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Analysis of Nkx3.1 Target Genes in Prostate Cancer

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Analysis of Nkx3.1 Target Genes in Prostate Cancer ANALYSIS OF NKX3.1 TARGET GENES IN PROSTATE CANCER By Ashish Popatrao Mogal Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Pathology August, 2007 Nashville, Tennessee Approved: Professor Fritz Parl Professor David Head Professor Pampee Young Professor Simon Hayward Professor Zu-Wen Sun To my parents, sisters and lovely wife for their enormous support, love and encouragement ii ACKNOWLEDGEMENTS First and foremost, I would like to thank my mentor, Dr. Sarki Abdulkadir. Dr. Abdulkadir has been a great mentor and I am really fortunate to have a mentor like him who has such a fascination and an enthusiasm for pathology. I am really grateful for the guidance, knowledge and support that I received from him both at the scientific and personal levels. I sincerely feel that he has provided me with a strong scientific foundation that will serve as my one of the greatest assets for my future endeavors. Secondly, I would like to thank the members of my dissertation committee, Dr. Fritz Parl, Dr. David Head, Dr. Pampee Young, Dr. Simon Hayward and Dr. Zu- Wen Sun for their excellent guidance, suggestions and insightful comments about my project throughout my training. I am very grateful for their enormous support and encouragement which really helped me in moving forward with such a challenging project. I would like to thank Dr. Philip Crooke from the Department of Mathematics, Vanderbilt University. Dr. Crooke is an excellent mathematician who has formulated a mathematical model based on our experimental observations. There are a number of present and past members of Abdulkadir lab that I would like to acknowledge for their help during my graduate career. I especially want to thank Riet van der Meer, without whom my numerous experiments would have never been so successful. I do respect her a lot and I am forever indebted to her for the precious assistance and support that she has provided to me. I want to thank Dr. Meejeon Roh who is a research instructor in the lab for the advice about science and iii life in general that I got from her at the various stages of my graduate studies. I would like to thank Jongchan Kim, a graduate student in the lab. Jongchan and I joined the lab at the same time and we have shared lots of moments of joy and disappointment together. Many times we have supported each other and I will always value our friendship. I want to thank Jie Wang, Sydika Banks and Erin Kristobak who are junior graduate students in our lab. I want to acknowledge Nadia Ehtesham our previous lab manager, Irina Doubinskaia our current lab manager and Karen Morris our secretary for their great help in ordering and other lab related matters. I would like to thank Nady Roodi and Chastity Bradley from Dr. Parl’s lab. I am especially indebted to Nady as I have borrowed so many priceless things from her. She has been extremely helpful and always given me nice suggestions to troubleshoot my experimental difficulties. I have developed a special bond with Riet and Nady that I will cherish forever and I will deeply miss them. Chas has been a wonderful fellow student and a great friend of mine. Last but not least, I would like to thank my wonderful family. Whoever I am today and whatever I have achieved so far is because of them. My parents serve as role models for me and I am very fortunate to have such a loving parents. My parents are always with me how far I may be from my family. I also want to thank my sisters Pankaja and Sujata for their unconditional love and support. I am so blessed to have sisters like them. One of the greatest accomplishments during my graduate career was my marriage. My wonderful wife Suvarna has kindly supported me during my studies. She has always been my biggest inspiration especially during the times of disappointments. I am truly blessed to share my rest of the life with such an amazing iv person. Finally, this work would not have been possible without financial support from grant CA94858 from the NCI (SAA). v TABLE OF CONTENTS DEDICATION.................................................................................................................... ii ACKNOWLEDGEMENTS............................................................................................... iii LIST OF TABLES............................................................................................................. ix LIST OF FIGURES .............................................................................................................x Chapter I. INTRODUCTION.....................................................................................................1 Prostate Cancer ....................................................................................................1 Epidemiology...............................................................................................1 Prostate anatomy and development .............................................................3 Molecular genetics of prostate cancer..........................................................7 Nkx3.1................................................................................................................10 Nkx subfamily of Homeobox proteins.......................................................10 Nkx3.1 gene structure ................................................................................12 Transcriptional activities of Nkx3.1 ..........................................................13 Nkx3.1 and androgen signaling .................................................................16 Nkx3.1 in prostate development ................................................................17 Nkx3.1 in prostate cancer ..........................................................................19 Haploinsufficiency.............................................................................................22 Definition and origin..................................................................................22 Haploinsufficiency and tumorigenesis.......................................................25 Haploinsufficiency and developmental syndromes ...................................29 Haploinsufficiency at the Nkx3.1 locus: Dosage sensitive, stochastic gene regulation..................................................................................30 Nkx3.1 regulates cell cycle exit.................................................................30 Dosage sensitivity of Nkx3.1 target genes.................................................32 Stochastic expression on Nkx3.1 target genes...........................................34 Model of Nkx3.1 haploinsufficiency .........................................................38 Noise (Stochasticity) in gene expression ..........................................................39 Definition ...................................................................................................39 Sources and measurement..........................................................................39 Noise analysis ............................................................................................40 Noise in biology.........................................................................................41 Significance................................................................................................42 Control of noise..........................................................................................43 Chromatin remodeling .......................................................................................45 Epigenetics.................................................................................................45 vi DNA methylation.......................................................................................46 Histone modifications ................................................................................48 Histone acetylation...................................................................49 Histone methylation.................................................................54 Histone phosphorylation ..........................................................55 Histone code hypothesis ............................................................................56 Hypothesis & rationale ......................................................................................58 Gaps in the knowledge...............................................................................58 Hypothesis..................................................................................................59 Rationale ....................................................................................................59 Specific aims..............................................................................................61 II. MATERIALS AND METHODS............................................................................62 ChIP Assays & Two-step ChIP Assays .............................................................62 Trichostatin A Preparation.................................................................................64 Prostate Explants & TSA Treatment..................................................................64 RNA isolation & Quantitative RT-PCR ............................................................65 Western Blot Analysis .......................................................................................66 Immunohistochemistry ......................................................................................67
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