Zambetti The p53 Tumor Suppressor Pathway and Cancer

1. Auflage 2007
ISBN: 978-0-387-30127-3
Verlag: Springer US
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 2, 246 Seiten

Reihe: Protein Reviews

The current year (2004) marks the Silver Anniversary of the discovery of the p53 tumor suppressor. The emerging ?eld ?rst considered p53 as a viral antigen and then as an oncogene that cooperates with activated ras in transforming primary cells in culture. Fueling the concept of p53 acting as a transforming factor, p53 expression was markedly elevated in various transformed and tumorigenic cell lines when compared to normal cells. In a simple twist of fate, most of the studies conducted in those early years inadvertently relied on a point mutant of p53 that had been cloned from a normal mouse genomic library. A bona ?de wild-type p53 cDNA was subsequently isolated, ironically, from a mouse teratocarcinoma cell line. A decade after its discovery, p53 was shown to be a tumor suppressor that protects against cancer. It is now recognized that approximately half of all human tumors arise due to mutations within the p53 gene. As remarkable as this number may seem, it signi?cantly underrepresents how often the p53 pathway is targeted during tumorigenesis. It is my personal view, as well as many in the p53 ?eld, that the p53-signaling pathway is corrupted in nearly 100% of tumors. If you are interested in understanding cancer and how it develops, you must begin by studying p53 and its pathway. After demonstrating that p53 functions as a tumor suppressor the ?eld exploded and p53 became a major focus of scientists around the world.

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.

Autoren/Hrsg.

Zambetti, Gerard P.

