Enders Cell Cycle Deregulation in Cancer

1. Auflage 2010
ISBN: 978-1-4419-1770-6
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 206 Seiten

Reihe: Current Cancer Research

Cancer is fundamentally a disease of abnormal cell proliferation: Cancer cells multiply when and where they should not. This proliferation entails escape from normal bounds imposed by the tissue environment, the internal biology of the cell (DNA damage, chromosomal imbalances, disorganized mitotic spindles), and the proliferative history of the cell (normal generational times). Some of the key oncogenic events in cancer directly perturb proteins that regulate progression through the cell division cycle, others alter cell cycle progression indirectly, through effects on signaling pathway that impinge on the cell cycle. This biology is fundamentally important in cancer therapy. Many of the workhorse treatments for cancer rely on killing proliferating cells. Furthermore, there is growing recognition that stem cell-transit amplifying cell hierarchies may persist or be generated during tumorigenesis, generating important functional heterogeneity in cell cycle control among tumor cells, with far-reaching scientific and clinical implications. This volume outlines major cell cycle perturbations that drive tumorigenesis and considers the prospects for using such knowledge in cancer therapy.

Autoren/Hrsg.

Enders, Greg H.

Inhaltsverzeichnis

1;Contents;6
2;Contributors;8
3;Part I Starting the Cell Division Cycle;10
3.1;1 Escape from Cellular Quiescence;11
3.1.1;1.1 Quiescence: The Reversible State;11
3.1.2;1.2 Overcoming the Restriction Point;13
3.1.2.1;1.2.1 The Restriction Point;13
3.1.2.2;1.2.2 G1-Cyclins/CDK, pRB, and E2F Transcription Factors;14
3.1.2.3;1.2.3 Is Inactivation of Pocket Proteins Beyond a Certain Threshold Sufficient for Passage Through R?;16
3.1.2.4;1.2.4 What Are Cells Doing as They Exit Quiescence Back into G1?;17
3.1.3;1.3 Oncogenes That Cooperate to Bypass Quiescence;18
3.1.4;1.4 SV40 and Exit from Quiescence;21
3.1.4.1;1.4.1 SV40 Tumor Antigens and Their Cellular Targets;21
3.1.4.2;1.4.2 SV40 Small t Antigen Promotes Exit from Quiescence;23
3.1.5;1.5 Future Directions;25
3.1.6;References;26
3.2;2 Interplay Between Cyclin-Dependent Kinases and E2F-Dependent Transcription;31
3.2.1;2.1 Cell Cycle Progression Is Driven by the Integrated Action of Cyclin-Dependent Kinases and a Transcriptional Network;31
3.2.2;2.2 Rb and E2F Proteins Regulate the G1 to S-Phase Transition in Higher Eukaryotes;33
3.2.3;2.3 CDK Phosphorylation Is One of Several Mechanisms That Regulate E2F Activity;35
3.2.4;2.4 How Do E2Fs Activate Transcription?;37
3.2.5;2.5 Drosophila as a Model System to Study E2F Activity In Vivo;39
3.2.6;2.6 CDK8Cyclin C Negatively Regulates E2F1-Dependent Transcription;40
3.2.7;2.7 Deregulation of CDK8CycC in Human Cancers;42
3.2.8;2.8 Conclusions and Future Directions;43
3.2.9;References;44
3.3;3 Regulation of Pre-RC Assembly: A Complex Symphony Orchestrated by CDKs;50
3.3.1;3.1 The Pre-replication Complex;50
3.3.2;3.2 Cyclin-Dependent Kinases (CDKs) and General Cell Cycle Control;51
3.3.3;3.3 Positive Impact of CDKs on Pre-RC Assembly (G0G1 Phase);54
3.3.4;3.4 Negative Impact of CDKs on Pre-RC Assembly (SM Phase);55
3.3.5;3.5 Perturbations of Pre-RC Assembly and Cancer;56
3.3.5.1;3.5.1 Functional Effects of Deregulated Pre-RC Assembly;56
3.3.5.2;3.5.2 Deregulation of Pre-RC Components in Cancer;57
3.3.6;3.6 Conclusions;57
3.3.7;3.7 Future Directions;58
3.3.8;References;58
4;Part II Proliferation Under Duress;63
4.1;4 Mitotic Checkpoint and Chromosome Instability in Cancer;64
4.1.1;4.1 Chromosome Instability (CIN);65
4.1.1.1;4.1.1 Chromosome Missegregation, Aneuploidy, and CIN;65
4.1.1.2;4.1.2 What Are the Defects That Result in Chromosome Missegregation in CIN Cells?;66
4.1.2;4.2 The Mitotic Checkpoint;66
4.1.3;4.3 Aneuploidy/CIN, Mitotic Checkpoint, and Cancer;69
4.1.4;4.4 Mitosis as a Target for Chemotherapy;72
4.1.5;4.5 Conclusions and Future Directions;74
4.1.6;References;75
4.2;5 Mitotic Catastrophe;83
4.2.1;5.1 Introduction;83
4.2.2;5.2 Normal Control of Mitosis and the Spindle-Assembly Checkpoint;84
