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The Molecular Basis of Transcriptional Activation by the CDP/Cux Transcription Factor

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The Molecular Basis of Transcriptional Activation by the CDP/Cux Transcription Factor The Molecular Basis of Transcriptional Activation by the CDP/Cux Transcription Factor Mary Truscott A thesis submitted to the Faculty of Graduate and Post-doctoral Studies in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of B iochemistry McGill University Montreal, Quebec, Canada August 2006 © Mary Truscott, 2006 Library and Bibliothèque et 1+1 Archives Canada Archives Canada Published Heritage Direction du Branch Patrimoine de l'édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A ON4 Ottawa ON K1A ON4 Canada Canada Your file Votre référence ISBN: 978-0-494-32391-5 Our file Notre référence ISBN: 978-0-494-32391-5 NOTICE: AVIS: The author has granted a non­ L'auteur a accordé une licence non exclusive exclusive license allowing Library permettant à la Bibliothèque et Archives and Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par télécommunication ou par l'Internet, prêter, telecommunication or on the Internet, distribuer et vendre des thèses partout dans loan, distribute and sell th es es le monde, à des fins commerciales ou autres, worldwide, for commercial or non­ sur support microforme, papier, électronique commercial purposes, in microform, et/ou autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriété du droit d'auteur ownership and moral rights in et des droits moraux qui protège cette thèse. this thesis. Neither the thesis Ni la thèse ni des extraits substantiels de nor substantial extracts from it celle-ci ne doivent être imprimés ou autrement may be printed or otherwise reproduits sans son autorisation. reproduced without the author's permission. ln compliance with the Canadian Conformément à la loi canadienne Privacy Act some supporting sur la protection de la vie privée, forms may have been removed quelques formulaires secondaires from this thesis. ont été enlevés de cette thèse. While these forms may be included Bien que ces formulaires in the document page count, aient inclus dans la pagination, their removal does not represent il n'y aura aucun contenu manquant. any loss of content from the thesis. ••• Canada Abstract The CDP/Cux transcription factor is expressed as a 200 kDa protein that interacts rapidly and transiently with DNA. Proteolytic processing generates a shorter isoform, pli 0 CDP/Cux, that binds stably to DNA. Processing occurs at the G liS transition of the cell cycle in normal cells, and constitutively in transformed cells. pllO CDP/Cux stimulates cell proliferation by acce1erating entry into S phase. Transgenic mice expressing pli 0 CDP/Cux are more susceptible to different cancers. CDP/Cux was originally described as a repressor of transcription. My goal was to verify whether CDP/Cux might also participate in transcription al activation and characterize the molecu1ar basis for transcriptional activation by CDP/Cux. Using the DNA polymerase a gene promoter as a model system, 1 showed that stimulation of a DNA pol a reporter correlated with DNA binding. Importantly, pllO CDP/Cux stimulated expression from the endogenous DNA pol a promoter. Linker-scanning analysis of the DNA pol a promoter identified a cis-element that was required for p110- mediated activation, yet was not bound by it. 1 determined that E2F1 and E2F2 cooperated with pllO in activating the DNA pol a promoter, and did so via this cis­ element. Furthermore, CDP/Cux recruited these E2Fs to the promoter in chromatin immunoprecipitation experiments. Location array analysis revealed many targets common to p110 and E2Fl. DNA metabolism and cell cycle targets were overrepresented, and further studies showed that pli 0 and E2F cooperated to activate many cell cycle genes. 1 also described a second proteolytic event, which generated an isoform lacking two active repression domains in the C-terminus. Processing was observed in S phase, but not in early G 1, suggesting that processing occurs in proliferating cells. 1 determined that caspases were responsible for this processing, and that this occurs in non-apoptotic conditions. A C-terminally-truncated CDP/Cux protein was a more potent activator of cell cycle-regulated promoters, and accelerated entry of Kit225 T cells into S phase, while uncleavable pllO CDP/Cux proteins were inactive in both assays. These results identified p110 CDP/Cux as a substrate of caspases in proliferating ceIls, and suggested a mechanism by which caspases may accelerate cell cycle progression. 