APC Proteins (eBook)

Inke Näthke is the professor of Epithelial Biology at the University of Dundee. Her research interest is to determine how specific molecular changes produce changes in cells and ultimately in whole tissues during early stages of tumourigenesis. Her focus is on colorectal cancers but the common epithelial origin of most tumours makes this work relevant to many other organs. Her work has led her to examine not only how cells move and divide but also how they know where they are, and how they work together to build a functional tissue. Professor Näthke received her training at San Jose State University, the University of California San Francisco, Stanford and Harvard Medical Schools. Brooke McCartney is an Assistant Professor of Biological Sciences at Carnegie Mellon University. She is interested in how signaling pathways regulate the cytoskeleton and how this leads to changes in cytoskeletal and tissue architecture. The focus of her lab is the role of APC proteins and Wnt signaling in morphogenesis, both at the level of the cytoskeleton and at the level of tissues, using Drosophila melanogaster as a model system. Dr. McCartney received her training at Mount Holyoke College, Duke University, and the University of North Carolina at Chapel Hill.

DEDICATION 6
PREFACE 7
ABOUT THE EDITORS... 9
ABOUT THE EDITORS... 10
PARTICIPANTS 11
Table of Contents 13
CHAPTER 1 APC and ß-Catenin Degradation 17
Introduction 17
APC Is a Critical Component of the ß-Catenin Destruction Complex 17
The Role of APC in Recruiting ß-Catenin to the Complex 19
Phosphorylation of APC Enhances Affinity for ß-Catenin 20
A Possible Role of PP2A in Regulating Competition between APC and Axin for ß-Catenin Binding 20
Is There a Role for the Destruction Complex in the Nucleus? 22
Regulation of APC and the Destruction Complex by Wnt Signaling 22
Phospho-Dvl and Frat 22
Axin/LRP Binding 23
Wnt Regulation of APC Stability 24
Does APC also Play a Positive Role in Wnt/ß-Catenin Signaling? 24
Conclusion 24
References 25
CHAPTER 2 Nuclear APC 29
Abstract 29
Introduction 29
Detection of Nuclear APC 29
APC Domains Contributing to Nuclear Import and Export 30
APC Shuttles between the Nucleus and Cytoplasm 34
Factors that Affect the Subcellular Distribution of APC 34
APC and Nuclear Export of ß-Catenin 37
APC and Nuclear Sequestration of ß-Catenin 38
The Role of Other Nuclear Proteins in APC Mediated ß-Catenin Sequestration 39
Interaction of APC with DNA and Other Nuclear Proteins 40
The Requirement for Nuclear APC in Tumor Suppression 40
Future Applications, New Research, and Anticipated Developments 42
Acknowledgements 42
References 43
CHAPTER 3 APC in Cell Migration 46
Abstract 46
Introduction 46
APC Localization in Migrating Cells 47
Actin-Dependent Localization of APC at Cell-Cell Contacts 48
Microtubule-Dependent Localization of APC at Protrusive Sites 48
Regulation of APC Localization During Cell Migration 49
APC and Protrusive Activity 50
APC and Regulation of the Microtubule Cytoskeleton 50
APC and Regulation of the Actin Cytoskeleton 50
APC and Cell Polarity 51
APC, Microtubule Anchoring and Centrosome Reorientation 51
APC and Polarity Proteins 52
Conclusion 52
Acknowledgements 53
References 53
CHAPTER 4 The APC-EB1 Interaction 57
Abstract 57
Introduction 57
EB1 Is an Evolutionarily Conserved Microtubule Plus-End Binding Protein 57
The EB1 Binding Region in APC 58
The APC Binding Site in EB1 58
Interphase Functions of the APC-EB1 Interaction 60
Mitotic Functions of the APC-ED1 Interaction 61
APC-EB1 Interactions in Other Organisms 63
Conclusion 63
Acknowledgments 63
References 63
CHAPTER 5 The Role of APC in Mitosis and in Chromosome Instability 67
Abstract 67
Introduction 67
APC in Mitotic Cells 68
APC Regulates Microtubule Dynamics in Mitosis 71
APC Function in the Spindle Checkpoint 73
APC and Microtubule Dynamics in Cytokinesis 74
The Dominant Activity of APC in Mitosis-The Tip of the Iceberg 77
References 78
CHAPTER 6 Role of APC and Its Binding Partners in Regulating Microtuhules in Mitosis 81
Abstract 81
Introduction 81
APC at the Kinetochore: Regulation of Microtubule Dynamics 81
APC at the Cortex: Role in Spindle Positioning 83
APC at Centrosomes: Potential Roles 85
Connecting APC Functions in Regulating Wnt Signaling and Microtubules 86
Multiple Mechansims by which APC Mutations Contribute to Cancer 86
Acknowledgements 87
References 87
CHAPTER 7 The Adenomatous Polyposis Coli Tumor Suppressor and Wnt Signalingin the Regulation of Apoptosis 91
Abstract 91
Introduction 91
Overview of Apoptotic Cell Death 92
APC Prevents Neuronal Apoptosis during Retinal Development in Drosophila 93
APC Prevents the Apoptotic Death of Mammalian Cephalic and Cardiac Neural Crest Cells 95
APC Loss and Activation of Wnt Signaling Results in Both Increased Cell Proliferation and Increased Apoptosis in Mammalian Intestinal Epithelia 96
Promotion of Cell Survival and Negative Regulation of Apoptosis by Wnt Signaling in Carcinomas 96
Conclusion 97
Acknowledgements 97
References 98
CHAPTER 8 APC and Its Modifiers in Colon Cancer 101
Abstract 101
Colorectal Cancer 101
Biology of the Human Intestine 102
Development of Human Intestinal Tumors 102
Discovery of APC Mutations in Human Colon Cancer 103
Function of Apc 103
Structure of APC 104
Genotype-Phenotype Correlation in FAP 104
Biology of the Murine Intestine: An Introduction to Murine Models of Colon Cancer 106
Mouse Models of Intestinal Cancer 106
Biology of Mouse Intestinal Tumors 107
Rat Models of Intestinal Cancer 107
Apc Mutations in Other Organisms 109
Mechanisms of Loss of Heterozygosity at the Apc Locus 109
Are Some Apc Truncation Peptides Dominant Negative? 110
Modifiers of Murine Intestinal Cancer 111
Conclusion 113
References 116
CHAPTER 9 Tissue-Specific Tumour Suppression by APC 123
Abstract 123
Introduction 123
Apc Gene Deletion in the Intestinal Epithelium 124
The Phenotype of Apc Loss and Wnt Signalling 124
PPAR ß/d 126
Cyclin D1 126
Myc 127
Wnt-Independent Consequences Induced by Loss of Apc 128
Deletion of Ape in the Liver 130
Deletion of Apc in the Kidney 131
Deletion of Apc in the Mammary 132
Conclusion 132
References 133
CHAPTER 10 Extra-Colonic Manifestations of Familial Adenomatous Polyposis Coli 135
Abstract 135
Desmoids 136
Introduction 135
Congenital Hypertrophy of the Retinal Pigment Epithelium 137
Oral and Maxillofacial Manifestations 138
Extra-Gastrointestinal Tumour Predisposition 139
Marfanoid Habitus 140
References 141
INDEX 144