Two Faces of Evil: Cancer and Neurodegeneration (eBook)

Two Faces of Evil: Cancer and Neurodegeneration 3
Foreword 5
Acknowledgments 7
Contents 9
Contributors 11
Updating the Mammalian Cell Cycle: The Role of Interphase Cdks in Tissue Homeostasis and Cancer 15
1 Mammalian Cdks and the Classical Cell Cycle Model 17
2 Interphase Cdks are Not Essential for the Mammalian Cell Cycle 19
3 Limited Compensatory Activities Among Interphase Cdks 21
4 Interphase Cdks Have Evolved to Drive Proliferation of Highly Specialized Cells 24
5 Cell Cycle Cdks and Cancer 25
6 Are Interphase Cdks Required for Tumor Development? 26
References 29
The Role of Cdk5 as a Cell Cycle Suppressor in Post-mitotic Neurons 31
1 Introduction 32
2 Cdk5 Plays an Important Role in Neuronal Development 32
3 Cdk5 Serves Important Functions in the Regulation of Synaptic Function 33
4 Cdk5 is a Cell Cycle Suppressor in Post-mitotic Neurons 33
5 Cdk5 Inhibits the Cell Cycle in a Kinase-Independent Fashion 34
6 Cdk5 Inhibits the Cell Cycle by Sequestering E2F1 35
7 The Implications of the Central Role of Cdk5 in Neuronal Cell Cycle Suppression 36
References 38
Actin-SRF Signaling in the Developing and Mature Murine Brain 40
1 Principles of Actin-SRF Signaling in Brain Cells 40
1.1 Actin Dynamics Regulates Gene Expression Upon Activation of MRTF-SRF Signaling 40
1.2 Actin Dynamics in Neuronal Network Assembly 41
1.3 Actin-MRTF-SRF interplay in Neuronal Signaling 42
2 Essential functions of SRF and MRTF in Mouse Brain Development 43
2.1 Embryonic Neuronal Migration 43
2.2 Axonal Outgrowth, Guidance, and Synaptic Targeting 44
3 Functional Actin-SRF Interplay in the Mature Brain 45
3.1 Activity-Induced Gene Expression 45
3.2 Learning and Memory 45
4 Linking SRF to Neurodegenerative Diseases, Psychiatric Disorders, and Addiction 46
4.1 SRF Protects Against Axonal De-myelination and Degeneration 46
4.2 SRF and Epileptic Seizure-Induced Neuronal IEG Expression 47
4.3 SRF in M. Alzheimer 47
4.4 SRF as a Novel Player in Addictive Behavior and Hyperactive Disorder 48
References 49
The E3 Ubiquitin Ligase Ube3A Regulates Synaptic Function Through the Ubiquitination of Arc 53
1 A Role for Ube3A in Human Disorders of Cognitive Function 54
2 Ube3a is a Neuronal Activity-Regulated Gene 56
3 Regulation of Synaptic AMPA Receptor Function by Ube3A 57
4 A Novel Proteomic Approach to Ube3A Substrate Identification 60
5 Arc is a Neuronal Ube3A Substrate that Mediates the Effect of Ube3A on AMPAR Trafficking 62
6 Discussion 64
References 66
Targeting Children´s Brain Tumors: Development of Hedgehog Pathway Inhibitors for Medulloblastoma 69
1 Introduction 69
2 Role of the Hh Pathway in Medulloblastoma 71
3 Targeting Smoothened 72
4 Hh Pathway is Downregulated in Tumor Cell Lines 73
5 Direct Allografts Retain Hh Pathway Activity 74
6 Testing Targeted Therapies in Mice 75
7 HhAntag Eradicates Large Tumors in PtchI+/-p53-/- Mice 75
8 Hh Pathway Inhibition Causes Bone Defects in Young Mice 77
9 Inhibiting the Hh Pathway in the Clinic 79
References 80
Primary Cilia as Switches in Brain Development and Cancer 84
1 Introduction 84
2 Ciliogenesis 85
3 Primary cilia and Hh signaling 86
4 Primary Cilia in the Specification of Neural Progenitors 88
5 Primary Cilia and Tumorigenesis 89
6 Conclusion 90
References 91
Nervous System Aging, Degeneration, and the p53 Family 94
1 Introduction 94
2 The p53 Family Regulates Neuronal Survival and Longevity 96
3 p73 Regulates Neurodegeneration 97
4 The p53 Family Regulates Aging in Part by Regulating Adult Stem Cell Pools 99
5 The p53 Family and Neural Precursor Cells 100
6 A Model for the p53 Family and Neurodegeneration 101
References 102
p53, a Molecular Bridge Between Alzheimer´s Disease Pathology and Cancers? 105
1 Introduction 105
2 p53 and Members of the gamma-Secretase Complex: an Intimate Functional Cross-Talk 106
3 Cancer and AD: Is There a Molecular Link? 108
References 109
RNA regulation in Neurodegeneration and Cancer 112
1 Neurologic Disease and Cancer: The Paraneoplastic Neurologic Degenerations 112
2 RNA Binding Proteins in Neurologic Disease and Cancer 114
3 Back to the Basics: RBP Functional Studies 114
4 Genetic Systems and RBP Function 115
5 Bioinformatics, Genetics and Biochemistry: Beginnings of a Holistic Approach to RBP Function 115
6 HITS-CLIP and the Development of a Comprehensive Approach to RBP Function 116
References 118
Bridging Environment and DNA: Activity-Induced Epigenetic Modification in the Adult Brain 121
1 Introduction 121
2 DNA Methylation in the Brain 123
3 Active Modification of DNA Methylation in Neurons 124
4 Gadd45b Links Neuronal Activity to DNA Demethylation 125
5 Neuronal Activity Modifies the DNA Methylation Landscape 127
6 Future Perspectives 128
References 129
Intrinsic Brain Signaling Pathways: Targets of Neuron Degeneration 132
1 Introduction 133
2 Phosphorylation in SCA1: An Intrinsic Pathway that Drives Pathogenesis 133
3 Phosphorylation in Some Other Polyglutamine Neurodegenerative Diseases 136
4 Perspective 136
References 137
The miRNA System: Bifurcation Points of Cancer and Neurodegeneration 139
1 Introduction 139
2 miRNAs and Cancer 141
3 A Specialized Role for miRNAs at the Synapse 142
4 Which mRNAs are Regulated by miRNAs at the Synapse? 144
5 Function of miRNA Regulation of Translation at Synapses 145
References 146
Molecular Mechanisms for the Initiation and Maintenance of Long-Term Memory Storage 149
1 Memory Has Both A Short-term and A Long-Term Component 150
2 Initiation: Transcription, Transport and Local Translation 151
3 Initiation: Synapse-Specific Induction of Long-Term Memory 154
4 Persistence of Memory Storage Requires Local Cytoplasmic Polyadenylation 156
5 A Prion-Like Mechanism of CPEB Regulates Cytoplasmic Polyadenylation 157
6 ApCPEB Represents a New Class of Functional Prions 160
7 Conclusions 161
References 162
Index 167