4.2.3;5.3 Mitotic Catastrophe Caused by Mitotic Block and Mitotic Slippage;87
4.2.4;5.4 Normal Control of the DNA Damage and Replication Checkpoints;89
4.2.5;5.5 Mitotic Catastrophe Caused by Abrogation of DNA Integrity Checkpoints;91
4.2.6;5.6 Mitotic Catastrophe as a Specialized Form of Cell Death Involving CDK1;92
4.2.7;5.7 Mitotic Catastrophe and Cancer: Future Directions;93
4.2.8;References;95
4.3;6 p53, ARF, and the Control of Autophagy;101
4.3.1;6.1 The ARF Tumor Suppressor and Autophagy;101
4.3.2;6.2 ARF Induces Autophagy;102
4.3.3;6.3 ARF-Mediated Autophagy Can Enhance Cell Survival and Promote Tumor Progression;103
4.3.4;6.4 The p53 Tumor Suppressor and Autophagy: p53 Induces Autophagy;104
4.3.5;6.5 p53 Transactivates the Autophagy Gene DRAM;104
4.3.6;6.6 Nutrient Stress Signals to p53;105
4.3.7;6.7 p53 Negatively Regulates Autophagy in Unstressed Cells;105
4.3.8;6.8 Conclusions and Future Directions;106
4.3.9;References;107
5;Part III Long-Term Proliferation;110
5.1;7 Regulation of Self-Renewing Divisions in Normal and Leukaemia Stem Cells;111
5.1.1;7.1 Self-Renewal Potential of Normal Haematopoietic Stem Cells Is Limited;111
5.1.2;7.2 Haematopoietic Stem Cells Are Deeply Dormant;112
5.1.3;7.3 Genetic Models of Stem Cell Exhaustion;114
5.1.4;7.4 Molecular Mechanisms of Stem Cell Quiescence;116
5.1.5;7.5 Molecular Mechanisms of Stem Cell Exhaustion;117
5.1.6;7.6 Existence of Leukaemic Stem Cells;118
5.1.7;7.7 Leukaemic Stem Cells Are Quiescent;119
5.1.8;7.8 Regulation of Quiescence and Self-Renewal in Leukaemic Stem Cells;119
5.1.9;7.9 A Common Paradigm in Stem Cell Exhaustion;120
5.1.10;7.10 Future Directions;122
5.1.11;References;123
5.2;8 Maintenance of Telomeres in Cancer;128
5.2.1;8.1 Telomere Length in Mammals;128
5.2.2;8.2 Telomere Dysfunction;129
5.2.3;8.3 Chromosome End Protection: The Shelterin Complex;130
5.2.4;8.4 Telomere Elongation in Cancer;131
5.2.5;8.5 Telomere Instability and Cancer Progression;133
5.2.6;8.6 Future Perspectives;135
5.2.7;References;136
5.3;9 The Senescence Secretome and Its Impact on Tumor Suppression and Cancer;140
5.3.1;9.1 Triggers of Cell Senescence;140
5.3.2;9.2 Senescence Signaling Pathways;141
5.3.3;9.3 The Altered Secretory Phenotype of Senescent Cells The Senescence Secretome;142
5.3.3.1;9.3.1 Growth Regulators;143
5.3.3.2;9.3.2 Inflammatory Regulators;144
5.3.3.3;9.3.3 Stromal Regulators;144
5.3.3.4;9.3.4 Regulation of the Secretome;145
5.3.4;9.4 The Senescence Secreteome in Tumor Suppression;146
5.3.5;9.5 Summary;149
5.3.6;References;150
6;Part IV Applications in Preventing and Treating Cancer;156
6.1;10 Cell Cycle Deregulation in Pre-neoplasia: Case Study of Barrett's Oesophagus;157
6.1.1;10.1 Introduction to Pre-neoplasia;157
6.1.2;10.2 Introduction to Barretts Oesophagus and Oesophageal Cancer;158
6.1.3;10.3 Proliferation in Barretts Carcinogenesis;160
6.1.4;10.4 Factors Influencing Cell Cycle Progression;160
6.1.4.1;10.4.1 Role of Growth Factors and Oncogenes;161
6.1.4.2;10.4.2 Role of Luminal Factors;162
6.1.5;10.5 Conclusions and Future Directions;162
6.1.6;References;163
6.2;11 Targeting Cyclin-Dependent Kinases for Cancer Therapy;167
6.2.1;11.1 Introduction;167
6.2.2;11.2 Targeting Cdk4 and Cdk6;168
6.2.3;11.3 Targeting Cdk2 and Cdk1;170
6.2.4;11.4 Combined Targeting of Cdks and Anti-apoptotic Proteins;171
6.2.4.1;11.4.1 Transcriptional Cdk Inhibition;171
6.2.4.2;11.4.2 Survivin as a Target of Cdk1;172
6.2.5;11.5 Reduced Cyclin D1 Expression Mediated by Transcriptional Cdk Inhibition;172
6.2.6;11.6 Modulation of the p53 and p21 Waf1/Cip1 by Transcriptional Cdk Inhibition ;173
6.2.7;11.7 Cdks and E2F-1 Activity;173
6.2.7.1;11.7.1 Cdk Inhibition and the Prevention of Neutralization of E2F-1 Activity During S Phase;173
6.2.7.2;11.7.2 Role of Cdk8 in Modulation of E2F-1 Activity;174
6.2.8;11.8 Cdk Inhibition and DNA Damage;175
6.2.8.1;11.8.1 Induction of DNA Damage by Cdk Inhibition;175
6.2.8.2;11.8.2 Cdk Inhibition in DNA Damage-Induced Checkpoint Control;175
6.2.8.3;11.8.3 Cdk Inhibition and DNA Repair;178
6.2.9;11.9 Future Perspectives;179
6.2.10;References;180
7;Index;186