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Transcriptional Regulation by Brn-3 POU Domain-Containing Transcription Factors

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Transcriptional Regulation by Brn-3 POU Domain-Containing Transcription Factors Transcriptional regulation by Brn-3 POU domain-containing transcription factors Jonathan Hancock Dennis A thesis submitted for the degree of Doctor of Philosophy Medical Molecular Biology Unit Department of Molecular Pathology University College London London January 2001 ProQuest Number: U644107 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U644107 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ABSTRACT Bm-3a and Bm-3b are closely related members of the POU domain-containing transcription factors. While Bm-3a is associated with neuronal differentiation and Bm- 3b with neuronal proliferation, their expression is not strictly limited to the nervous system. It has been shown that these Bm-3 proteins are expressed in non-neuronal tissues including cervical epithelium, testis and breast. Moreover, these Bm-3 proteins functionally interact with the estrogen receptor and in association with the estrogen receptor have differing transactivation potentials. The p i60 steroid receptor coactivators (Srcs) are also able to interact with the estrogen receptor in a ligand dependent manner and are able to enhance estrogen dependent transcription. This work describes a functional interaction between Bm-3 proteins and members of the steroid receptor coactivator family. In affinity chromatography and coimminoprecipitation experiments, Src-1 proteins were shown to physically interact with Bm-3a and Bm-3b. In addition, the transactivation potential of the Bm-3/Src complexes was tested on two promoters in three different cell lines. The steroid receptor coactivators potentiated the transcriptional effects of Bm-3 a and Bm-3b. The Src proteins, however, differed in their ability to potentiate the transcriptional activity of Bm- 3 proteins on different promoters in transiently transfected cells. In addition, maximal activation of the Bm-3/Src complex differed between cell lines, indicating that additional cell-type specific proteins are important for maximal activation by the complex. It has recently been shown that Bm-3b may play a role in regulating BRCA-1 in mammary tumors as its expression is enhanced in primary breast tumors with reduced BRCA-1 expression. Moreover, this elevated Bm-3b expression is not seen in normal mammary cells, benign tumors, or malignant tumors which do not have reduced levels of BRCA-1. This work also describes the effects of stable Bm-3b overexpression and reduction in the estrogen receptor positive breast adenocarcinoma cell line MCF7. Overexpression of Bm-3b resulted in increased growth rate, saturation density, proliferation, and ability to form anchorage independent colonies when compared to mock transfected cells. MCF7 cells with reduced Bm-3b levels exhibited a significant decrease in growth rate, saturation density, proliferation, and ability to form anchorage independent colonies when compared to mock transfected controls. Differential gene expression in these cell lines was examined using both specific western immunodetection as well as comprehensive DNA array technology. Immunodetection revealed increases in ER, HSP-27, and Bm-3 a in Bm-3b overexpressing cells as well as a decrease in these proteins in the Bm-3b reduced cell lines. The DNA array including 1200 cancer related genes revealed several genes differentially expressed when the Bm- 3b overexpressing and reduced cell line mRNAs were comj^ared. Finally, the results of three of the genes shown to be differentially regulated in the cDNA array differential display were corroborated by semi-quantitative RT-PCR. Dedicated to the memory of Paul B. Sigler (1934-2000) ACKNOWLEDGMENTS I would first like to thank Professor David S. Latchman for the opportunity to come to London and work in his laboratory. David’s broad base of knowledge, insight, practicality, efficiency, patience, optimism, and support have been invaluable over the past few years, and will continue to be characteristics I will work towards as I pursue my own career. I would also like to thank Dr. Vishwanie Budhram-Mahadeo for her guidance during this Ph.D. The work in this thesis stems from work she completed showing the relevance of Bm-3 proteins in estrogen responsiveness. In addition, I must extend my thanks to the members of the Bm-3 group, both past and present, who have always been generous with their time and expertise. In particular, I would like to thank Dr. Sally Dawson who advised and supervised me when I initially joined the laboratory. Several additional unmentioned individuals in the Windeyer Institute and The Institute of Child Health have helped with their assistance and friendship over the past four years.. .thank you. I would like to thank my family for their constant support and encouragement throughout this Ph.D. and the circuitous path that led to it. Finally, I would like to thank Marie Charrel for her daily encouragement, support, patience, and love that helped me keep everything in perspective. This work was supported by the Countess of Lisbume Medical Research Fellowship from the University College London Medical School, and an Overseas Research Studentship. LIST OF CONTENTS I General Introduction ....................................................................................................... 27 LI Transcription. ........................................................................................................... 27 1.1.1 Cellular communication results in the regulation of transcription ................... 27 1.1.2 Every cell contains the same set of genes ......................................................... 28 1.1.3 There are three types of RNA polymerase ........................................................ 28 1.1.4 Promoters, Enhancers, and UPEs control transcription. ................................... 29 1.1.4.A Promoters .................................................................................................. 29 1.1.4.B Upstream promoter elements .................................................................... 29 1.1.4.C Enhancers.................................................................................................. 29 1.1.4.D The beta-globin gene ................................................................................. 30 1.1.5 Gene specific promoter elements ...................................................................... 30 1.1.6 The five stages of transcription. ........................................................................ 31 1.1.6. A The formation of the pre-initiation complex..............................................31 1.1.6.A.a Stepwise assembly. ............................................................................. 31 l.l.ô.A.b The holo-RNA polymerase 11 complex...., ..........................................32 1.1.6.B The initiation of transcription and promoter clearance ............................. 32 1.1.6.C Transcript elongation and termination ................ 32 1.1.7 Gene specific transcription factors .................................................................... 33 1.1.7.A Gene-specific transcription factors have a modular structure ................... 33 1.1.8 Transcription factors have several different types of DNA-binding domain.... 34 1.1.8.A.a Helix-tum-helix .................................................................................. 34 1.1.8.A.b Zinc-finger ......................................................................................... 35 1.1.8.A.C Leucine zipper and basic DNA-binding domain ................................ 36 1.1.8.A.d Helix-loop-helix domain .................................................................... 37 1.1.8.A.e Other DNA-binding motifs ................................................................ 37 1.1.9 Activation and inhibition of gene transcription by transcription factors .......... 38 1.1.10 Chromatin remodeling by transcription factors .............................................. 38 1.1.11 Combinatorial regulation of transcription .......................................................39 1.2 The nuclear receptor superfamily. .......................................................................... 42 1.2.1 History. .............................................................................................................42 1.2.2 The general structural and functional domains of nuclear hormone receptors. 42 1.2.2.A Structural domains .................................................................................... 42 1.2.2.B Functional domains ................................................................................... 43 1.2.3 The members of the nuclear receptor superfamily. ........................................... 45 1.2.4 Class I, the steroid hormone receptors .............................................................. 46 1.2.4.A Description. ............................................................................................... 46 1.2.4.B The unliganded steroid nuclear receptor ..................................................
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