11 Résumé CDPICux est un facteur de transcription de 200 kDa interagissant de façon rapide et transitoire avec l'ADN. Son clivage protéolytique génère une isoforme plus courte, appelée CDPICux pllO, se liant de façon stable à l'ADN. Ce clivage a lieu lors de la transition G 1/S du cycle cellulaire dans les cellules normales, et est constitutif dans les cellules transformées. plI 0 stimule la prolifération cellulaire en accélérant l'entrée en phase S du cycle cellulaire. Ainsi des souris transgéniques exprimant plI 0 sont plus susceptibles de développer différents cancers. CDPICux a originellement été décrit comme un répresseur transcriptionnel. Le but de mon travail a été de vérifier s'il pouvait également participer à l'activation transciptionnelle ainsi que de caractériser les bases moléculaires de cette activation transcriptionnelle. En utilisant le promoteur du gène de l'ADN polymérase acomme modèle d'étude, j'ai pu montrer que la stimulation d'un gène rapporteur sous le contrôle du promoteur de l'ADN polymérase a était corrélée à la liaison de CDPICux à l'ADN. De plus, pllO stimule l'expression de l'ADN polymérase a endogène. L'analyse séquentielle du promoteur de l'ADN polymérase a a permis l'identification d'un élément cis requis pour l'activation par pllO, mais sur lequel pllO ne se lie pas. J'ai déterminé qu'E2Fl et E2F2 coopèrent avec pllO pour activer le promoteur de l'ADN polymérase a, et ceci via cet élément cis. De plus, des expériences d'immunoprécipitation de chromatine ont révélé que CDPICux recrute les facteurs E2Fs sur le promoteur. Par des analyses de ChIP-chip, j'ai mis en évidence de nombreux gènes cibles communs à pllO et E2Fl. Parmi eux, les gènes impliqués dans le métabolisme de l'ADN et dans la progression du cycle cellulaire sont surreprésentés. Des études complémentaires ont montré que plI 0 et E2F coopèrent pour activer la plupart des gènes impliqués dans la progression du cycle cellulaire. J'ai par ailleurs décrit un second événement protéolytique, permettant d~ générer une isoforme ne possédant pas deux des domaines répresseurs actifs présents dans la région carboxy-terminale de la protéine. Ce clivage est seulement observé au cours de la phase S, et non lors de la phase G 1 précoce, suggérant qu'il a lieu dans les cellules en prolifération. J'ai déterminé que les caspases étaient responsables de ce clivage, et ceci de façon indépendante de l'apoptose. Une forme de CDPICux tronquée de sa région 111 carboxy-terminale représente un meilleur activateur des cibles impliquées dans le cycle cellulaire et accélère l'entrée des cellules Kit225 T en phase S, alors qu'une forme non­ clivable de plI 0 CDP/Cux est inactive dans ces deux essais. Ces derniers résultats ont identifié pllO CDP/Cux comme un substrat des caspases dans les cellules en prolifération, et suggèrent un mécanisme par lequel les caspases pourraient accélérer la progression du cycle cellulaire. IV Acknowledgements First, 1 would like to acknowledge my supervisor, Dr. Alain Nepveu for his guidance, encouragement, advice, and criticism throughout the course of my studies. 1 would like to thank my thesis advisory committee for their help: Dr. Mark Featherstone, Dr. Jacques Drouin, and Dr. John Mort 1 am grateful to CUITent and former members of Dr. Nepveu's laboratory for their advice and friendship: Marianne Santaguida, Lam Leduy, Ginette Bérubé, Hélène Gingras, Rachel Dudley, Laurent Sansregret, Charles Vadnais, Nishant Ramlal, Valérie Kédinger, Chantal Cadieux, Vi-Minh-Tri Su, Ryoko Harada, Rania Siam, Brigitte Goulet, Lélia Raynal, Oriana Muzzin, Nam Sung Moon, Adela Reid, Yelena Markovic, and Brian Wilson. 1 would also like to thank current and former members of the Molecular Oncology Group for scientific discussion, friendship and support, especially Jasmine Abella, Janelle Barry, Pascal Peschard, Nancy Dionne, Julia Brain, Melanie Frigault, Claire Tuason, Kelly Fathers, Hayley Mak, Christine Parachoniak, Nathalie Dourdin, Caroline Saucier, Lina Musallam, RafNotarmaso, and Anna Moriatis. 1 would like to ex tend my gratitude to Laurent Sansregret, Brigitte Goulet, Brian Wilson, Rachel Dudley, and Rebecca Pearce for proofreading my thesis. Thank you, Valérie Kédinger, for translating my abstract into French. 1 am grateful to the Fonds de Recherche en Santé du Québec, the National Cancer Institute (Terry Fox Foundation), the Royal Victoria Hospital Research Institute/McGill University Health Centre, and the McGill University Faculty of Medicine for financial support. 1 would like to say a special thank you to sorne women who have been good friends and raIe models: Oona Johnstone, Rebecca Pearce, Barbara Freedman, Robin Neilson, Jill Barker, Lisa Heggum, Alda Truscott and Nina Truscott. A heartfelt thanks also to Patrick Cafferty, Clarisse Kehler-Siebert, Mary Chamberlin, Jennifer Hassard, and Jason Baardsnes for their friendship. 1 would like to express my appreciation to Pascal Poulin for his love and support. My progress this far would not have been possible without my family - my parents Bill and Nina Truscott, my brother Mark, my sister-in-law Lisa Heggum, Mary Lou Lascelles, and last but not least, my grandmother, Agnia Elensky. Thank you for your love, encouragement, and continuous support. v Preface The guidelines conceming thesis preparation issued by the Faculty of Graduate and Postdoctoral Studies at McGill University reads as follows: 1.
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