Two Faces of Evil: Cancer and Neurodegeneration (Research and Perspectives in Alzheimer's Disease)

The two greatest medical fears of the aging population are cancer and Alzheimer’s disease. Despite dramatic advances in understanding the molecular etiology of these disorders, therapeutic options for many patients with advanced disease have changed little and outcomes remain dismal. Paradoxically, recent findings suggest that some of the same molecules and biochemical processes underlying cancer may also participate in neurodegeneration. Therefore, it would be very useful to bring together experts from the fields of cancer research and neurodegeneration for discussions of the latest advances and ideas, with a particular emphasis on areas of overlap, to stimulate transdisciplinary interactions with the hope of accelerating progress. Cancer arises as a consequence of a breakdown in the genetic and epigenetic processes governing cell proliferation and cell death. Alterations in several classes of signaling molecules, both oncogenes and tumor suppressor genes, lead to uncontrolled cell growth. Over the past two decades, details of the intricate signaling pathways, from cell surface receptors through protein kinase cascades, transcription factors and modulators of chromatin, as well as the DNA damage response pathways linked to cell cycle control that guard the genome, have been uncovered. In some instances, key regulatory proteins have provided novel targets for development of small molecule inhibitors that are currently being tested in the clinic. The development of the nervous system relies on many of the signaling pathways and growth control processes that go awry in cancer. However, in mature neurons, the very same signaling proteins participate in transduction cascades linking short-term stimuli, elicited by synaptic stimulation, to long-term alterations in neuronal circuits through the regulation of gene expression and chromatin structure. These long-term adaptive modifications lead to changes in synaptic structure and function that contribute to learning and memory. The persistence of growth regulatory molecules in postmitotic neurons provides an opportunity for their contribution to pathophysiological processes resulting in neuronal loss. Recently, evidence has accumulated suggesting an association of cell cycle proteins and signal transduction proteins with neurodegeneration. Indeed, inhibitors of histone deacetylation have shown promise both as anti-cancer agents and in the prevention of neuronal loss Front Matter....Pages i-xiii Updating the Mammalian Cell Cycle: The Role of Interphase Cdks in Tissue Homeostasis and Cancer....Pages 1-16 The Role of Cdk5 as a Cell Cycle Suppressor in Post-mitotic Neurons....Pages 17-25 Actin-SRF Signaling in the Developing and Mature Murine Brain....Pages 27-39 The E3 Ubiquitin Ligase Ube3A Regulates Synaptic Function Through the Ubiquitination of Arc....Pages 41-56 Targeting Children’s Brain Tumors: Development of Hedgehog Pathway Inhibitors for Medulloblastoma....Pages 57-71 Primary Cilia as Switches in Brain Development and Cancer....Pages 73-82 Nervous System Aging, Degeneration, and the p53 Family....Pages 83-93 p53, a Molecular Bridge Between Alzheimer’s Disease Pathology and Cancers?....Pages 95-101 RNA regulation in Neurodegeneration and Cancer....Pages 103-111 Bridging Environment and DNA: Activity-Induced Epigenetic Modification in the Adult Brain....Pages 113-123 Intrinsic Brain Signaling Pathways: Targets of Neuron Degeneration....Pages 125-131 The miRNA System: Bifurcation Points of Cancer and Neurodegeneration....Pages 133-142 Molecular Mechanisms for the Initiation and Maintenance of Long-Term Memory Storage....Pages 143-160 Back Matter....Pages 161-163 Annotation Homeostasis involves a delicate interplay between generative and degenerative processes to maintain a stable internal environment. In biological systems, equilibrium is established and controlled through a series of negative feedback mechanisms driven by a range of signal transduction processes. Failures in these complex communication pathways result in instability leading to disease. Cancer represents a state of imbalance caused by an excess of cell proliferation. In contrast, neurodegeneration is a consequence of excessive cell loss in the nervous system. Both of these disorders exhort profound tolls on humanity and they have been subject to a great deal of research designed to ameliorate this suffering. For the most part, the topics have been viewed as distinct and rarely do opportunities arise for transdisciplinary discussions among experts in both fields. However, cancer and neurodegeneration represent yin-yang counterpoints in the regulation of cell growth, and it is reasonable to hypothesize that key regulatory events mediated by oncogenes and tumor suppressor genes in cancer may also affect neurodegenerative processes Two Faces of Evil: Cancer and Neurodegeneration 4 Foreword 6 Acknowledgments 8 Contents 10 Contributors 12 Updating the Mammalian Cell Cycle: The Role of Interphase Cdks in Tissue Homeostasis and Cancer 16 The Role of Cdk5 as a Cell Cycle Suppressor in Post-mitotic Neurons 32 Actin-SRF Signaling in the Developing and Mature Murine Brain 41 The E3 Ubiquitin Ligase Ube3A Regulates Synaptic Function Through the Ubiquitination of Arc 54 Targeting Children ́s Brain Tumors: Development of Hedgehog Pathway Inhibitors for Medulloblastoma 70 Primary Cilia as Switches in Brain Development and Cancer 85 Nervous System Aging, Degeneration, and the p53 Family 95 p53, a Molecular Bridge Between Alzheimer ́s Disease Pathology and Cancers? 106 RNA regulation in Neurodegeneration and Cancer 113 Bridging Environment and DNA: Activity-Induced Epigenetic Modification in the Adult Brain 122 Intrinsic Brain Signaling Pathways: Targets of Neuron Degeneration 133 The miRNA System: Bifurcation Points of Cancer and Neurodegeneration 140 Molecular Mechanisms for the Initiation and Maintenance of Long-Term Memory Storage 150 Index 168