The Ubiquitin System in Health and Disease (Ernst Schering Foundation Symposium Proceedings)

The ubiquitin system plays an essential role in numerous cellular processes by controlling protein stability and function. A deregulation of this system has been reported in various pathologies including cancer, neurodegenerative diseases and immune disorders. Most of the enzymes involved in adding or removing ubiquitin chains have been identified, but often their direct substrate and the type of ubiquitylation remains to be clarified. A better understanding of the mechanisms governing these processes is likely to allow the identification of novel targets for pharmacological intervention and pave the way for improved therapies. The latest developments in this rapidly moving field are presented in this book. 3540851062......Page 1 Contents......Page 7 1. The SUMO Pathway......Page 16 2. The RING Finger Protein 4 Family: SUMO-Dependent E3 Ubiquitin Ligases......Page 19 3. Principles of Crosstalk Between SUMOylation and Ubiquitination......Page 24 References......Page 26 A Tale of Two Giant Proteases......Page 32 1. Intracellular Proteolysis......Page 33 2. The 26S Proteasome......Page 34 2.1 The 20S Proteasome......Page 35 2.2 The Regulatory Complexes......Page 36 2.3 The 26S Proteasome from Drosophila Melanogaster......Page 39 3. Tripeptidyl Peptidase II......Page 41 3.1 TPPII Structure......Page 42 3.2 Size–Activity Relationship......Page 43 3.3 Structure–Function Relationship......Page 44 4. Conclusions......Page 47 References......Page 48 Molecular Genetics of the Ubiquitin-Proteasome System: Lessons from Yeast......Page 56 1. Introduction......Page 57 2. Identification of the Doa10 Ubiquitin Ligase......Page 59 3. Sequence Features of Doa10......Page 61 4. Diversity of Substrates Targeted by the Doa10 Pathway......Page 63 5. Doa10 Traverses the Nuclear Pore Complex Membrane to Access Nuclear Substrates......Page 64 6. Stepwise Subunit Addition and Rate-Limiting Steps for 20S Proteasome Assembly In Vivo......Page 68 7. Identification of the Pba1-Pba2 Proteasome Assembly Chaperone......Page 71 8. The Pba3-Pba4 Assembly Chaperone Controls 20S Proteasome Composition......Page 72 9. Perspectives......Page 76 References......Page 77 Less Is More: How Protein Degradation Regulates Muscle Development......Page 82 References......Page 87 Transcriptional Control and the Ubiquitin–Proteasome System......Page 89 1. Introduction......Page 90 2. Historical Ties Between the Transcription and Ubiquitin–Proteasome Systems......Page 91 3. Relationship Between Transcription Factor Activity and Destruction......Page 92 4. How Ub-Dependent Proteolysis Contributes to Transcription Factor Activity......Page 97 5. Role for the Proteasome in Transcription......Page 102 6. Implications for Cancer......Page 104 7. Summary......Page 105 References......Page 106 1. Introduction......Page 112 2. Turnover of Myc......Page 114 3. Ubiquitin Ligases and Their Regulation......Page 116 5. Ubiquitination of Myc: Beyond Turnover?......Page 120 References......Page 122 Regulation of Apoptosis and Cytokinesis by the Anti-apoptotic E2/E3 Ubiquitin-Ligase BRUCE......Page 127 2. BRUCE Is a Cell Death Regulator......Page 128 3. Regulation of Cytokinesis......Page 130 4. Final Stages of Cytokinesis Are Controlled by BRUCE......Page 133 References......Page 135 Dissecting Roles of Ubiquitination in the p53 Pathway......Page 139 1. Introduction......Page 140 2. Ubiquitination of p53 Is a Pivotal Event for Its Regulation......Page 141 3. ARF-BP1 Is a Potential Therapeutic Target in Tumors Regardless of p53 Status......Page 143 4. Ubiquitination of p53 Is Reversible......Page 144 5. Identification of Novel Deubiquitinases in Cancer Pathways......Page 145 References......Page 147 Regulation of T Cell Differentiation and Allergic Responses by the E3 Ubiquitin Ligase Itch......Page 149 1. The Ubiquitin Conjugation System......Page 150 2. Ubiquitination in Immune Regulation......Page 151 3. The E3 Ligase Itch......Page 152 4. Itch Regulates Th2 Development......Page 153 6. Itch in Th2 Tolerance Induction......Page 154 7. Regulatory T Cells......Page 155 8. TGF-β Signaling in Immune Regulation......Page 156 9. Itch in the Development of Regulatory T Cells......Page 157 10. Itch Promotes Ubiquitination of TIEG1......Page 158 11. Perspectives......Page 159 References......Page 160 Approaches to Discovering Drugs that Regulate E3 Ubiquitin Ligases......Page 165 1. Introduction......Page 166 2. Targeting E3 RING Finger Domains: Substrate-Independent Ubiquitination Assays......Page 168 3. Targeting Specific Substrate Ubiquitination: Substrate-Dependent Ubiquitination Assays......Page 170 4. Targeting Protein–Protein Interaction Interfaces: E3–Substrate Interactions, Adaptor Protein Interactions......Page 172 4.1 p53-Mdm2......Page 173 4.2 SCF E3 Ligases and Their Substrates......Page 176 4.3 IAPs......Page 177 5. Concluding Remarks......Page 178 References......Page 179 Inhibiting Hdm2 and Ubiquitin-Activating Enzyme: Targeting the Ubiquitin Conjugating System in Cancer......Page 183 1. Introduction......Page 184 2. Targeting Hdm2......Page 185 3. The Hdm2 Ligase Inhibitor Family of 5-Deazaflavins......Page 186 4. Natural Products Screens......Page 188 5. Inhibiting Ubiquitin-Activating Enzyme, Identification of PYR-41......Page 194 6. Discussion......Page 197 References......Page 199 Crosstalk Between The Sumo And Ubiquitin Pathways -- Tale Of Two Giant Proteases -- Molecular Genetics Of The Ubiquitin-proteasome System: Lessons From Yeast -- Less Is More: How Protein Degradation Regulates Muscle Development -- Transcriptional Control And The Ubiquitin-proteasome System -- Ubiquitination Of Myc: Proteasomal Degradation And Beyond -- Regulation Of Apoptosis And Cytokinesis By The Anti-apoptotic E2/e3 Ubiquitin-ligase Bruce -- Dissecting Roles Of Ubiquitination In The P53 Pathway -- Regulation Of T Cell Differentiation And Allergic Responses By The E3 Ubiquitin Ligase Itch -- Approaches To Discovering Drugs That Regulate E3 Ubiquitin Ligases -- Inhibiting Hdm2 And Ubiquitin-activating Enzyme: Targeting The Ubiquitin Conjugating System In Cancer. Editors, S. Jentsch, B. Haendler. Includes Bibliographical References. The ubiquitin system plays an essential role in numerous cellular processes by controlling protein stability and function. An understanding of the mechanisms governing these processes is likely to allow the identification of novel targets for pharmacological intervention. This work covers the developments in this field.