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Regulation of FOXO Stability and Activity by MDM2 E3 Ligase Wei Fu University of South Florida

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Regulation of FOXO Stability and Activity by MDM2 E3 Ligase Wei Fu University of South Florida University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School 2007 Regulation of FOXO stability and activity by MDM2 E3 ligase Wei Fu University of South Florida Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the American Studies Commons Scholar Commons Citation Fu, Wei, "Regulation of FOXO stability and activity by MDM2 E3 ligase" (2007). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/2181 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Regulation of FOXO Stability and Activity by MDM2 E3 Ligase By WEI FU A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Pathology and Cell Biology College of Medicine University of South Florida Major Professor: Wenlong Bai, Ph.D. George Blanck, Ph.D. Jiandong Chen, Ph.D. Santo V. Nicosia, M.D John C.M. Tsibris, Ph.D. Date of Approval: Nov., 2007 Key words: Forkhead Transcriptional Factors, MDM2, Ubiquitination, Protein Degradation, Apoptosis ©Copyright 2007, Wei Fu Dedication To my parents, my in-laws, my brother, my husband, Zhigang and my little pumpkin, caroline. Without their love, understanding and support, I could not have done even one piece of it. Acknowledgement I would like to extend my sincere appreciation to Dr. Wenlong Bai for guiding me in the development of this project and the invaluable support from him at each step throughout my graduate studies. My appreciation also goes to Dr. Santo V. Nicosia for being helped in every way. I would like to thank my adviser and committee members, Drs Bai, Blanck, Chen, Nicosia and Tsibris for their guidance, valuable suggestion and their word of encouragement. My appreciation also goes to Dr. Yanping Zhang for willing to be my outside chair. Thanks to Dr. Jiandong Chen and the members in his lab, in particular to Lihong Chen, for their generous supply of the cell lines, plasmids, antibodies and priceless technical assistant. Thanks to Dr. Xiaohong (Mary) Zhang for all her kindly help. Thanks to all the colleagues in Dr. Bai’s and Dr. Zhang’s Lab: Qiuping Ma, Yonghua Yang, Pengfei Li, Heehyoung Lee, Feng Jiang, Chunrong Li, Betty Bean, Xiaohui Zhang, Junying Bao, Lucy Hou, Zheng Shen, Guoqing Liu, Latasha Lee, Ushiwa Jinwal, Tung Hsieh, Yingtao Zhang, Sarah Yong, Huiqin Dong and Mu Zhang for sharing their opinions and joy with me. Thanks to Dr. Patricia Kruk and all the members in her lab. Thanks to Dr. Jin Cheng and the members in his lab, especially to Mei Sun, Zengqiang Yuan and Hua Yang for valuable suggestion. I would like thank to all the members in the Department of Pathology and Cell Biology. Addtionally, I would like to thank everyone in Graduate Affairs Office, especially to Dr. Barber, Dr. Joseph Krzanowski, Ms Kathy Zahn, Ms Susan Chapman. Thanks to Moffitt & College of Medicine core facility for some analysis. Thanks to all my friends who guide me, encourage me and help me on the way. This thesis is dedicated to my family. Word cannot express my grateful feeling. I want to say thanks to my husband, Zhigang, for his loving and my daughter, Caroline, for her shining smile that let me feel I am the happiest mother in the world. I would like to thank my parents and my brother, for their life-long loving. I would also like to thank my in-laws for their kindly help. The research in this dissertation has been partially supported by Predoctoral Fellowship from American Heart Association. Thanks to Dr. Tsibris and Dr. Aslam for reading this thesis and their valuable suggestions. Table of Contents List of Figures................................................................................................................... vi List of Tables..................................................................................................................... x Abstract ............................................................................................................................ xi INTRODUCTION............................................................................................................... 1 1. FOXO Family...................................................................................................... 1 1.1. FOX Family................................................................................................ 1 1.2. FOXO Family............................................................................................. 4 1.2.1. Classification of Human FOXO Factors............................................ 