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Expression and Function of Regulator of G-Protein Signaling 10 EXPRESSION AND FUNCTION OF REGULATOR OF G-PROTEIN SIGNALING 10 (RGS10) IN OVARIAN CANCER AND MICROGLIA by MOURAD WAGDY AHMED ALI (Under the Direction of Shelley B. Hooks) ABSTRACT G-Protein coupled receptors (GPCRs) mediate a wide array of cellular functions, such as cell proliferation, migration, and survival. Regulators of G-protein signaling (RGS) proteins are a diverse family of proteins that regulate signaling pathways downstream of GPCRs by acting on G-proteins. The focus of this dissertation is on the regulation of G-protein pathways in cancer and inflammation by RGS proteins, particularly by RGS10. We focused on signaling initiated by two related receptor families, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) receptors, which are implicated in ovarian cancer and neuroinflammation, respectively. Aberrant expression and mutations in RGS proteins have been implicated in diseases such as cancer and autoimmune disorders. The aim of this study was to define the function and the expression of RGS proteins, particularly RGS10, in ovarian cancer and microglia. LPA is the predominant growth factor in ovarian cancer, promoting proliferation, migration, and survival. RGS proteins negatively regulate LPA-mediated effects in ovarian cancer. We determined that RGS proteins, RGS10 and RGS17 regulate LPA- mediated survival in ovarian cancer cells. Specifically, our data demonstrate that RGS10 and RGS17 negatively regulate LPA-mediated AKT survival pathway in ovarian cancer cells. Further, we show that RGS10 and RGS17 are down-regulated in chemoresistant ovarian cancer cells, and our results show that RGS10 is epigenetically silenced in chemoresistant ovarian cancer cells via increased DNA methylation and decreased histone acetylation of the RGS10 promoter by DNA methyltransferase 1 (DNMT1), and histone deacetylase 1 (HDAC1), respectively. In addition to its role in chemoresistant ovarian cancer cells, RGS10 has been shown to exert an anti-inflammatory effect in microglia, the brain’s innate immune cells, via blunting pro-inflammatory cytokines signaling, and RGS10 is suppressed in activated microglia. We investigated the mechanism by which RGS10 is down-regulated in activated microglia, as well as the mechanism by which RGS10 regulates signaling pathways in microglia. Our results indicate that RGS10 is epigenetically suppressed via decreased histone acetylation of its promoter in activated microglia. Our results also suggest that RGS10 negatively regulates protein kinase A (PKA) and glycogen synthase kinase-3 beta (GSK-3β) downstream of lipopolysaccharide (LPS) and S1P, which may account for its regulation of pro-inflammatory cytokine signaling in activated microglia. INDEX WORDS: G-protein coupled receptors, regulator of G-protein signaling proteins, lysophosphatidic acid, sphingosine-1-phosphate, epigenetics, ovarian cancer, microglia EXPRESSION AND FUNCTION OF REGULATOR OF G-PROTEIN SIGNALING 10 (RGS10) IN OVARIAN CANCER AND MICROGLIA by MOURAD WAGDY AHMED ALI B.S., Ain Shams University, Egypt, 2003 A Dissertation Submitted to the Graduate Faculty of The University of Georgia in Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY ATHENS, GEORGIA 2014 © 2014 Mourad Wagdy Ahmed Ali All Rights Reserved EXPRESSION AND FUNCTION OF REGULATOR OF G-PROTEIN SIGNALING 10 (RGS10) IN OVARIAN CANCER AND MICROGLIA by MOURAD WAGDY AHMED ALI Major Professor: Shelley B. Hooks Committee: James L. Franklin Mandi M. Murph Rajgopal Govindarajan Xiaoqin Ye Electronic Version Approved: Maureen Grasso Dean of the Graduate School The University of Georgia May 2014 DEDICATION I would like to dedicate this work to my family, friends, and teachers. I could not have earned this degree without your help. To my father, Wagdy Salem, you have always been my role model and my inspiration. To my mother, Nabila, I could not have achieved anything in my life without your support and guidance. To my sister, Radwa, you have always believed in me and supported me throughout the years. Thank you for everything. To all my friends, thank you for putting your trust in me and for helping me through good and hard times. To my teachers throughout elementary, middle, and high schools, college, and graduate school, everything you ever taught me helped shape the man I am today. I owe you a lot. iv ACKNOWLEDGEMENTS First and foremost, all praise, thanks, and gratitude goes to Allah (God) for His countless blessings and His immeasurable bounties. I would like to thank Dr. Shelley Hooks whom I had the privilege of working with and learning from over the past five years. I am thankful for her excellent mentoring. I would also like to thank my committee members for their input and feedback. I learned a lot from