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The Role of CDCA7 in Akt-Mediated Myc-Dependent Apoptosis and Proliferation

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The Role of CDCA7 in Akt-Mediated Myc-Dependent Apoptosis and Proliferation The Role of CDCA7 in Akt-mediated Myc-Dependent Apoptosis and Proliferation Tim Gabor A dissertation submitted to the Faculty of Graduate Studies In partial fulfillment of the requirements for the degree of Doctor of Philosophy Graduate Program in Biology York University Toronto, Ontario, Canada May 2018 © Tim Gabor, 2018 Abstract CDCA7, or cell division cycle associated protein A7, was described in 2001 by Prescott and colleagues as a target of Myc-dependent transcriptional regulation (Prescott et al., 2001). We have identified CDCA7 as associating with the transcription factor Myc and is the target of phosphorylation by the prosurvival serine/threonine kinase Akt. Phosphorylation by Akt at threonine 163 disrupts CDCA7 association with Myc, promotes binding to 14-3-3 and sequestration in the cytoplasm. Coexpression of CDCA7 and Myc in fibroblasts potentiates Myc- dependent apoptosis upon serum withdrawal. In contrast, knockdown of CDCA7 by shRNA abrogated Myc-dependent apoptosis. Myc induced transformation of fibroblasts was reduced in the presence of CDCA7 and significantly inhibited by the expression of the non-Myc binding mutant ∆(156-187) CDCA7. We have shown that CDCA7 enhances the activation of an E-box in a Myc-binding dependent manner. CDCA7 increases Myc occupancy of the proapoptotic BAX promoter, elevates BAX and Cyclin B1 mRNA levels while reducing p15INK4B mRNA levels. This data points to a novel mechanism which implicates Akt phosphorylation of CDCA7 as participating in the dual signal model of Myc of function and thus affecting Myc-dependent growth and transformation. In this study, we have also shown that expression of CDCA7 reduces proliferation rates and shifts cell cycle distribution towards G2/M phase and that phosphorylation of CDCA7 at T163 occurs strictly in G2/M. CDCA7 phosphorylated at threonine 163 colocalizes with the centrosomal protein marker γ-Tubulin and activated Akt (phospho-serine 473) in mitotic cells. Finally, we have shown that CDCA7 co-associates with monomers of itself which is dependent on amino acids 187- 234, adding to the possible mechanisms by which CDCA7 function may be regulated. ii Dedication and Acknowledgments I would like to thank my supervisor, Mike Scheid for his invaluable mentorship and guidance over the course of my graduate studies. Dr. Scheid sparked my interest in molecular biology and gave me the opportunity to pursue and nurture a lifelong long passion. I would like to also extend my sincerest appreciation to my supervisory committee, Dr. Sam Benchimol and Dr. John McDermott for their advice and direction during my graduate school career. As we are all the product of the sum of our life experience, I would be remiss not to thank all the students and colleagues I have had the pleasure of working with, especially Amber Couzens, Adi Rakowski and Shaon Parial. I sincerely value the friendship and help you have offered me over the years, without it many of the long hours would have felt so much longer. I would like to give a special mention to Monty Gill for bestowing upon me a vast repertoire of protocols, methods and everyday lab-hacks that have helped mold me into the scientist that I am. You taught me that “There’s always a reason”. Finally, I would like to extend my greatest appreciation to my family for supporting me and my quest to achieve all the goals I have set before me over the past many years. And to my unconditionally loving wife, Lena Gabor, thank you for your unwavering patience and support while I venture down this long and winding road. iii Table of contents Abstract ........................................................................................................................................... ii Dedication and Acknowledgments ................................................................................................ iii List of figures ................................................................................................................................. vi Chapter 1: Introduction and Research Objectives .......................................................................... 1 MYC ........................................................................................................................................... 3 Molecular Profile of Myc ............................................................................................................ 4 Myc and Cell Proliferation.......................................................................................................... 5 Myc and Apoptosis ..................................................................................................................... 7 Phosphoinositide-3 Kinase and Akt .......................................................................................... 15 Molecular Profile of Akt ........................................................................................................... 16 Akt and Cell Survival................................................................................................................ 18 The Akt Signalling Pathway and Cancer .................................................................................. 20 PI3K and Akt Inhibitors as Therapeutic Intervention ............................................................... 23 CDCA7 – MYC Associated Protein and Target of Akt ............................................................ 25 CDCA7 – 2001-2006 ............................................................................................................ 25 CDCA7 – Gill, Gabor, Couzens and Scheid (2013) ............................................................. 27 CDCA7 – 2014-2017 ............................................................................................................ 28 Significance of Research and Research Objectives .................................................................. 30 Research Objective 1: Investigate Consensus Sites within CDCA7’s Amino Acid Sequence ............................................................................................................................................... 30 Research Objective 2: Does CDCA7 Interact with the Oncogene Myc? ............................. 31 Research Objective 3: Map the Subcellular Localization of CDCA7 .................................. 31 Research Objective 4: How Does CDCA7 Affect Apoptosis and Proliferation? ................. 32 Research Objective 5: Does CDCA7 Exist as a Monomer or a Homodimer? ...................... 32 Research Objective 6: How Does CDCA7 Affect Gene Expression? .................................. 32 Research Objective 7: How Does CDCA7 Affect the Cell Cycle? ...................................... 33 Chapter 2: The MYC-associated protein CDCA7 is phosphorylated by Akt to regulate MYC- dependent apoptosis and transformation ....................................................................................... 36 Abstract ..................................................................................................................................... 37 Introduction ............................................................................................................................... 37 Methods and materials .............................................................................................................. 39 iv Results ....................................................................................................................................... 47 Discussion ................................................................................................................................. 70 Acknowledgements ................................................................................................................... 73 References ................................................................................................................................. 74 Chapter 3: CDCA7 Co-association and 14-3-3 Binding............................................................... 79 Introduction ............................................................................................................................... 79 Results ....................................................................................................................................... 83 Discussion ............................................................................................................................... 110 Materials and Methods ............................................................................................................ 115 Chapter 4: CDCA7, 14-3-3 Association and the Cell Cycle ...................................................... 119 Introduction ............................................................................................................................. 119 Results ..................................................................................................................................... 130 Discussion ............................................................................................................................... 148 Materials and Methods ............................................................................................................ 151 Chapter 5: Concluding Discussion and Future Directions .......................................................... 157 Discussion ..............................................................................................................................
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