Mikhail V. Blagosklonny Cell Cycle Checkpoints and Cancer Cell Cycle Checkpoints and Cancer BLAGOSKLONNY MBIU 15 MOLECULAR BIOLOGY INTELLIGENCE UNIT 15 Mikhail V. Blagosklonny Bethesda, Maryland, U.S.A. Cell Cycle Checkpoints and Cancer MOLECULAR BIOLOGY INTELLIGENCE UNIT 15 E UREKAH . COM A USTIN , T EXAS U.S.A. L ANDES B IOSCIENCE G EORGETOWN , T EXAS U.S.A. Molecular Biology Intelligence Unit Eurekah.com Landes Bioscience Copyright ©2001 Eurekah.com All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Printed in the U.S.A. Please address all inquiries to the Publishers: Eurekah.com / Landes Bioscience, 810 South Church Street Georgetown, Texas, U.S.A. 78626 Phone: 512/ 863 7762; FAX: 512/ 863 0081 www.Eurekah.com www.landesbioscience.com Library of Congress Cataloging-in-Publication Data Cell cycle checkpoints and cancer / [edited by] Mikhail V. Blagosklonny. p.; cm. (Molecular biology intelligence unit; 15) ISBN 1-58706-067-1 (alk. paper) 1. Cancer cells Regulation. 2. Cell cycle. 3. Cellular signal transduction. 4. Cell transformation. 5. Carcinogenesis. [DNLM: 1. Cell Transformation, Neoplastic. 2. Cell Cycle. QZ 202 C39253 2001] I. Blagosklonny, Mikhail V. II. Series. RC269.7 .C455 2001 616.99´407 dc21 2001002072 ISBN: 1-58706-067-1 CELL CYCLE CHECKPOINTS AND CANCER CONTENTS Preface xii 1. Autocrine Transformation: Cytokine Model 1 James A. McCubrey, Xiao-Yang Wang, Paul A. Algate, William L. Blalock and Linda S. Steelman Abstract 1 Cytokine Regulation of Growth 1 2. Signal Transduction Pathways: Cytokine Model 17 James A. McCubrey, William L. Blalock, Fumin Chang, Linda S. Steelman, Steven C. Pohnert, Patrick M. Navolanic, John G. Shelton, Paul E. Hoyle, Phillip W. Moye, Stephanie M. Oberhaus, Martyn K. White, John T. Lee and Richard A. Franklin Abstract 17 Cytokine-Induced Signal Transduction Resulting in Growth and the Prevention of Apoptosis 17 Adaptor Proteins that Couple Receptors with Downstream Pathways 19 The Jak-STAT Pathway 19 The PI3K/Akt Pathway 22 The Ras/Raf/MEK/ERK Signal Transduction Pathway 22 The Ras/Raf/MEK/ERK Pathway: Downstream Kinase Activation 26 Interactions Between the Raf/MEK/ERK and the PI3K/Akt Pathways 28 The Ras/Raf/MEK/ERK Pathway: A Tether Enhancing Signal Transduction 28 The Ras/Raf/MEK/ERK Pathway: Regulation of Downstream Transcription Factors 28 Induction of Autocrine Gene Expression by Altered Raf/MEK and PI3K/Akt Expression 29 Mutations of Ras/Raf/MEK/ERK Cascade which Result in Neoplasia 29 Regulatory Phosphatases of the Ras/Raf/MEK/ERK Pathway 29 Alternative MAPK Pathways Activated by Stress 31 Default Pathways which Dampen Signaling 31 Jak/STAT Inhibitors 33 PI3K/p70S6K Inhibitors 33 Ras/Raf/MEK/ERK Pathway Inhibitors 33 PKC Inhibitors 33 Cytokine Regulation of Cell Cycle Progression 34 Links Between the Ras/Raf/MEK/ERK Pathway and Cell Cycle Proteins 34 Cytokine Regulation of Apoptosis and Cell Death 34 Apoptotic Mediators: The Caspases 34 Roles of Bcl-2 Family Members in Cytokine-Mediated Regulation of Apoptosis 35 Mitochondrial Regulated Apoptosis 35 Interactions Between Cytokine Signaling Pathways and Apoptosis 36 Phosphorylation of Bcl-2: Positive and Negative Effects 36 Future Remarks 36 Acknowledgments 37 3. The Restriction Point of the Cell Cycle 52 Mikhail V. Blagosklonny and Arthur B. Pardee Mitogen-Dependent and -Independent Phases of the Cell Cycle 52 The Restriction Point 52 In Search of Mediators of the Restriction Point 53 Cyclins: From Mitogen Signaling to the Restriction Point 54 The Restriction Point: a Knot of Mitogen and Inhibitory Signaling 55 Growth Arrest versus Proliferation 57 From Restriction- to “Check”-Points 58 The Restriction Point and G1 Checkpoint 59 The Restriction Point and Therapy 60 4. DNA Damage, Cell Cycle Control and Cancer 65 Jens Oliver Funk, Temesgen Samuel and H. Oliver Weber Abstract 65 Introduction 65 Origins of DNA Damage 66 DNA Damage of Intrinsic Origin 66 DNA Damage