Cell Cycle Checkpoints and Cancer

267 Pages·2001·3.475 MB·English

by  Mikhail V. Blagosklonny

MOLECULAR BIOLOGY INTELLIGENCE UNIT 15
Mikhail V. Blagosklonny
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OLECULAR
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NTELLIGENCE
U 15
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Cell Cycle Checkpoints
and Cancer
Mikhail V. Blagosklonny
Bethesda, Maryland, U.S.A.
LANDES BIOSCIENCE EUREKAH.COM
GEORGETOWN, TEXAS AUSTIN, TEXAS
U.S.A. U.S.A.
C C C C
ELL YCLE HECKPOINTS AND ANCER
Molecular Biology Intelligence Unit
Eurekah.com
Landes Bioscience
Copyright ©2001 Eurekah.com
All rights reserved.
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ISBN: 1-58706-067-1
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
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
EDITOR
Mikhail V. Blagosklonny
Bethesda, Maryland, U.S.A.
Chapter 3
CONTRIBUTORS
Paul A. Algate Fumin Chang
Corixa Corporation Department of Microbiology
Seattle Washington, U.S.A. and Immunology
Chapter 1 East Carolina University School
of Medicine
William L. Blalock Greenville, North Carolina, U.S.A.
Department of Microbiology Chapter 2
and Immunology
East Carolina University School Duncan J. Clarke
of Medicine, The Scripps Research Institute
Greenville, North Carolina, U.S.A. La Jolla, California, U.S.A.
Chapters 1, 2 Chapter 5
Eugenia V. Broude Carlo M. Croce
Department of Molecular Genetics Kimmel Cancer Center
University of Illinois Thomas Jefferson University
Chicago, Illinois, U.S.A. Philadelphia, Pennsylvania, U.S.A.
Chapter 12 Chapter 8
John K. Buolamwini Wafik El-Deiry
Department of Pharmaceutical Departments of Medicine, Genetics
Sciences, and Pharmacology
College of Pharmacy Howard Hughes Medical Institute,
University of Tennessee University of Pennsylvania School
Health Sciences Center, of Medicine
Memphis, Tennessee, U.S.A. Philadelphia, Pennsylvania, U.S.A.
Chapter 14 Chapter 7
Bey-Dih Chang David E. Fisher
Department of Molecular Genetics Division of Pediatric
University of Illinois Hematology/Oncology
Chicago, Illinois, U.S.A. Boston Children’s Hospital
Chapter 12 & Dana Farber Cancer Institute
Boston, Massachusetts, U.S.A.
Chapter 11
Richard A. Franklin Ygal Haupt
Department of Microbiology Lautenberg Center for General
and Immunology and Tumor Immunology
East Carolina University School The Hebrew University
of Medicine, Hadassah Medical School
Greenville, North Carolina, U.S.A. Jerusalem, Israel
Chapter 2 Chapter 6
Rachel A. Freiberg Igal Louria Hayon
Stanford University School of Medicine Lautenberg Center for General
Division Radiation Biology/ Department and Tumor Immunology
of Radiation Oncology Stanford, The Hebrew University
California, U.S.A. Hadassah Medical School
Chapter 9 Jerusalem, Israel
Chapter 6
Jens Oliver Funk
Laboratory of Molecular Tumor Biology Paul E. Hoyle
Department of Dermatology Department of Microbiology
University of Erlangen-Nuremberg and Immunology
Erlangen, Germany East Carolina University School
Chapter 4 of Medicine,
Greenville, North Carolina, U.S.A.
Amato J. Giaccia Chapter 2
Stanford University School of Medicine,
Division Radiation Biology/Dept. Rosandra Kaplan
Radiation Oncology Department of Medicine
Stanford, California, U.S.A. Boston Children’s Hospital
Chapter 9 Boston, Massachusetts, U.S.A.
Chapter 11
Juan F. Giménez-Abián
Centro de Investigaciones Biológicas Ronit Vogt Sionov
Consejo Superior de Investigaciones Lautenberg Center for General
Científicas and Tumor Immunology
Velázquez, Madrid, Spain The Hebrew University
Chapter 5 Hadassah Medical School
Jerusalem, Israel
Susannah L. Green Chapter 6
Stanford University School of Medicine
Division Radiation, Biology/Dept. John T. Lee
Radiation Oncology Department of Microbiology
Stanford, California, U.S.A. and Immunology
Chapter 9 East Carolina University
School of Medicine,
Greenville, North Carolina U.S.A.
Chapter 2