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Polyploidization and Cancer

:	Randy Y. C. Poon
:	Randy Y.C. Poon
:	Polyploidization and Cancer
:	Springer-Verlag
:	9781441961990
:	Advances in Experimental Medicine and Biology
:	1
:	CHF 135.30
:

:	Nichtklinische Fächer
:	English

:	151
:	Wasserzeichen/DRM
:	PC/MAC/eReader/Tablet
:	PDF

Limiting genome replication to once per cell cycle is vital for maintaining genome stability. Although polyploidization is of physiologically importance for several specialized cell types, inappropriate polyploidization is believed to promote aneuploidy and transformation. A growing body of evidence indicates that the surveillance mechanisms that prevent polyploidization are frequently perturbed in cancers. Progress in the past several years has unraveled some of the underlying principles that maintain genome stability. This book brings together leaders of the field to overview subjects relating to polyploidization and cancer.

Randy Y.C. Poon is a professor of Biochemistry at the Hong Kong University of Science and Technology. He was educated at Tonbridge School and received his Master of Arts degree from St. Catharine's College at the University of Cambridge. He then studied for a Doctor of Philosophy degree at the University of Cambridge and Cancer Research UK with Tim Hunt, FR S. Dr. Poon conducted postdoctoral training at the Salk Institute with Tony Hunter, FR S. Dr. Poon is a member of Editorial Board of numerous international journals, including the Biochemical Journal and Cancer Biology and Therapy. His research interests focus on understanding the molecular basis of cell cycle control in normal and cancer cells.

	Title Page	3
	Copyright Page	4
	DEDICATION	5
	PREFACE	6
	ABOUT THE EDITOR...	7
	PARTICIPANTS	8
	Table of Contents	10
	Chapter 1. POLYPLOIDY, ANEUPLOIDY AND THE EVOLUTION OF CANCER	13
	Introduction	13
	The Tetraploidy to Aneuploidy Progression in Carcinogenesis	13
	Tetraploidy and Aneuploidy in Barrett s Esophagus	14
	p16	15
	p53	15
	Tetraploidy	15
	Aneuploidy	15
	Not All Aneuploids Are Equal	16
	Why Do Cancer Cells Survive with Such Massive Alterations to Their Genome?	17
	Aneuploidy in Development	18
	Polyploidy in the Evolution of Species	19
	Why Is Aneuploidy Common in Neoplastic Progression?	19
	A Competitive Advantage of Aneuploidy	19
	Aneuploidy May Generate Advantageous Lesions	20
	Aneuploidy May Be an Evolutionarily Neutral By-Product of Carcinogenesis	21
	DNA Damage Sensing by Linkage	22
	Ancient and Recent Cancer Genes	22
	Conclusion	22
	Acknowledgements	23
	References	23
	Chapter 2. MOLECULAR MECHANISMS AND FUNCTION OF THE SPINDLE CHECKPOINT, A GUARDIAN OF THE CHROMOSOME STABILITY	26
	Introduction	26
	Bipolar Attachment and Chromosome Congression	27
	Molecular Basis of the Spindle Checkpoint	28
	Activation of the Spindle Checkpoint Signaling	30
	Mad2 Template Model	31
	Phosphorylation and Spindle Checkpoint Function	32
	Silencing the Spindle Checkpoint	33
	Additional Surveillance System	33
	A Trigger of Tumorigenesis	35
	Conclusion	35
	References	36
	Chapter 3. UNDERSTANDING CYTOKINESIS FAILURE	38
	Cytokinesis Occurs in Multiple Stages	38
	Stage I. Positioning the Division Plane and Initiating Cytokinesis	39
	The Importance of Microtubules	39
	The RhoA Pathway Plays an Essential Role in Furrow Initiation	39
	Failure of Cytokinesis During Stage I	41
	Stage II. Ingression of the Cleavage Furrow	41
	Stimulation of Actin Filament Assembly	41
	Localization and Activation of Myosin	42
	Organization of Actin and Myosin in the Furrow	43
	Scaffolding Proteins in the Furrow	44
	Anillin	44
	Septins	44
	Stage III. Formation of the Midbody	45
	Stage IV. Abscission	46
	Membrane Trafficking and Cytokinesis	46
	The Role of the Secretory Pathway	46
	The Role of Endocytosis and the Recycling Endosome Pathway	48
	Membrane Fusion During Abscission	48
	Role of the ESCRT Machinery	48
	Regulation of Cytokinesis	49
	Regulation of Cytokinesis by Protein Kinases	49
	Regulation of Cytokinesis by CDK Activity	49
	Regulation by Polo Kinase	50
	Regulation by Aurora B and the Chromosome Passenger Complex	51
	Regulation of Cytokinesis by Tyrosine Kinases	52
	Regulation of Cytokinesis by Lipids	52
	Coupling of Cytokinesis to Other Cellular Pathways	53
	Cytokinesis and Protein Synthesis	53
	Cytokinesis and DNA Replication	53
	Cytokinesis and DNA Damage	53
	Conclusion	54
	Acknowledgements	55
	References	55
	Chapter 4. DNA DAMAGE AND POLYPLOIDIZATION	67
	Polyploidization and Cancer	67
	Mechanisms of Polyploidization	68
	The DNA Damage Checkpoints	70
	Polyploidization Induced by DNA Damage	72
	The Sensitivity of Polyploid Cells to DNA Damage	74
	Polyploidization and Cancer Therapies	74
	Conclusion	75
	Acknowledgements	76
	References	76
	Chapter 5. ROLE OF THE p53 FAMILY IN STABILIZING THE GENOME AND PREVENTING POLYPLOIDIZATION	82
	p53 Tumor Suppressor	82
	p53 and Genomic Stability	83
	p53 and Cell Cycle Checkpoints	83
	G1/S Checkpoint	83
	p53 Model	83
	Intra-S Phase Checkpoint	83
	p53 Model	83
	G2/M Checkpoint	84
	p53 Model	84
	Mitotic Checkpoint or Spindle Assembly Checkpoint	84
	The p53 Model Is Controversial	84
	p53 in DNA Repair	84
	Mechanisms of Polyploidization	85
	Disadvantages of Polyploidy	85
	Tetraploidy Checkpoint Theory	86
	Agonists and Antagonists of p53 Function in Genome Stability	87
	Introduction to p73	87
	p73 Functions	88
	The Role of p73 in Genomic Stability	89
	Combined Loss of p53 and p73 Leads to Excess Polyploidy and Aneuploidy	89
	The Ploidy Defect Is Not Due to a Mitotic Defect but a Failure of Premitotic Mechanisms	89
	Excess Failure of the G2/M DNA Damage Checkpoint and Constitutive Deregulation of Cyclin-Cdk and p27/Kip1 Fuel Aberrant Ploidy upon p73 Loss	90
	Conclusion	95
	References	95
	Chapter 6. CENTROSOMES, POLYPLOIDY AND CANCER	101
	Introduction	101
	The Centrosome Duplication Cycle	102
	Aberrant Centrosome Numbers in Cancer Cells	102
	Multiple Pathways Can Lead to Aberrant Centrosome Numbers: Studies Using Human Papillomavirus (HPV) Oncoproteins	103
	Mechanisms o