p53 Tumor Suppressor Pathway and Cancer (eBook)

Dr. Gerard Zambetti began working on p53 as a Damon-Runyon Postdoctoral Fellow in the laboratory of Arnie Levine at Princeton University in 1990. During his fellowship he developed the first mammalian promoter-reporter assay to monitor p53 transcriptional activity. A close colleague in the lab, Jamil Momand, identified Mdm2 as a 90 kD protein that binds wild-type p53. At the same time Donna George at Penn reported that Mdm2 promotes tumor growth. They rationalized that Mdm2 could be oncogenic by binding and inactivating p53. This hypothesis was borne out by Dr. Zambetti's demonstration that Mdm2 blocks the ability of p53 to transactivate a wild-type p53 responsive promoter-reporter. These findings established Mdm2 as a negative regulator of p53 and gave rise to the p53-Mdm2 field. Subsequent studies showed that Mdm2 inactivates p53 in human tumors. There is now a biannual international Mdm2 meeting and nearly 2000 published studies regarding Mdm2. Dr. Zambetti is presently an Associate Member at St. Jude Children’s Research Hospital in Memphis, Tennessee. He has recently been involved in the identification and characterization of a novel germline p53 mutation that selectively predisposes carriers to pediatric adrenal cancer. His lab has also identified cytokine signaling pathways that repress the apoptotic function of p53. These findings could be exploited for the development of strategies to reduce the toxic side effects of radiation and chemotherapy. Dr. Zambetti also studies how p53 becomes activated during cell stress and how it kills tumor cells and his interests continue along these exciting, clinically important lines of research.

Preface 6
Contents 10
1 The p53 Network 12
SUMMARY 12
1.1. HISTORICAL PERSPECTIVES 13
1.2. THE SMALL DNA TUMOR VIRUSES UNCOVER p53 14
1.3. THE Rb PATHWAY 16
1.4. THE p53 PATHWAY 18
1.5. DETECTING p53 RESPONSIVE ELEMENTS IN THE GENOME 24
1.6. BREAKING THE p53 CODE 27
1.7. CONCLUSIONS 29
REFERENCES 30
2 The Three-Dimensional Structure of p53 35
2.1. p53 DOMAINS AND REGIONS 35
2.2. MODELS FOR THE STRUCTURE OF FULL-LENGTH p53 HOMOTETRAMERS 49
2.3. STRUCTURES OF p53 WITH 53BP1 AND 53BP2 52
2.4. STRUCTURE OF THE p73 C-TERMINAL SAM DOMAIN 56
2.5. CONCLUSIONS AND FUTURE DIRECTIONS 57
ACKNOWLEDGMENTS 58
REFERENCES 58
3 Transcriptional Activation by p53: Mechanisms and Targeted Genes 63
SUMMARY 63
3.1. INTRODUCTION 64
3.2. POSTTRANSLATIONAL MODIFICATIONS 64
3.3. p53 BINDING PROTEINS THAT AFFECT TRANSCRIPTION 69
3.4. BINDING OF p53 TO REGULATORY REGIONS 73
3.5. TRANSCRIPTIONAL TARGETS OF p53 76
3.6. THERAPEUTICS 82
3.7. CONCLUSIONS 82
REFERENCES 83
4 Transcriptional Repression by the p53 Tumor Suppressor Protein 91
SUMMARY 91
4.1. BACKGROUND 92
4.2. p53 REPRESSED GENES 96
4.3. MECHANISMS OF REPRESSION BY p53: p53 – HDAC COMPLEXES 100
