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Beryllium Is a Potent and Unique GSK-3Β Inhibitor with Potential to Differentially Regulate Glycogen Synthase and Β-Catenin

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Beryllium Is a Potent and Unique GSK-3Β Inhibitor with Potential to Differentially Regulate Glycogen Synthase and Β-Catenin UNLV Theses, Dissertations, Professional Papers, and Capstones 5-1-2015 Beryllium is a potent and unique GSK-3β inhibitor with potential to differentially regulate glycogen synthase and β-catenin Ata Ur Rahman Mohammed Abdul University of Nevada, Las Vegas Follow this and additional works at: https://digitalscholarship.unlv.edu/thesesdissertations Part of the Biochemistry Commons, and the Chemistry Commons Repository Citation Mohammed Abdul, Ata Ur Rahman, "Beryllium is a potent and unique GSK-3β inhibitor with potential to differentially regulate glycogen synthase and β-catenin" (2015). UNLV Theses, Dissertations, Professional Papers, and Capstones. 2391. http://dx.doi.org/10.34917/7645977 This Dissertation is protected by copyright and/or related rights. It has been brought to you by Digital Scholarship@UNLV with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/or on the work itself. This Dissertation has been accepted for inclusion in UNLV Theses, Dissertations, Professional Papers, and Capstones by an authorized administrator of Digital Scholarship@UNLV. For more information, please contact [email protected]. BERYLLIUM IS A POTENT AND UNIQUE GSK-3β INHIBITOR WITH POTENTIAL TO DIFFERENTIALLY REGULATE GLYCOGEN SYNTHASE AND β-CATENIN By Ata Ur Rahman Mohammed Abdul Bachelor of Science in Microbiology, Botany and Chemistry Kakatiya University 2001 Master of Science in Biotechnology University College of Sciences Osmania University 2004 A dissertation submitted in partial fulfillment of the requirements for the Doctor of Philosophy - Chemistry Department of Chemistry and Biochemistry College of Sciences The Graduate College University of Nevada, Las Vegas May 2015 We recommend the dissertation prepared under our supervision by Ata Ur Rahman Mohammed Abdul entitled Beryllium Is a Potent and Unique GSK-3β Inhibitor with Potential to Differentially Regulate Glycogen Synthase and β-catenin is approved in partial fulfillment of the requirements for the degree of Doctor of Philosophy - Chemistry Department of Chemistry Ronald K. Gary, Ph.D., Committee Chair Ernesto Abel-Santos, Ph.D., Committee Member Bryan L. Spangelo, Ph.D., Committee Member Balakrishnan Naduvalath, Ph.D., Committee Member Helen J. Wing, Ph.D., Graduate College Representative Kathryn Hausbeck Korgan, Ph.D., Interim Dean of the Graduate College May 2015 ii ABSTRACT Beryllium is a potent and unique GSK-3β inhibitor with potential to differentially regulate glycogen synthase and β-catenin By Ata Ur Rahman Mohammed Abdul Dr. Ronald K Gary Examination Committee Chair Associate Professor Department of Chemistry and Biochemistry University of Nevada, Las Vegas Glycogen Synthase Kinase-3β (GSK-3β) is an important serine/threonine kinase that phosphorylates/regulates diverse and metabolically important proteins. Some of the important substrates of GSK-3β are glycogen synthase, tau, β-catenin, cyclin D1, axin, c-jun, c-myc, Heat Shock Factor–1, BCL-3, CREB, Histone H1.5, mdm2, p21 (CIP1), pyruvate dehydrogenase and many more. De-regulation of GSK-3β has been implicated in diseases like cancer, Alzheimer’s disease, bipolar disorder and type 2 diabetes mellitus. Currently, GSK-3β is one of the most widely studied proteins and there is a great interest in developing potent and efficient GSK-3β- inhibitors for research as well as therapeutic purposes. We demonstrate that beryllium in the form of BeSO4 salt is a much more potent GSK-3β-inhibitor compared to LiCl. We observed that one of the unique properties of beryllium is its modus operandi to regulate the inhibitory Ser-9 phosphorylation of GSK-3β in a cell type specific manner. Our study for the first time validates the potential of beryllium to function as a biologically relevant GSK-3β- iii inhibitor. Beryllium induces a decrease in the phosphorylation of glycogen synthase in cultured NIH/3T3 cells. This decrease in phosphorylated form of glycogen synthase demonstrates the ability of beryllium to inhibit GSK-3β’s kinase activity in treated cells. One of the most important substrates in relation to GSK-3β’s inhibition is β-catenin – one of the downstream effector molecules of the Wnt signaling pathway. Our results in NIH/3T3 and A172 cells indicate that beryllium has minimal effect on Wnt signaling/ β-catenin pathway compared to other established GSK-3β-inhibitors. The minimal effect of beryllium at physiologically effective concentrations on Wnt signaling/β-catenin pathway indicates that it could be a more