Inhaltsverzeichnis

1;Preface;6
2;Contents;10
3;1 The p53 Network;12
3.1;SUMMARY;12
3.2;1.1. HISTORICAL PERSPECTIVES;13
3.3;1.2. THE SMALL DNA TUMOR VIRUSES UNCOVER p53;14
3.4;1.3. THE Rb PATHWAY;16
3.5;1.4. THE p53 PATHWAY;18
3.6;1.5. DETECTING p53 RESPONSIVE ELEMENTS IN THE GENOME;24
3.7;1.6. BREAKING THE p53 CODE;27
3.8;1.7. CONCLUSIONS;29
3.9;REFERENCES;30
4;2 The Three-Dimensional Structure of p53;35
4.1;2.1. p53 DOMAINS AND REGIONS;35
4.2;2.2. MODELS FOR THE STRUCTURE OF FULL-LENGTH p53 HOMOTETRAMERS;49
4.3;2.3. STRUCTURES OF p53 WITH 53BP1 AND 53BP2;52
4.4;2.4. STRUCTURE OF THE p73 C-TERMINAL SAM DOMAIN;56
4.5;2.5. CONCLUSIONS AND FUTURE DIRECTIONS;57
4.6;ACKNOWLEDGMENTS;58
4.7;REFERENCES;58
5;3 Transcriptional Activation by p53: Mechanisms and Targeted Genes;63
5.1;SUMMARY;63
5.2;3.1. INTRODUCTION;64
5.3;3.2. POSTTRANSLATIONAL MODIFICATIONS;64
5.4;3.3. p53 BINDING PROTEINS THAT AFFECT TRANSCRIPTION;69
5.5;3.4. BINDING OF p53 TO REGULATORY REGIONS;73
5.6;3.5. TRANSCRIPTIONAL TARGETS OF p53;76
5.7;3.6. THERAPEUTICS;82
5.8;3.7. CONCLUSIONS;82
5.9;REFERENCES;83
6;4 Transcriptional Repression by the p53 Tumor Suppressor Protein;91
6.1;SUMMARY;91
6.2;4.1. BACKGROUND;92
6.3;4.2. p53 REPRESSED GENES;96
6.4;4.3. MECHANISMS OF REPRESSION BY p53: p53 – HDAC COMPLEXES;100
6.5;4.4. FUTURE CONSIDERATIONS;101
6.6;REFERENCES;102
7;5 Posttranslational Modi.cations of p53: Upstream Signaling Pathways;105
7.1;SUMMARY;105
7.2;5.1. INTRODUCTION;105
7.3;5.2. STRUCTURE OF HUMAN p53;107
7.4;5.3. p53 POSTTRANSLATIONAL MODIFICATIONS;109
7.5;5.4. SIGNALING TO p53;112
7.6;5.5. NONGENOTOXIC STRESS AND p53 EFFECTOR KINASES;117
7.7;5.6. CONCLUSIONS;119
7.8;ACKNOWLEDGMENTS;119
7.9;REFERENCES;119
8;6 p53 in Human Cancer – Somatic and Inherited Mutations and Mutation- independent Mechanisms;125
8.1;SUMMARY;125
8.2;6.1. INTRODUCTION;126
8.3;6.2. BIOLOGICAL ACTIVITIES OF p53;126
8.4;6.3. p53 STRUCTURE AND FUNCTION;127
8.5;6.4. MECHANISMS OF p53 INACTIVATION IN HUMAN TUMORS;128
8.6;6.5. INHERITED MUTATIONS OF p53;137
8.7;6.6. TARGETING p53 REGULATORS;140
8.8;6.7. VIRAL TARGETING OF WILD-TYPE p53;151
8.9;6.8. SUBCELLULAR LOCALIZATION OF p53;151
8.10;6.9. INACTIVATION OF DOWNSTREAM EFFECTORS: Apaf-1;152
8.11;6.10. p53 STATUS AND PROGNOSIS;153
8.12;6.11. DIRECTIONS FOR FUTURE RESEARCH;154
8.13;ACKNOWLEDGMENTS;154
8.14;REFERENCES;154
9;7 MDM2 and MDMX Regulators of p53 Activity;165
9.1;SUMMARY;165
9.2;7.1. INTRODUCTION;166
9.3;7.2. MDM2 AND MDMX STRUCTURE/FUNCTION RELATIONSHIPS;166
9.4;7.3. STRESSOR INDUCED REGULATION OF MDM2 – p53 INTERACTION;178
9.5;7.4. GENETICS OF MDM2 AND MDMX;181
9.6;7.5. THE AUTOREGULATORY LOOP;182
9.7;7.6. mdm2 GENE STRUCTURE AND TRANSCRIPTION;184
9.8;7.7. MDM2 AND MDMX INVOLVEMENT IN CANCERS;185
9.9;7.8. CONCLUDING REMARKS;186
9.10;ACKNOWLEDGEMENTS;187
9.11;APPENDIX 7.1. CALCULATIONS AND REFERENCES FOR CITATIONS USED TO SET ARROW THICKNESS IN FIGURE 7.4.;187
9.12;REFERENCES;190
10;8 p53 Family Members: p63 and p73;196
10.1;SUMMARY;196
10.2;8.1. INTRODUCTION TO THE p53 FAMILY;197
10.3;8.2. p63 AND p73: ORIGIN AND STRUCTURE;197
10.4;8.3. THE p53 FAMILY TREE;198
10.5;8.4. PHENOTYPES OF THE p63 AND p73 KNOCKOUT MICE;200
10.6;8.5. p63 AND p73 EXHIBIT p53 – LIKE PROPERTIES;201
10.7;8.6. p63 AND p73 IN THE DNA DAMAGE RESPONSE;202
10.8;8.7. IMPLICATIONS FOR CANCER AND THE FUTURE;204
10.9;REFERENCES;205
11;9 The Oncogenic Activity of p53 Mutants;208
11.1;SUMMARY;208
11.2;9.1. INTRODUCTION;208
11.3;9.2. ONCOGENIC EFFECTS OF p53 MUTANTS I: DOMINANT NEGATIVE SUPPRESSION;211
11.4;9.3. ONCOGENIC EFFECTS OF p53 MUTANTS II: GOF;212
11.5;9.4. PROPOSED MECHANISMS OF GOF;214
11.6;9.5. COMBINED EFFECTS OF NEGATIVE DOMINANCE AND GOF;216
11.7;9.6. THE STABILIZATION OF MUTANT p53 PROTEINS;216
11.8;9.7. CLINICAL MANIFESTATIONS OF MUTANT p53 ONCOGENICITY;217
11.9;9.8. DIFFERENCES BETWEEN p53 MUTANTS;218
11.10;9.9. THERAPEUTIC APPROACHES;220
11.11;9.10. CONCLUSION;223
11.12;APPENDIX 9.1;224
11.13;RECENT REVIEWS;224
11.14;USEFUL WEBSITES;225
11.15;REFERENCES;225
12;10 Therapeutic Strategies Based on Pharmacological Modulation of p53 Pathway;233
12.1;SUMMARY;233
12.2;10.1. WHY p53 IS A THERAPEUTIC TARGET;233
12.3;10.2. THERAPIES BASED ON PHARMACOLOGICAL ACTIVATION OF p53;235
12.4;10.3. PROSPECTIVE THERAPEUTIC APPLICATIONS OF p53 INHIBITORS;241
12.5;10.4. CONCLUDING REMARKS: PERSPECTIVES OF PHARMACOLOGICAL MODULATORS OF p53;245
12.6;ACKNOWLEDGMENTS;246
12.7;REFERENCES;246
13;Index;251