Cell Division Machinery And Disease (advances In Experimental Medicine And Biology)

This book critically evaluates the causal link between cell division machinery and disease. Further, it identifies key open questions in the field and the means for exploring them. Throughout the various chapters, internationally known contributors present the evidence for and against a causal link between key elements of the cell division machinery and diseases such as cancer, neuropathologies, aging, and infertility. A more clinically oriented chapter further discusses the current and future applications of anti-mitotic drugs in these diseases. __Cell Division Machinery and Disease__ is essential reading for graduate or advanced graduate students, researchers or scientists working on cell division as well as clinicians interested in the molecular mechanisms of the discussed diseases. Preface 5 Acknowledgments 8 Contents 9 Contributors 10 Chapter 1: Meiotic Divisions: No Place for Gender Equality 12 1.1 Meiotic Cell Division 13 1.2 Monopolar Attachment in Meiosis I 13 1.3 Chiasmata 16 1.4 Cohesin Removal 16 1.5 Spindle Assembly Checkpoint 18 1.6 Age-Related Differences in Male and Female Gametogenesis 19 1.7 How Meiotic Segregation Errors Occur 19 1.7.1 Errors in Male Meiosis 19 1.7.2 Errors in Female Meiosis 20 1.8 Genetic Predispositions to Error Prone Chromosome Segregation in Meiosis 21 1.9 Other Genetic Reasons Why Meiosis May Go Awry 22 1.10 Consequences of Meiotic Missegregations 22 1.11 Conclusion 24 References 24 Chapter 2: Consequences of Centrosome Dysfunction During Brain Development 29 2.1 The Centrosome Duplication Cycle 29 2.1.1 Proteins Required for Centrosome Duplication 30 2.2 The Centrosome and the Mitotic Spindle 31 2.3 The Centrosome and the Cilium 32 2.4 General Principles Governing the Effects of Centrosome Dysfunction 33 2.5 Neocortex Development: Evolutionary Insights 34 2.5.1 Centrosome and Brain Development: Lessons from Drosophila 35 2.5.2 Centrosome and Brain Development: Lessons from Zebrafish 36 2.5.3 Centrosome and Brain Development: Lessons from Mouse 36 2.6 The Centrosome and Its Role in Primordial Microcephalic Disorders 37 2.6.1 Autosomal Recessive Primary Microcephaly (MCPH: Microcephaly Primary Hereditary) 38 2.6.1.1 Centriole Duplication Genes: CEP152, STIL, CEP135, CEP63, SAS-6 and CPAP/CENPJ 39 2.6.1.2 Genes Encoding PCM Proteins: CDK5RAP2 and CDK6 40 2.6.1.3 Genes Encoding Spindle-Pole Associated Proteins: ASPM and WDR62 40 2.6.2 Majewski/Microcephalic Osteodysplastic Primordial Dwarfism Type II (MOPD-II) 41 2.6.3 Seckel Syndrome (SCKS) 42 2.7 Centrosomal Genes and Other Growth Syndromes 42 2.8 Other Centrosome-Related Developmental Syndromes 43 2.9 Concluding Remarks and Current Opinions on Microcephaly 44 References 45 Chapter 3: Dividing with Extra Centrosomes: A Double Edged Sword for Cancer Cells 56 3.1 Introduction 56 3.2 Centrosome Amplification and Cancer 58 3.3 Centrosome Amplification: A Double Edged Sword? 60 3.3.1 p53-Dependent Cell Cycle Arrest 60 3.3.2 Dividing with Extra Centrosomes 61 3.3.2.1 Centrosome Clustering 62 Spindle Assembly Checkpoint and Chromosomal Passenger Complex 63 Kinetochore-Microtubule Tension 63 Actin Cytoskeleton 64 Microtubule Associated Proteins (MAPs) 65 3.3.2.2 Centrosome Inactivation 66 3.3.2.3 Centrosome Loss 67 3.4 Are there Benefits to Centrosome Amplification? 67 3.4.1 Chromosome Instability (CIN) 67 3.4.2 Asymmetric Stem Cell Division 69 3.4.3 Cell Invasion 69 3.5 Therapeutic Advantage 70 3.6 Concluding Remarks 71 References 71 Chapter 4: Kinetochore Malfunction in Human Pathologies 77 4.1 Mitosis and Mitotic Surveillance Mechanisms 78 4.1.1 Kinetochores 78 4.1.2 Error-Correction and the SAC 80 4.1.3 Microtubule Motors at Kinetochores 80 4.2 Aneuploidy and Chromosomal Instability 81 4.3 Congenital Kinetochore Syndromes 82 4.3.1 Primary Microcephaly (MCPH): CASC5/KNL1 and CENP-E 83 4.3.2 Strømme Syndrome: CENP-F 85 4.3.3 Microhydranencephaly and Microlissencephaly: NDE1 85 4.3.4 Mental Retardation-40: CHAMP1 86 4.3.5 Mosaic Variegated Aneuploidy: BUB1B and CEP57 86 4.3.6 Kinetochore Mutations in Microcephaly Syndromes: One Common Pathway? 