5 1.2.2. Domain Structure of FOXO............................................................... 7 1.3. Function of FOXO Factors......................................................................... 9 1.3.1. FOXO and Cell Cycle Checkpoint and DNA Repair ....................... 10 1.3.1.1. FOXO and G1/S Checkpoint.................................................. 10 1.3.1.2. FOXO and G2/M Checkpoint and DNA Repair...................... 11 1.3.2. FOXO and Apoptosis...................................................................... 12 1.3.3. FOXO and Atrophy......................................................................... 13 1.3.4. FOXO and ROS Detoxification in Stem Cells ................................. 14 1.3.5. FOXO and Tissue Differentiation.................................................... 15 1.3.6. FOXO and Glucose and Energy Metabolism.................................. 16 i 1.3.7. FOXO and Longevity...................................................................... 17 1.4. Posttranslational Modifications of FOXO Proteins................................... 18 1.4.1. Phosphorylation of FOXO............................................................... 18 1.4.1.1. PKB and FOXO...................................................................... 18 1.4.1.2. SGK and FOXO ..................................................................... 20 1.4.1.3. IκB Kinase and FOXO3A ....................................................... 21 1.4.1.4. CK1 and FOXO...................................................................... 21 1.4.1.5. CDK2 and FOXO ................................................................... 21 1.4.1.6. JNK and FOXO...................................................................... 21 1.4.1.7. MST and FOXO3A................................................................. 22 1.4.2. Acetylation and Deacetylation of FOXO ......................................... 23 1.4.2.1. Acetylation and Deacetylation................................................ 23 1.4.2.2. Acetylation of FOXO .............................................................. 23 1.4.2.2.1. P300 and CBP.............................................................. 23 1.4.2.2.2. P300/CBP and FOXO Acetylation................................. 25 1.4.2.3. Deacetylation of FOXO by HDAC.......................................... 26 1.4.2.3.1. SIRT1 ............................................................................ 26 1.4.2.3.2. SIRT1 and FOXO Deacetylation................................... 28 1.4.3. Ubiquitination and Deubiquitination of FOXO ................................. 30 1.4.3.1. Ubiquitination and Degradation of FOXO.............................. 30 1.4.3.2. Deubiquitination of FOXO...................................................... 31 2. Ubiquitin, Proteasome and MDM2 as an E3 Ligase......................................... 32 2.1. Ubiquitin-proteasome System.................................................................. 32 2.1.1. Ubiquitin and Ubiqutination............................................................. 32 2.1.2. Deubiquitination .............................................................................. 33 ii 2.1.3. Ubiquitination Machinery and Proteasome Pathway ...................... 35 2.2. MDM2 as an Ubiquitin E3 Ligase ............................................................ 37 2.2.1. General Information about MDM2................................................... 37 2.2.2. Functions of MDM2......................................................................... 38 2.2.2.1. MDM2 and Cell Cycle............................................................ 38 2.2.2.2. MDM2 and Differentiation...................................................... 38 2.2.2.3. MDM2 and Ribosome Biogenesis.......................................... 39 2.2.2.4. MDM2 and Transcription........................................................ 40 2.2.2.5. MDM2 and Protein Ubiquitination and Degradation............... 40 2.2.3. Regulation of MDM2 E3 Activity..................................................... 41 2.2.3.1. Sumoylation of MDM2............................................................ 41 2.2.3.1.1. SUMO and Sumoylation................................................ 41 2.2.3.1.2. Sumoylation and MDM2................................................ 43 2.2.3.2. Ubiquitination and Degradation of MDM2.............................. 43 2.2.3.3. Phosphorylation of MDM2...................................................... 44 2.2.3.3.1. DNA-PK, ATM and MDM2............................................ 44 2.2.3.3.2. PKB and MDM2............................................................ 45 2.2.3.3.3. c-Abl and MDM2..........................................................
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