pathway specific inhibitor. One of the most intriguing discoveries of our study has been the lithium induced increase in the phosphorylated form of β-catenin, which is against the “accepted dogma”. Here we propose an alternative model explaining the regulation of the Wnt/β-catenin signaling pathway by lithium. Use of GSK-3β-inhibitors for therapeutic purposes presents the risk of inducing cancer in patients due to accumulation of β-catenin, an oncogene activator. The unique ability of beryllium to repress the kinase activity of GSK-3β without inducing a heavy nuclear localization of β- catenin might provide an opportunity to develop a potentially potent, efficient, pathway-specific and biologically active GSK-3β inhibitor with minimal adverse effects. iv ACKNOWLEDGEMENT I moved to Las Vegas in September of 2008 and since then many people have helped and influenced me in different ways. First and foremost I would like to thank Dr. Ronald K Gary, my advisor for not only teaching me how to do research but also inculcating a thought process in me. He has been an extremely patient mentor who gave me all the freedom to do what I wanted to do. I would like to thank my Ph.D committee members; Dr. Bryan L Spangelo, Dr. Ernesto Abel- Santos, Dr. Balakrishnan Naduvalath and Dr. Helen Wing for their support and time. I would like to thank (late) Dr. Dennis Lindle, Dr. David Hatchett (Chair, Department of Chemistry) and Dr. Kathleen Robins (graduate co ordinator) for supporting me. I would like to thank Dr. Priyatham Gorjala for being an amazing colleague. I would like to thank Carlos Atrian and Ekram Yusuf (undergraduate research fellows) for helping me conduct my research. I would like to thank Casey Hall, Shirley Shen from genomics core lab and Sophie Choe from confocal imaging facility. I have met many amazing people at UNLV and would like to thank them all Chelsea Ross, Padma Priyatham, Swapna Mudireddy, Dr. Van Vo, Surbhi Sharma, Rohit Asuri, Kamal Kaiser, Gaurav Kovvori, Kranthi Kumar, Nagur, Amit Sharma, Spandana, Hassan Rizvi and many more. I would like to thank my family for their unflinching support. Finally I would like to thank my wife Tabassum Fatima for understanding and accommodating me. It would have been extremely difficult for me to carry on with my graduate studies without her support. v TABLE OF CONTENTS Page ABSTRACT .................................................................................................................................... iii ACKNOWLEDGEMENTS ............................................................................................................. v LIST OF TABLES ......................................................................................................................... xii LIST OF FIGURES ...................................................................................................................... xiii LIST OF SUPPLEMENTARY FIGURES ................................................................................... xvi LIST OF SCHEMATIC DIAGRAMS ......................................................................................... xvii CHAPTER 1 OVERVIEW .............................................................................................................. 1 Research purpose ................................................................................................................ 1 Research questions .............................................................................................................. 2 CHAPTER 2 GSK-3β: An important Ser/Thr kinase ...................................................................... 5 GSK-3 family ...................................................................................................................... 5 GSK-3β – A brief introduction ........................................................................................... 8 GSK-3β and the Wnt signaling ......................................................................................... 12 GSK-3β and its role in insulin signaling ........................................................................... 15 GSK-3β and the Hedgehog pathway................................................................................. 15 GSK-3β and diseases ........................................................................................................ 16 Alzheimer’s disease .................................................................................................... 16 Insulin resistance and diabetes mellitus type 2........................................................... 17 Cancer......................................................................................................................... 17 Regulation of GSK-3β
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