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Proquest Dissertations University of Alberta Function and regulation of the FOXC transcription factors by Lijia Huang A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medical Sciences Medical Genetics ©Lijia Huang Fall 2009 Edmonton, Alberta Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission. Library and Archives Bibliotheque et 1*1 Canada Archives Canada Published Heritage Direction du Branch Patrimoine de I'edition 395 Wellington Street 395, rue Wellington OttawaONK1A0N4 Ottawa ON K1A 0N4 Canada Canada Your file Votre ref6rence ISBN: 978-0-494-55816-4 Our file Notre reference ISBN: 978-0-494-55816-4 NOTICE: AVIS: The author has granted a non­ L'auteur a accorde une licence non exclusive exclusive license allowing Library and permettant a la Bibliotheque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par telecommunication ou par I'lntemet, preter, telecommunication or on the Internet, distribuer et vendre des theses partout dans le loan, distribute and sell theses monde, a des fins commerciales ou autres, sur worldwide, for commercial or non­ support microforme, papier, electronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriete du droit d'auteur ownership and moral rights in this et des droits moraux qui protege cette these. Ni thesis. Neither the thesis nor la these ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent etre imprimes ou autrement printed or otherwise reproduced reproduits sans son autorisation. without the author's permission. In compliance with the Canadian Conformement a la loi canadienne sur la Privacy Act some supporting forms protection de la vie privee, quelques may have been removed from this formulaires secondaires ont ete enleves de thesis. cette these. While these forms may be included Bien que ces formulaires aient inclus dans in the document page count, their la pagination, il n'y aura aucun contenu removal does not represent any loss manquant. of content from the thesis. ••I Canada Examining Committee Dr. Michael A. Walter, Medical Genetics Dr. D. Moira Glerum, Cell Biology Dr. Heather E. McDermid, Biological Sciences Dr. Yves Sauve, Ophthalmology Dr. Ted Allison, Biological Sciences Dr. Judith West-Mays, Pathology and Molecular Medicine, McMaster University Abstract FOXCl and FOXC2 are the two members of FOXC transcription factors. Both of them play an important role in the embryonic development of multiple systems including the anterior segment of the eye. Transcription factors such as FOXCl and FOXC2 interact with other proteins to fulfill their function. I screened a human trabecular meshwork cDNA library using yeast two-hybrid methods in order to discover novel FOXCl or FOXC2 protein-protein interactions. From these experiments, human p32 was identified as a FOXCl interacting protein, and human Protein Inhibitors of Activated STAT 3 (PIAS3) was isolated as a FOXC2 interacting protein. These interactions have functional consequences. p32 is able to repress FOXCl transactivation in luciferase assays; whereas its impaired interaction with the transactivation-deficient FOXCl Fl 12S suggests that p32 may regulate FOXCl activity both positively and negatively. These results also indicate that impaired protein-protein interaction may be an underlying mechanism of Axenfeld-Rieger malformation. Study of the effect of PIAS3 on FOXC2 transactivation in luciferase assays revealed that PIAS3 itself induces the expression of the reporter gene in a FOXC-binding site dependent manner. However, PIAS3 doesn't physically bind FOXC-binding sequence indicating that PIAS3 can up-regulate endogenous transcription factor(s) which may include FOXC2 to induce the expression of the reporter gene. Knocking down FOXC2 results in a decreased PIAS3-induced expression of the reporter gene, supporting the idea that PIAS3 can activate endogenous FOXC2. Further investigations are necessary to reveal the biological and clinical significance of FOXC2/PIAS3 interaction. In the last part of the thesis, I report that both FOXC transcription factors regulate the expression of FGF19 and FOXOlA in an ocular cell line, supporting the hypothesis that FOXC1 and FOXC2 have common target genes. Furthermore, I discovered for the first time that FOXC1 and FOXC2 can physically interact and regulate each other's