of External Origin 66 Upstream DNA Damage Signaling 66 ATM-Dependent Signaling Pathways 67 CHK2—The Next Line of Defense 67 p53—The Core of the DNA Damage Pathways 68 Regulatory Effects Converging on p53 69 The G1/S Checkpoint 70 p21CIP1—A Two-Tailed Cell Cycle Regulator 70 The G2/M Checkpoint 71 Control of the Unperturbed G2/M Transition 71 Regulation of the CDC25C Phosphatase 72 DNA Damage and the G2/M Transition 72 Links to Cancer and Genetic Instability 73 5. DNA-Damage-Independent Checkpoints from Yeast to Man 79 Duncan J. Clarke, Adrian P.L. Smith and Juan F. Giménez-Abián Abstract 79 Budding Yeast versus Higher Eukaryotes 79 S-Phase Checkpoint 81 Topoisomerase II-Dependent Checkpoint 86 Checkpoint Control in Prophase 87 Spindle Assembly Checkpoint 87 Checkpoint Control of Mitotic Exit 93 Oncological Implications of Mitotic Checkpoint Homologs 99 6. The Regulation of p53 Growth Suppression 106 Ronit Vogt Sionov, Igal Louria Hayon and Ygal Haupt Abstract 106 Introduction 106 Regulation of p53 107 Regulation of Intracellular Distribution of p53 110 p53-Mediated Growth Regulatory Functions 112 The Choice Between Growth Arrest and Apoptosis 115 Cell Type-Dependence 116 7. Functional Interactions Between BRCA1 and the Cell Cycle 126 Timothy K. MacLachlan and Wafik El-Deiry Introduction 126 BRCA1 Protein and mRNA during the Cell Cycle 126 Subcellular Localization 127 Activity at Cell Cycle Checkpoints 129 Interactions with Cell Cycle Proteins 130 Transcription of Cell Cycle Genes 131 Conclusion 132 8. The Role of FHIT in Carcinogenesis 135 Yuri Pekarsky, Kay Huebner and Carlo M. Croce Abstract 135 Chromosomal Changes in Cancer 135 FHIT Loci is the Target of Chromosomal Abnormalities at 3p14.2 136 Inactivation of FHIT mRNA and Protein Expression in Cancer. 137 The Tumor Suppressor Activity of FHIT 138 Toward Fhit Function 139 Conclusions 140 9. Hypoxia and Cell Cycle 143 Rachel A. Freiberg, Susannah L. Green and Amato J. Giaccia Introduction 143 Cell Cycle and Check Points 144 Hypoxia-Induced Arrest 146 Mechanisms Underlying Cell Cycle Arrest By Hypoxia 147 Hypoxia-Induced Inhibition of CDK2 Activity and Resistance to Chemotherapy 151 Acknowledgments 152 10. G2 Checkpoint and Anticancer Therapy 155 Zoe A. Stewart and Jennifer A. Pietenpol Abstract 155 Introduction 155 G2 Checkpoint Activation 157 G2 Checkpoint Maintenance 162 Modulation of the G2 Checkpoint—Therapeutic Implications 165 Future Directions 169 Acknowledgments 169 11. p53, Apoptosis and Cancer Therapy 179 Rosandra Kaplan and David E. Fisher Abstract 179 Introduction 179 p53’s Emergence as a Key Death Regulator 181 Clinical Aspects of p53 183 Cell Cycle Arrest 184 Apoptosis 184 Regulating p53 Activation in the Stress Response 187 Cell Cycle Arrest vs Death 187 Therapy 188 12. Non-Apoptotic Responses to Anticancer Agents: Mitotic Catastrophe, Senescence and the Role of p53 and p21 196 Igor B. Roninson, Bey-Dih Chang and Eugenia V. Broude Abstract 196 Can Apoptosis Account for Tumor Cell Response to Anticancer Agents? 196 p53 as a Negative Regulator of Mitotic Catastrophe 199 Induction of Senescence by DNA-Damaging Agents 200 Role of p53 and p21 in Damage-Induced Senescence and Abnormal Mitosis 202 Paracrine Activities of Senescent Cells: Implications for Treatment Outcome and Side Effects of Cancer Therapy 203 Mitotic Catastrophe and Senescence as Target Responses in Cancer Treatment 203 13. Small Molecule Inhibitors of Cyclin-Dependent Kinases 208 Geoffrey I. Shapiro Introduction 208 Flavopiridol 208 The Paullones 219 Purine Derivatives 220 UCN-01 221 Novel Selective Cdk Inhibitors 226 Conclusion 228 14. Cell Cycle Molecular Targets and Drug Discovery 235 John K. Buolamwini Abstract 235 Introduction 235 Events in Cell Cycle Progression 236 Regulatory Pathways 237 Oncogenic Cell Cycle Targets 239 Cell Cycle Molecular Target-Based Cancer Drug Discovery 239 Cancer Drug Development of Small Molecule CDK Inhibitors 