4.4. FUTURE CONSIDERATIONS 101
REFERENCES 102
5 Posttranslational Modi.cations of p53: Upstream Signaling Pathways 105
SUMMARY 105
5.1. INTRODUCTION 105
5.2. STRUCTURE OF HUMAN p53 107
5.3. p53 POSTTRANSLATIONAL MODIFICATIONS 109
5.4. SIGNALING TO p53 112
5.5. NONGENOTOXIC STRESS AND p53 EFFECTOR KINASES 117
5.6. CONCLUSIONS 119
ACKNOWLEDGMENTS 119
REFERENCES 119
6 p53 in Human Cancer – Somatic and Inherited Mutations and Mutation- independent Mechanisms 125
SUMMARY 125
6.1. INTRODUCTION 126
6.2. BIOLOGICAL ACTIVITIES OF p53 126
6.3. p53 STRUCTURE AND FUNCTION 127
6.4. MECHANISMS OF p53 INACTIVATION IN HUMAN TUMORS 128
6.5. INHERITED MUTATIONS OF p53 137
6.6. TARGETING p53 REGULATORS 140
6.7. VIRAL TARGETING OF WILD-TYPE p53 151
6.8. SUBCELLULAR LOCALIZATION OF p53 151
6.9. INACTIVATION OF DOWNSTREAM EFFECTORS: Apaf-1 152
6.10. p53 STATUS AND PROGNOSIS 153
6.11. DIRECTIONS FOR FUTURE RESEARCH 154
ACKNOWLEDGMENTS 154
REFERENCES 154
7 MDM2 and MDMX Regulators of p53 Activity 165
SUMMARY 165
7.1. INTRODUCTION 166
7.2. MDM2 AND MDMX STRUCTURE/FUNCTION RELATIONSHIPS 166
7.3. STRESSOR INDUCED REGULATION OF MDM2 – p53 INTERACTION 178
7.4. GENETICS OF MDM2 AND MDMX 181
7.5. THE AUTOREGULATORY LOOP 182
7.6. mdm2 GENE STRUCTURE AND TRANSCRIPTION 184
7.7. MDM2 AND MDMX INVOLVEMENT IN CANCERS 185
7.8. CONCLUDING REMARKS 186
ACKNOWLEDGEMENTS 187
APPENDIX 7.1. CALCULATIONS AND REFERENCES FOR CITATIONS USED TO SET ARROW THICKNESS IN FIGURE 7.4. 187
REFERENCES 190
8 p53 Family Members: p63 and p73 196
SUMMARY 196
8.1. INTRODUCTION TO THE p53 FAMILY 197
8.2. p63 AND p73: ORIGIN AND STRUCTURE 197
8.3. THE p53 FAMILY TREE 198
8.4. PHENOTYPES OF THE p63 AND p73 KNOCKOUT MICE 200
8.5. p63 AND p73 EXHIBIT p53 – LIKE PROPERTIES 201
8.6. p63 AND p73 IN THE DNA DAMAGE RESPONSE 202
8.7. IMPLICATIONS FOR CANCER AND THE FUTURE 204
REFERENCES 205
9 The Oncogenic Activity of p53 Mutants 208
SUMMARY 208
9.1. INTRODUCTION 208
9.2. ONCOGENIC EFFECTS OF p53 MUTANTS I: DOMINANT NEGATIVE SUPPRESSION 211
9.3. ONCOGENIC EFFECTS OF p53 MUTANTS II: GOF 212
9.4. PROPOSED MECHANISMS OF GOF 214
9.5. COMBINED EFFECTS OF NEGATIVE DOMINANCE AND GOF 216
9.6. THE STABILIZATION OF MUTANT p53 PROTEINS 216
9.7. CLINICAL MANIFESTATIONS OF MUTANT p53 ONCOGENICITY 217
9.8. DIFFERENCES BETWEEN p53 MUTANTS 218
9.9. THERAPEUTIC APPROACHES 220
9.10. CONCLUSION 223
APPENDIX 9.1 224
RECENT REVIEWS 224
USEFUL WEBSITES 225
REFERENCES 225
10 Therapeutic Strategies Based on Pharmacological Modulation of p53 Pathway 233
SUMMARY 233
10.1. WHY p53 IS A THERAPEUTIC TARGET 233
10.2. THERAPIES BASED ON PHARMACOLOGICAL ACTIVATION OF p53 235
10.3. PROSPECTIVE THERAPEUTIC APPLICATIONS OF p53 INHIBITORS 241
10.4. CONCLUDING REMARKS: PERSPECTIVES OF PHARMACOLOGICAL MODULATORS OF p53 245
ACKNOWLEDGMENTS 246
REFERENCES 246
Index 251