activity, indicating that FOXC1 and FOXC2 are not simply redundant. Instead, these two proteins have a complex relationship in how they co-regulate their target genes. These findings provide evidence of a novel regulatory mechanism to control the overall FOXC activity, which can be very critical for the normal development and cellular function. Acknowledgements I would first and foremost like to acknowledge my supervisory committee for their time and guidance. In particular, I would like to thank my supervisor, Dr. Michael Walter, for accepting me as his student and for his support and patience during my graduate studies. I would also like to thank the Glerum laboratory for their assistance in the yeast experiments. It has been a great pleasure working with all of the members of the ocular genetics laboratory, both past and present, during my PhD training. I wish everyone the best. Thanks to: Dr. Fred Berry for all the intelligent suggestions and for being a role model for me in the field of research; Michael Sharp for training me when I first came to the lab - it was fun working with you; Tim Footz and Farideh Mirzayans for technical support; Chanchal Birdi Larsen for your encouragement and help with my English study; Yoko Ito for your friendship and the delicious food from your Mom. I would also like to thank my friends from the department and outside the department. Thanks to: Ming ye and Jason Bush for your help with my research projects; Hongying Zhao, Wei Wang, Weizheng Guo, Ninghe Hu and Kelly Narine for being wonderful friends to me - it has been always enjoyable spending time with you guys. Finally, I would like to express my deepest appreciation to the most important people in my life: my parents, M.Mtfr and MMii, and my husband, T ^tiTc. Without your unconditional love and endless support, I would not have made it this far. Table of Contents CHAPTER 1. GENERAL INTRODUCTION 1 FORKHEAD DOMAIN STRUCTURE 2 FORKHEAD BOX TRANSCRIPTION FACTOR CI (FOXC1) 3 FOXC1 and Axenfeld-Rieger (AR) malformations 3 Domain Structures ofFOXCl and Molecular Analyses of Disease-causing FOXC1 Missense Mutations 5 FOXC1 Expression Pattern and Animal Models 6 Developmental Pathogenesis 12 Molecular Regulation ofFOXCl Transcription Activity 14 FORKHEAD BOX TRANSCRIPTION FACTOR C2 (FOXC2) 15 FOXC2 and Lymphedema-Distichiasis (LD) Syndrome 15 FOXC2 Expression Pattern and Animal Models 17 FOXC2 and Metabolism 20 FOXC2 and Cancer 22 FOXC2 and Its Direct Target Genes 22 FOXC1 AND FOXC2 23 Overlapping Expression ofFoxcl and Foxc2 23 Foxcl and Foxc2 Double Knockout Mouse Models * 24 RATIONALE OF MY THESIS RESEARCH 27 CHAPTER 2. HUMAN P32 IS A NOVEL FOXC1-INTERACTING PROTEIN THAT REGULATES FOXC1 TRANSCRIPTIONAL ACTIVITY IN OCULAR CELLS 67 INTRODUCTION 68 METHODS 71 Plasmids 71 Yeast two-hybrid screen 71 Mammalian cell culture and transfection 73 Immunoblot analysis 73 Ni2+-NTA pull-downs 74 Immunoprecipitation (IP) 75 Immunofluorescence 76 Transactivation assays 77 Electrophoretic mobility shift assay (EMSA) 78 Mutation screen ofp32 gene in AR patients 79 Realtime qPCR 79 RESULTS 81 Isolation ofp32 as a FOXC1 interacting protein by yeast two-hybrid (Y2H) screening 81 Confirmation of the interaction between FOXC1 andp32 82 Colocalization ofFOXCl andp32 82 The FOXC1 forkhead domain and intact p3 2 are required for the interaction between F0XC1 andp32 83 Mutation screen and detection of copy number variation ofp32 gene in AR patients 83 p32 inhibits FOXC1-mediated transactivation 84 p32 does not affect FOXC1 DNA binding ability 84 The FOXC1 carrying the patient mutation F112S displays an impaired interaction withp32 85 DISCUSSION 86 CHAPTER 3. ISOLATION AND ANALYSIS OF FOXC2 INTERACTING PROTEINS 108 INTRODUCTION 109 METHODS 112 Plasmids and reagents 112 Yeast two-hybrid screen 112 Mammalian cell culture and transfection 113 Immunoblot analysis 113 Immunoprecipitation (IP) 113 Immunofluorescence 114 Transactivation assays 114 siRNA transfection 115 Electrophoretic mobility shift assay (EMSA) 116 RESULTS 117 Isolation ofPIAS3 as a FOXC2 interacting protein by yeast two-hybrid screening 117 Confirmation of the interaction between F0XC2 and PIAS3 by immunoprecipitation 117 Colocalization ofFOXC2 and PIAS3 118 The effect ofPIAS3 on F0XC2-mediated trans activation 118
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