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i ACKNOWLEDGMENTS:  ii LIST OF TABLES:  v LIST OF FIGURES  vi LIST OF ABBREVIATIONS USED  viii GLOSSARY  x CHAPTER 1: Introduction and Background  1 THE CUL3 UBIQUITIN LIGASE  2 CELL CYCLE REGULATION: Basic mechanisms controlling proliferation  10 CELL CYCLE REGULATION: Cyclins and Cdks  11 CELL CYCLE REGULATION: Mechanisms controlling cyclin E abundance  15 CUL3 AND DISEASE: Cancer  16 CUL3 AND DISEASE: FHHt hypertension:  18 CUL3 AND DISEASE: Neuronal, eye, and skin conditions  19 SIGNIFICANCE  20 REFERENCES  21 CHAPTER 2: The N-terminus of Cyclin E is Required for Cul3-mediated Degradation  29 INTRODUCTION AND BACKGROUND:  30 RESULTS:  32 Cyclin E binds directly to Cul3 independently of BTB domain-containing proteins  32 Mutations in the N-terminal region of cyclin E prevent degradation by the Cul3 complex  37 Lysine 48 on cyclin E serves as a ubiquitination site for Cul3  42 The N-terminal domain of cyclin E is required for degradation  45 Cul3 cannot degrade endogenous LMW cyclin E  46 Cyclin E2 is not a substrate of Cul3  47 Loss of Cul3 results in early accumulation of cyclin E after release from serum starvation  48 RhoBTB3 interacts with UbE2E1 to facilitate complex formation  52 DISCUSSION:  56 MATERIALS AND METHODS  63 REFERENCES  66 CHAPTER 3: Identifying Possible Roles of Cul3 and Klhl3 in the Kidney  70 BACKGROUND: The role of Cul3 and Klhl3 in FHHt  71 RESULTS:  75 Identifying proteins that interact with Klhl3  75 Dynamitin/p50 binds Klhl3  77 P50 is stabilized in the presence of an FHHt-associated Klhl3 mutant  80 P50 binds Cul3  82 Cul3 and Klhl3 ubiquitinate p50/dynamitin in vitro  83 iv P50 levels appear to remain unchanged in vivo  85 Transfected p50 is destabilized by Cul3  86 DISCUSSION:  86 FUTURE DIRECTIONS:  87 The possibility of aquaporin regulation by Cul3  88 Other identified proteins that may interact with Klhl3  94 MATERIALS AND METHODS  95 REFERENCES  97 CHAPTER 4: Conclusions, Discussion, and Future Directions  101 RESEARCH QUESTION 1: What is the nature of the interactions between Cul3, Cdk2, and the LRR protein MUF1?  103 BACKGROUND: LRR proteins and Cul3  103 BACKGROUND: LRR5 (FMOD), LRR3 (SALM1) and Cul3  106 BACKGROUND: LRR5 (FMOD) interacts with the BTB protein FAZF  107 RESULTS: Exploring the interactions between the LRR protein MUF1, Cul3, and Cdk2  109 MUF1 binds Cdk2  112 Levels of MUF1 and cyclin E  112 DISCUSSION:  115 RESEARCH QUESTION 2: How does loss of Cul3 affect breast cancer cells?  118 RESEAERCH QUESTION 3: What other modifications may affect cyclin E in vivo?  119 RESEARCH QUESTION 4: How do BTB proteins affect the binding of E2 enzymes to Cul3based complexes?  123 RESEARCH QUESTION 5: Do changes in Nrf2 activity affect regulation of AQP2 in Cul3 conditional knockout or Cul3Δ403-459 mice?  125 FINAL THOUGHTS  127 METHODS:  127 REFERENCES  128 TERMINAL REFERENCE SECTION  132

The Cul3 Ubiquitin Ligase: An Essential Regulator of Diverse Cellular Processes