88 4.4 Kinetochore Proteins and Cancer 88 4.4.1 Premature Sister Chromatid Separation (PSCS) 89 4.4.2 Persistence of Erroneous Kinetochore-Microtubule Attachments 89 4.4.3 Tumor-Suppressor Loss and Kinetochore Function 90 4.5 Conclusions and Future Perspectives 91 References 92 Chapter 5: The Elephant in the Room: The Role of Microtubules in Cancer 100 5.1 Introduction 100 5.2 Mitosis in a Nutshell 102 5.3 Deregulation of Microtubule Dynamics and Chromosome Instability in Cancer 104 5.4 Microtubule Dynamics, CIN, Aneuploidy and Cancer: Evidence for and Against 107 5.5 Microtubule-Associated Proteins 110 5.6 Mutations of Tubulin Genes 111 5.7 Altered Expression of Tubulin Isotypes in Malignancies 112 5.8 Tubulin Post-Translational Modifications and Cancer 114 5.9 Conclusion 117 References 118 Chapter 6: Clinical Development of Anti-mitotic Drugs in Cancer 132 6.1 Introduction 132 6.2 Microtubule Targeting Agents 133 6.2.1 Microtubule Stabilizers 135 6.2.2 Microtubule Destabilizers 138 6.2.3 Antibody-Drug Conjugate 139 6.3 Polo-Like Kinase-1 140 6.4 Aurora Kinases 143 6.4.1 Aurora A Kinase Inhibitors 143 6.4.2 Aurora B Kinase Inhibitors 145 6.4.3 Dual Aurora Inhibitors 146 6.5 Kinesins 146 6.5.1 Kinesin-5 Inhibitors 146 6.5.2 CENP-E Inhibitor 148 6.6 Discussion/Perspectives 149 References 150 Chapter 7: Mitotic Dysfunction Associated with Aging Hallmarks 160 7.1 Age-Associated Aneuploidy 161 7.2 Mitotic Defects Associated with Primary Hallmarks of Aging 162 7.2.1 Genomic Instability 163 7.2.1.1 Nuclear DNA Damage 163 Nuclear DNA Damage and Aging 163 Mitotic Defects Induced by DNA Damage 164 7.2.1.2 Nuclear Lamina Defects 166 Nuclear Structure and Aging 166 Mitotic Defects in Progeroid Laminopathies 167 7.2.2 Telomere Attrition 169 7.2.2.1 Age-Related Telomere Erosion 169 7.2.2.2 Mitotic Defects Associated with Telomere Dysfunction 170 7.2.3 Epigenetic Alterations 172 7.2.3.1 Epigenetic Modifications and Aging 172 7.2.3.2 Mitotic Defects Associated with Aging Epigenetic Marks 173 7.2.4 Loss of Proteostasis 175 7.2.4.1 The Protein Control Machinery and Aging 175 7.2.4.2 Mitotic Defects Associated with Loss of Proteostasis 176 7.3 Aneuploidy Induces Aging 178 7.3.1 Aneuploidy-Driven Aging Hallmarks 178 7.3.1.1 Genomic Instability 178 7.3.1.2 Proteotoxicity 179 7.3.2 Aneuploidy and Premature Aging 181 7.4 Concluding Remarks and Future Perspectives 182 References 185 Chapter 8: Unbalanced Growth, Senescence and Aging 196 8.1 Introduction 196 8.2 Growth and Division: A Tight Balancing Act 198 8.3 Asymmetric Segregation During Cell Division 201 8.4 Quiescence: Not Dividing, but Keep on Ticking 202 8.5 Senescence: Growing Desperately, with No Possibility of Ever Dividing Again 204 8.6 Division Without Growth 206 8.7 Outlook 206 References 207 Chapter 9: The Spindle Orientation Machinery Beyond Mitosis: When Cell Specialization Demands Polarization 216 9.1 The Core Machinery Behind Oriented Divisions 217 9.2 Roles of the Core mInsc-LGN-Gαi Complex Beyond Spindle Recruitment 218 9.2.1 Modulating Neuronal Function 219 9.2.2 Regulating Cellular Movement 221 9.2.3 Regulating Hair Cell Morphogenesis in the Inner Ear 222 9.3 Further Evidence: Examples of Partner Proteins with Post-Mitotic Functions 224 9.3.1 Canoe/Afadin 224 9.3.2 Myosin VI 225 9.3.3 Additional Candidates 225 9.4 Summary 226 References 226 Editors’ Biographies 233 Index 235 "This book critically evaluates the causal link between cell division machinery and disease. Further, it identifies key open questions in the field and the means for exploring them. Throughout the various chapters, internationally known contributors present the evidence for and against a causal link between key elements of the cell division machinery and diseases such as cancer, neuropathologies, aging, and infertility. A more clinically oriented chapter further discusses the current and future applications of anti-mitotic drugs in these diseases. Cell Division Machinery and Disease is essential reading for graduate or advanced graduate students, researchers or scientists working on cell division as well as clinicians interested in the molecular mechanisms of the discussed diseases"--Publisher's description Front Matter....Pages i-xiv Meiotic Divisions: No Place for Gender Equality....Pages 1-17 Consequences of Centrosome Dysfunction During Brain Development....Pages 19-45 Dividing with Extra Centrosomes: A Double Edged Sword for Cancer Cells....Pages 47-67 Kinetochore Malfunction in Human Pathologies....Pages 69-91 The Elephant in the Room: The Role of Microtubules in Cancer....Pages 93-124 Clinical Development of Anti-mitotic Drugs in Cancer....Pages 125-152 Mitotic Dysfunction Associated with Aging Hallmarks....Pages 153-188 Unbalanced Growth, Senescence and Aging....Pages 189-208 The Spindle Orientation Machinery Beyond Mitosis: When Cell Specialization Demands Polarization....Pages 209-225 Back Matter....Pages 227-235