p53 (Molecular Biology Intelligence Unit)

Cover......Page 1
Title Page......Page 2
Copyright Page......Page 3
About the Editors.........Page 4
About the Editors.........Page 5
Table of Contents......Page 6
PREFACE......Page 12
Introduction......Page 13
Sequence Variations......Page 14
Other Alterations......Page 16
Types of Mutations......Page 17
Sequence Variation and Phenotype......Page 18
Mechanisms of Mutation......Page 20
Loss of Function......Page 22
TP53 Mutations as Markers of Exposure......Page 24
TP53 Mutations as Prognostic and Predictive Factors......Page 25
Therapies Targeting TP53 Mutations......Page 26
References......Page 27
Early Studies of p53 in the Mouse......Page 31
p53-/- Mice......Page 32
p53+/- Mice......Page 33
Effects of Genetic Background on p53 Knockout Phenotypes......Page 34
Carcinogenesis Studies......Page 35
Crosses with Oncogene-Expressing or Tumor Suppressor Knockout Strains......Page 36
Crosses with Telomerase-Deficient Mice......Page 37
p53 Tumor-Derived Mutants......Page 38
Mutants to Elucidate Mechanisms of p53 Action......Page 39
A Role for p53 in Aging?......Page 40
How p53 Acts as a Tumor Suppressor......Page 42
References......Page 43
Introduction......Page 48
Structural Homology between the Family Members......Page 49
The Proline-Rich Domain in the p53 Family......Page 51
Phylogeny of the TP53 Family......Page 52
Lessons from Knock-Out Mouse Models......Page 53
Inherited TP63 Mutations in Humans......Page 54
Expression of p63 and p73......Page 56
Regulation of p63 and p73 Stability......Page 57
Regulation of p63 and p73 in Response to Stress......Page 58
TP63 Amplification......Page 59
Conclusion......Page 60
References......Page 62
p53 Regulation......Page 65
Paradigm I: Kinase Regulation of the Specific DNA Binding Function of p53......Page 67
Paradigm II: Kinase Regulation of the Interaction of p53 with the Acetyltransferase p300......Page 69
Paradigm III: DNA-Dependent Acetylation of p53 and the Proline-Repeat Transactivation Domain......Page 70
Paradigm IV: How Cells Integrate the p53 Response through Distinct Stresses......Page 71
References......Page 74
Introduction......Page 77
The p53-Mdm2 Feedback Loop......Page 78
Mdm2-Mediated p53 Ubiquitination and Degradation......Page 79
Breaking the p53/Mdm2 Regulatory Loop......Page 80
P53 Activation by the ATM/ATR-Chk Pathways......Page 81
Mdm2 Inactivation by the ATM-c-Abl Pathway......Page 82
Stimulation of Mdm2 by the Akt/PTEN Pathway......Page 84
A Role for the Proline Rich Region of p53......Page 85
The ARF Oncogenic Pathway......Page 86
The Spatial Distribution Mode of Regulation: The Nuclear Cytoplasmic Boundary......Page 87
PML Nuclear Bodies as a Regulatory Junction......Page 88
References......Page 90
ntroduction......Page 97
Function of p53 as an Activating Transcription Factor......Page 99
DNA Binding and Nuclear Localization of p53......Page 100
Degradation of p53......Page 101
MDM2 and MDMX Abundance......Page 102
Activity of MDM2 as an E3 Ubiquitin-Ligase towards p53......Page 103
Response to Ionizing Radiation-Induced Genotoxic Stress......Page 105
References......Page 106
Introduction......Page 112
p21: Unstructured and Disordered......Page 113
Impact of COOH Terminal Binding Proteins on p21 Stability......Page 114
The Role of p21 NH2 Terminus in Regulating Stability......Page 116
Effect of Post-Translational Modifications on p21 Abundance......Page 117
The Role of Ubiquitination in Proteasomal p21 Degradation......Page 118
The Impact of Ubiquitinating Enzyme Manipulation on p21 Stability In Vivo......Page 120
Physiological Destabilization and Degradation of p21......Page 122
Ubiquitin-Mediated p21 Degradation under Conditions of Stress......Page 123
Ubiquitin Independent Protein Turnover......Page 125
References......Page 126
p53 Nuclear Import......Page 129
Sub-Nuclear Trafficking of p53......Page 131
p53 Nuclear Export......Page 132
p53 Trafficking to the Mitochondria......Page 135
References......Page 136
Introduction......Page 139
Allosteric/Conformational Mechanism......Page 140
The Novel Two-Binding Sites Hypothesis......Page 143
p53 Interactions with Chromatin......Page 144
Rescue of p53 Mutants by “Conformational” Drugs: A Proof of Principle Is Missing?......Page 149
Acknowledgements......Page 150
References......Page 151
Introduction......Page 154
p53 as a Transcription Factor......Page 155
Systems of Analysis......Page 156
Heterogeneity of the Microarray Based p53 Expression Profile Data......Page 158
Primary and Secondary Targets......Page 159
Major p53 Targets and Alternate Pathways Identified by Microarrays: Who Makes the Decisions?......Page 161
Inhibition of p53 Induced Apoptosis without Affecting p53 Transactivation......Page 162
Gene Suppression......Page 163
Signal Transduction......Page 166
Conclusion and Perspectives......Page 167
References......Page 168
Introduction......Page 172
Adenovirus......Page 173
SV40 and Polyomavirus......Page 175
Papillomavirus......Page 177
Epstein-Barr Virus......Page 180
Cytomegalovirus......Page 182
References......Page 183
Overview of the Immune System......Page 190
p53 Protects against Virus Infection......Page 191
Mechanisms of p53 Induction in Response to Viral Infection......Page 192
p53 and the dsRNA Response......Page 193
Opposing Roles of the Immune System in Carcinogenesis......Page 195
References......Page 196
Index......Page 199