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Identification of Unique Gene Expression Profiles for Estrogen Recepotr Alpha Or Beta

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Identification of Unique Gene Expression Profiles for Estrogen Recepotr Alpha Or Beta IDENTIFICATION OF UNIQUE GENE EXPRESSION PROFILES FOR ESTROGEN RECEPTOR ALPHA OR BETA By AMY GALADRIEL BIBY HURST Bachelor of Science Oklahoma State University Stillwater, Oklahoma 2000 Submitted to the Faculty of the Graduate College of the Oklahoma State University in partial fulfillment of the requirements for the Degree of DOCTOR OF PHILOSOPHY May, 2005 IDENTIFICATION OF UNIQUE GENE EXPRESSION PROFILES FOR ESTROGEN RECEPTOR ALPHA OR BETA Dissertation Approved: Jerry R. Malayer Dissertation Advisor Rodney Geisert Jerry Ritchey Charlotte Ownby Udaya DeSilva A. Gordan Emslie Dean of Graduate College ii ACKNOWLEDGEMENTS I would like to extend my deepest gratitude to Dr. Jerry R. Malayer, who has been more than a major advisor to me – he has been a mentor. He has been a driving force and an inspiration for my pursuit of a scientific career. He has offered guidance when needed, but also had the wisdom to allow me to explore research avenues on my own, which has prepared me for my future independent career. I would also like to thank the members of my committee; Dr. Rodney Geisert, Dr. Jerry Ritchey, Dr. Charlotte Ownby, and Dr. Udaya DeSilva. Each, in their own way, has contributed unique viewpoints which have been vital to my success as a student, and which I will take with me into my future career as a scientist. Additionally, I would like to extend my thanks to Dr. Larry Claypool in the Statistics Department who was vital in the statistical analysis of Chapters IV and V. I would also like to thank the Center for Veterinary Health Sciences and the Department of Physiological Sciences for granting me the opportunity to pursue this degree. My thanks also goes out to all the members of our lab and the CVHS family who have provided such a tremendous support system since I started working with this group as an undergraduate in the spring of 1997. It goes without saying that it would take pages and pages to list all individuals who have helped me, but I would especially like to thank Vivienne Woods, and David Goad who provided great help at the beginning of my scientific career. I would also like to thank Leanne Weir who has been a great friend, iii whom I will never forget, as well as Lori VanDeventer, Mahesh Mohan, Akhilesh Ramachandran, T.R. Nagaraja, James Flinchbaugh, and the ‘guys’ from Dr. Geisert’s lab, Jason Ross and Morgan Ashworth, you have all made the time go so fast & the path enjoyable. Additionally, I would like to thank Ms. Betty Handlin for her expert technical assistance over the years. Last, but by no means least, I would like to thank my family whose love and support has been immeasurable in my pursuit of this degree. Thank you to my mother, Judy A. Biby, and father, Dennis K. Biby, whom I hope that I have made proud. I love you both. I would especially like to thank my husband, Travis Hurst, for being so supportive (it is almost over dear). To my son Tanner; you have been the impetus for all that I have strived to become, never forget that you can achieve anything you set your heart to and that family will always help you to do this - I love you. iv TABLE OF CONTENTS Thesis Approval ................................................................................................................ ii Acknowledgements .......................................................................................................... iii Table of Contents ...............................................................................................................v List of Tables ................................................................................................................... vii List of Figures.....................................................................................................................x Nomenclature ................................................................................................................ xvii Foreword.....................................................................................................................................................1 CHAPTER I INTRODUCTION OVERVIEW OF PROJECT...............................................................................................................................2 CHAPTER II LITERATURE REVIEW INTRODUCTION............................................................................................................................................6 TRANSCRIPTIONAL REGULATION AND THE NUCLEAR RECEPTOR SUPERFAMILY.........................................7 LIGAND INDUCIBILITY OF ESTROGEN RECEPTORS.....................................................................................10 ESTROGEN RECEPTOR DISTRIBUTION AND STRUCTURE ............................................................................15 ESTROGEN RECEPTOR TRANSCRIPTIONAL REGULATION ...........................................................................20 ROLE OF ESTROGEN RECEPTOR IN HEALTH AND HEALTH MAINTENANCE ................................................28 MODEL SYSTEMS FOR ESTROGEN RECEPTOR FUNCTION...........................................................................36 REFERENCE LIST .......................................................................................................................................44 CHAPTER III INDEPENDENT DOWNSTREAM GENE EXPRESSION PROFILES IN THE PRESENCE OF ESTROGEN RECEPTOR ALPHA OR BETA ABSTRACT.................................................................................................................................................59 INTRODUCTION..........................................................................................................................................60 MATERIALS AND METHODS.......................................................................................................................62 Cell Culture and Reporter Assay .........................................................................................................62 Detection of Unique Gene Expression.................................................................................................63 Analysis of Unique Gene Expression...................................................................................................64 RESULTS....................................................................................................................................................68 Verification of E2 stimulation...............................................................................................................68 Suppression Subtractive Hybridization................................................................................................69 Qualitative analysis of differential screening following SSH ..............................................................69 Quantitative RT-PCR analysis of target genes of interest identified through SSH..............................70 Semi-quantitative analysis of additional genes of interest using RT-PCR...........................................72 DISCUSSION...............................................................................................................................................72 REFERENCE LIST .......................................................................................................................................77 CHAPTER IV EFFECT OF LIGAND AND EXPOSURE TIME ON PROGESTERONE RECEPTOR GENE EXPRESSION IN THE PRESENCE OF ESTROGEN RECEPTOR ALPHA OR BETA v ABSTRACT...............................................................................................................................................102 INTRODUCTION........................................................................................................................................103 MATERIALS AND METHODS.....................................................................................................................105 Chemicals ..........................................................................................................................................105 Cell culture and ligand treatment......................................................................................................106 Quantitative Analysis of Gene Expression.........................................................................................107 RESULTS..................................................................................................................................................109 PR expression in the presence of synthetic DES................................................................................110 PR expression following treatment with the SERMs OHT and RAL..................................................111 PR expression after GEN treatment...................................................................................................111 DISCUSSION.............................................................................................................................................112 REFERENCE LIST .....................................................................................................................................117 CHAPTER V LIGAND AND TIME COURSE EFFECT ON RACK1, COL1A2, PCOLCE, AND CTSL GENE EXPRESSION IN THE PRESENCE OF ESTROGEN RECEPTOR ALPHA OR BETA ABSTRACT...............................................................................................................................................139 INTRODUCTION........................................................................................................................................140
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