241 Other Targets 241 Index 247 Mikhail V. Blagosklonny Bethesda, Maryland, U.S.A. Chapter 3 EDITOR CONTRIBUTORS Paul A. Algate Corixa Corporation Seattle Washington, U.S.A. Chapter 1 William L. Blalock Department of Microbiology and Immunology East Carolina University School of Medicine, Greenville, North Carolina, U.S.A. Chapters 1, 2 Eugenia V. Broude Department of Molecular Genetics University of Illinois Chicago, Illinois, U.S.A. Chapter 12 John K. Buolamwini Department of Pharmaceutical Sciences, College of Pharmacy University of Tennessee Health Sciences Center, Memphis, Tennessee, U.S.A. Chapter 14 Bey-Dih Chang Department of Molecular Genetics University of Illinois Chicago, Illinois, U.S.A. Chapter 12 Fumin Chang Department of Microbiology and Immunology East Carolina University School of Medicine Greenville, North Carolina, U.S.A. Chapter 2 Duncan J. Clarke The Scripps Research Institute La Jolla, California, U.S.A. Chapter 5 Carlo M. Croce Kimmel Cancer Center Thomas Jefferson University Philadelphia, Pennsylvania, U.S.A. Chapter 8 Wafik El-Deiry Departments of Medicine, Genetics and Pharmacology Howard Hughes Medical Institute, University of Pennsylvania School of Medicine Philadelphia, Pennsylvania, U.S.A. Chapter 7 David E. Fisher Division of Pediatric Hematology/Oncology Boston Children’s Hospital & Dana Farber Cancer Institute Boston, Massachusetts, U.S.A. Chapter 11 Richard A. Franklin Department of Microbiology and Immunology East Carolina University School of Medicine, Greenville, North Carolina, U.S.A. Chapter 2 Rachel A. Freiberg Stanford University School of Medicine Division Radiation Biology/ Department of Radiation Oncology Stanford, California, U.S.A. Chapter 9 Jens Oliver Funk Laboratory of Molecular Tumor Biology Department of Dermatology University of Erlangen-Nuremberg Erlangen, Germany Chapter 4 Amato J. Giaccia Stanford University School of Medicine, Division Radiation Biology/Dept. Radiation Oncology Stanford, California, U.S.A. Chapter 9 Juan F. Giménez-Abián Centro de Investigaciones Biológicas Consejo Superior de Investigaciones Científicas Velázquez, Madrid, Spain Chapter 5 Susannah L. Green Stanford University School of Medicine Division Radiation, Biology/Dept. Radiation Oncology Stanford, California, U.S.A. Chapter 9 Ygal Haupt Lautenberg Center for General and Tumor Immunology The Hebrew University Hadassah Medical School Jerusalem, Israel Chapter 6 Igal Louria Hayon Lautenberg Center for General and Tumor Immunology The Hebrew University Hadassah Medical School Jerusalem, Israel Chapter 6 Paul E. Hoyle Department of Microbiology and Immunology East Carolina University School of Medicine, Greenville, North Carolina, U.S.A. Chapter 2 Rosandra Kaplan Department of Medicine Boston Children’s Hospital Boston, Massachusetts, U.S.A. Chapter 11 Ronit Vogt Sionov Lautenberg Center for General and Tumor Immunology The Hebrew University Hadassah Medical School Jerusalem, Israel Chapter 6 John T. Lee Department of Microbiology and Immunology East Carolina University School of Medicine, Greenville, North Carolina U.S.A. Chapter 2 [...]... of cell cycle checkpoints By arresting the cell cycle, activation of checkpoints presumably allows cells to repair DNA In “DNA damage, cell cycle control, and cancer Jens Oliver Funk et al describes series of events that is triggered in cells upon DNA damage as well as a framework for the understanding of the functions of the core components involved in the cell cycle response to DNA damage Cell cycle. .. Book Overview This book Cell Cycle Checkpoints and Cancer addresses mechanisms of normal and cancer cell cycling, checkpoint control, the link of mitogenic signaling and cell cycle machinery Considerable attention is devoted to the analysis of checkpoint mechanisms from yeast to man allowing us to understand the logic of the cell cycle Applications to current and future anticancer therapies is