kindness. iv Dedication This thesis is dedicated to my little sister Amy, and to my mom Lynne and dad Paul, for helping me to climb mountains and reach for the stars. I wouldn't be where I am without you. V TABLE OF CONTENTS Approval Page ii Abstract iii Acknowledgements iv Dedication v Table of Contents vi List of Tables ix List of Figures x List of Abbreviations xi CHAPTER 1: INTRODUCTION 1 Breast Cancer and Tumor Suppressor Genes 2 Identification of the ING1 Gene 3 ING1 and Cancer 4 Structure of the ING1 Gene 6 ING1 Homologous Gene 6 ING1 Protein Motifs 8 Functions of the ING1 Gene 8 a) Apoptosis and DNA Repair 8 b) Cellular Growth and Senescence 10 c) Chromatin Remodeling 11 d) Cell Cycle Control 13 Research Hypothesis 14 CHAPTER 2: MATERIALS AND METHODS 18 Cell Culture Procedures 19 Animal Procedures 21 Generation of stably integrated inducible cell lines 22 Amplification and Manipulation of DNA 25 Protein analysis by quantitation, gel electrophoresis and western 28 Magnetic cell separation techniques 30 cDNA Microarray Techniques 31 CHAPTER 3: RESULTS 39 vi Part 1: The ecdysone inducible vector system 40 The ecdysone-inducible vector system is appropriate 41 ING1b sense, ING1b antisense, ING1a sense and p53 sense cDNAs can be cloned into the pIND inducible vector 42 Parental breast cancer cell lines are sensitive to antibiotics 42 Transiently transfected breast cancer cells can be induced to overexpress ING1b 43 Increasing levels of gene expression correspond with increasing levels of Muristerone A inducing agent 43 Stably integrated pVgRXR clones can be induced to overexpress pIND/LacZ 44 Stably integrated pVgRXR clones can overexpress plND/ING1b 45 Dual stable integrants are capable of overexpressing high levels of ING1b in initial immunofluorescence assays 45 Dual stable integrants are not capable of expressing high levels of protein upon induction with hormones 46 Single-cell subcloning of initially clonal population does not restore inducibility of the C5 ING1b clone 47 ING1b C5 stable clone is not inducible when either pVgRXR or plND/ING1b vectors alone are transfected in 47 Inducible transgene cannot be amplified in ING1b C5 stable clone, while antibiotic resistance in culture is still retained 48 PART 2: The murine mammary fatpad model is used to study human breast cancer growth and metastasis 49 Equivalent human breast tumors can be established 50 MDA MB 468 mammary fatpad tumors do not metastasize to the lung or contralateral fatpad tissue in a SCID mouse model 51 PART 3: Overexpression of the ING1b and ING1c gene isoforms result in upregulation and downregulation of other genes, as shown by cDNA microarray 52 Transiently transfected breast cancer cells express H-2Kk 54 Transfected cells purified on the MACs column overexpress ING1b and ING1c proteins 55 Total RNA can be isolated from MACs purified cells without significant degradation 55 Overexpression of ING1b and ING1c genes leads to the upregulation and downregulation of various genes in three different breast cancer cell lines 56 a) Fluorescent intensity ratios for each gene on the microarray slide are generated 56 b) Generation of Log-Transformed Intensity Ratios for Genes that are Unidirectionally Expressed 57 c) Cluster and Treeview Analysis of Gene Arrays 58 d) Significance Analysis of Microarrays 60 vii CHAPTER 4: DISCUSSION 101 Part I: The ecdysone-inducible vector system is effective for obtaining high levels of expression in transient assays 102 The Efficacy of Ecdysone-inducible Vector System for Generation of Transient and Stable Cell Lines 102 Cells transfected with ING1 antisense constructs do not consistently show decreases in ING1b levels 103 The ecdysone system is effective for generating stable pVgRXR clones in several breast cancer cell lines 104 Optimization of Conditions for C5 Induction and Expression Experiments are Inconclusive 106 Original C5 clone ceases to overexpress ING1b after several weeks in culture due to loss of transgene 107 PART II: The Murine Mammary Fatpad Model is Effective for generating human breast cancer tumors in SCID mice 110 PART III: The Role of INGIon transcription in breast cancer cells 111 The Origins of the cDNA Microarray 111 The ING1 cDNA Microarray 113 Upregulation of PCNA and MeiS2 115 Upregulation of signaling pathways 116 Upregulation of Receptors and Growth Factors 116 Upregulation of Enzymes and Cytochrome C 117 Downregulation of Proteins involved in RNA and Protein Synthesis 118 Downregulation of cell structural components and related proteins 119 Downregulation of the p53 tumor suppressor gene 121 Downregulation of c-Myb and A-Myb 123 Downregulation of the Rb-family pocket protein p107 125 Other downregulated genes of potential importance 126 Conclusions and Perspectives 127 Do ING1b and ING1c isoforms exert different effects? 127 Limtations of the cDNA Microarray Procedure 128 CHAPTER 5: BIBLIOGRAPHY 131 Appendix A: Buffer Solutions 148 Appendix B: Structures of antibiotics used for selection 151 viii LIST OF TABLES Table 1.
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