each and every one of them. Thanks to my lab mates: Jill Hurst, Phillip Callihan, Juliet Onunkwo, Song Kue, April Chan, Katie Tuggle, Zoe Wickham, Hector Salazar, Vitoria Kuzolitz, and Mugdha Joshi. Thanks to my fellow graduate students in the Department of Pharmaceutical and Biomedical Sciences. Special thanks to the Murph, Cummings, Capomacchia and Beedle labs for helping out and letting me to use their reagents and instruments. Thanks to ours collaborators, especially Dr. Suzanna Greer, and Ercan Cacan at Georgia State University. Thanks to the funding agencies that provided the financial support necessary to finish this work. Thanks to the Graduate School at the University of Georgia for their generous financial support. v TABLE OF CONTENTS Page ACKNOWLEDGEMENTS .................................................................................................v LIST OF FIGURES .......................................................................................................... vii CHAPTER 1 INTRODUCTION AND LITERATURE REVIEW: REGULATION OF G- PROTEIN SIGNALING IN OVARIAN CANCER AND MICROGLIA .........1 2 REGULATOR OF G-PROTEIN SIGNALING RGS10 AND RGS17 REGULATE AKT ACTIVATION IN OVARIAN CANCER CELLS... .......31 3 TRANSCRIPTIONAL SUPPRESSION, DNA METHYLATION, AND HISTONE DEACETYLATION OF THE REGULATOR OF G-PROTEIN SIGNALING 10 (RGS10) GENE IN OVARIAN CANCER CELLS.............42 4 HISTONE DEACETYLATASE HDAC1 AND DNA METHYLTRANSFERASE DNMT1 REGULATE EXPRESSION LEVEL OF REGULATOR OF G-PROTEIN SIGNALING RGS10 AND CELL VIABILITY IN CHEMORESISTANT OVARIAN CANCER CELLS A2780- AD... .................................................................................................................79 5 EXPRESSION AND FUNCTION OF REGULATOR OF G-PROTEIN SIGNALING 10 (RGS10) IN MICROGLIA ..................................................95 6 SUMMARY ...................................................................................................127 REFERENCES ....................................................................................................132 vi LIST OF FIGURES Page Figure 1.1: G-Protein Activation/Deactivation Cycle .......................................................28 Figure 1.2: LPA Receptor Signaling Pathways .................................................................29 Figure 1.3: S1P Receptor Signaling Pathways ..................................................................30 Figure 2.1: RGS10 and RGS17 Inhibit LPA-Stimulated AKT Activation. .......................40 Figure 2.2: Model of Working Hypothesis for RGS Regulation of Acquired Chemoresistance ....................................................................................................41 Figure 3.1: Loss of RGS10 Expression in Ovarian Cancer Cells ......................................66 Figure 3.2: RGS10 Gene Structure and RGS10 Transcript Expression in IOSE, CAOV-3, A2780, and A2780-AD Cells .................................................................................67 Figure 3.3: Regulation of RGS Genes by DNA methylation.............................................69 Figure 3.4: Bisulfite Sequencing of RGS10-1 Promoter-RegionBS10-1 ..........................70 Figure 3.5: Bisulfite Sequencing of RGS10-1 Promoter-RegionBS10-2 ..........................71 Figure 3.6: Bisulfite Sequencing of RGS10-1 Promoter-RegionBS10-3 ..........................72 Figure 3.7: Bisulfite Sequencing of RGS10-1 Promoter-RegionBS10-4 ..........................73 Figure 3.8: Methylated Fraction of CpG Dinucleotides across the RGS10-1 Promoter in Ovarian Cell Lines .................................................................................................74 vii Figure 3.9: Histone Acetylation and HDAC Binding at the RGS10-1 Promoters in Chemoresistant A2780-AD Cells and Parental A2780 Cells ................................75 Figure 3.10: Histone Acetylation and HDAC Binding at the RGS10-1 Promoters in IOSE and CAOV-3 Ovarian Cells ...................................................................................77 Figure 4.1: HDAC1 Over-expression Decreases RGS10 Expression in Chemoresistant Cells… ...................................................................................................................90 Figure 4.2: Effects of HDAC Inhibitor Trichostatin A (TSA) and DNMT Inhibitor 5-Aza- 2′-deoxycytidine (5-Aza-dC) on RGS10 Transcript Expression ...........................91 Figure 4.3: Effects of HDAC Inhibitor Trichostatin A (TSA) and DNMT Inhibitor 5-Aza- 2′-deoxycytidine (5-Aza-dC) on Cell Viability in Chemoresistant Ovarian Cancer Cells.... ...................................................................................................................92 Figure 4.4: Suppression of RGS10 Expression Did Not Reverse the Effect
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