discussed... hallmarks of cancer Cell 2000; 100:57-70 Sherr CJ The Pezcoller lecture: Cancer cell cycle revisited Cancer Res 2000; 60:3689-3695 Kaelin WGJ Choosing anticancer drug targets in the postgenomic era J Clin Invest 1999; 104:1503-1506 Shapiro GI, Harper JW Anticancer drug targets: cell cycle and checkpoint control J Clin Invest 1999; 104:1645-1653 Gibbs JB Mechanism-based target identification and drug discovery... Checkpoints and Cancer, edited by Mikhail V Blagosklonny ©2001 Eurekah.com 2 Cell Cycle Checkpoints and Cancer investigators under a variety of aliases It was called persisting cell- stimulating factor (PSF),6 mast cell growth factor (MCGF), 7 hematopoietic cell growth factor (HCGF), 8 histamine-producing cell- stimulating factor,9 multi-colony stimulating factor (Multi-CSF),10 Thy-1-inducing factor,5 and burst... normal cells The absence of cancer- selective targets is the most important problem of the anticancer drug-screen, because compounds toxic to cancer cells also kill normal cells, therefore side-effects are inevitable Besides, natural compounds are synthesized by microorganisms, plants and animals in order to kill other organisms They are not intended to discriminate between normal and cancer cells and. .. unspecific attempts to block cell cycle progression, which are less likely to distinguish between cancerous and normal cells.14 Aiming at defective cell cycle checkpoints is different from targeting cancer- specific molecules In the checkpoint approach, it is not necessary to target cancer- promoting or key-functional molecules (e.g., CDK), nor the molecule which is altered in cancer (mutated, overexpressed,... expression and factor-dependency In Figure 4, Panel B, we 10 Cell Cycle Checkpoints and Cancer Fig 4 (see figure legend on opposite page) have illustrated the recombinant IL-3 constructs and their abilities to abrogate the cytokine-dependency of the parental FL5.12 cells Transfection of cells with a germline IL-3 gene did not result in the frequent isolation of factor-independent cells In those cells that... Although the same molecule will be targeted in both cancer and normal cells, the functional outcome can be different in cells with defective checkpoints For example, loss of the G1 checkpoint is common in cancer cells with mutant p53 In response to DNA damage, such cancer cells are arrested in G2 The arrest at G2/M is dramatically sensitive to even one double strand break because failure to arrest would lead... degradation.35 p53 can induce growth arrest and/ or apoptosis Intriguingly, p53-mediated apoptosis involves both transcription-dependent and independent mechanisms.36 In this book, R Vogt Sionov, I L Hayon and Ygal Haupt discuss mechanisms of p53 induction and its effect on cell cycle checkpoints As emphasized, p21 is an important regulator of cell cycle checkpoints The identification of p21 (also named... protein, is normally expressed in epithelial tissues and is inactivated in most common cancers including lung and breast cancer It is inactivated in more than 50% of these tumors FHIT is the most common genetic alteration in human cancer Amato J Giaccia and his colleagues discuss hypoxia and the cell cycle When tumors are more than 150 µm or approximately ten cells in diameter, they exceed their ability to . Blagosklonny Cell Cycle Checkpoints and Cancer Cell Cycle Checkpoints and Cancer BLAGOSKLONNY MBIU 15 MOLECULAR BIOLOGY INTELLIGENCE UNIT 15 Mikhail V. Blagosklonny Bethesda, Maryland, U.S.A. Cell Cycle Checkpoints and. manipulating the cell cycle will bring anticancer che- motherapy to a new level. 32 The Book Overview This book Cell Cycle Checkpoints and Cancer addresses mechanisms of normal and cancer cell cycling,. Protein and mRNA during the Cell Cycle 126 Subcellular Localization 127 Activity at Cell Cycle Checkpoints 129 Interactions with Cell Cycle Proteins 130 Transcription of Cell Cycle Genes 131 Conclusion