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1 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 Signal Transduction Pathways: Cytokine Model 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 Cytokine-Induced Signal Transduction Resulting in Growth and the Prevention of Apoptosis Adaptor Proteins that Couple Receptors with Downstream Pathways The Jak-STAT Pathway The PI3K/Akt Pathway The Ras/Raf/MEK/ERK Signal Transduction Pathway The Ras/Raf/MEK/ERK Pathway: Downstream Kinase Activation Interactions Between the Raf/MEK/ERK and the PI3K/Akt Pathways The Ras/Raf/MEK/ERK Pathway: A Tether Enhancing Signal Transduction The Ras/Raf/MEK/ERK Pathway: Regulation of Downstream Transcription Factors Induction of Autocrine Gene Expression by Altered Raf/MEK and PI3K/Akt Expression Mutations of Ras/Raf/MEK/ERK Cascade which Result in Neoplasia Regulatory Phosphatases of the Ras/Raf/MEK/ERK Pathway Alternative MAPK Pathways Activated by Stress Default Pathways which Dampen Signaling Jak/STAT Inhibitors PI3K/p70S6K Inhibitors Ras/Raf/MEK/ERK Pathway Inhibitors PKC Inhibitors Cytokine Regulation of Cell Cycle Progression Links Between the Ras/Raf/MEK/ERK Pathway and Cell Cycle Proteins Cytokine Regulation of Apoptosis and Cell Death Apoptotic Mediators: The Caspases... 34

2 Roles of Bcl-2 Family Members in Cytokine-Mediated Regulation of Apoptosis Mitochondrial Regulated Apoptosis Interactions Between Cytokine Signaling Pathways and Apoptosis Phosphorylation of Bcl-2: Positive and Negative Effects Future Remarks Acknowledgments The Restriction Point of the Cell Cycle Mikhail V. Blagosklonny and Arthur B. Pardee Mitogen-Dependent and -Independent Phases of the Cell Cycle The Restriction Point In Search of Mediators of the Restriction Point Cyclins: From Mitogen Signaling to the Restriction Point The Restriction Point: a Knot of Mitogen and Inhibitory Signaling Growth Arrest versus Proliferation From Restriction- to Check -Points The Restriction Point and G1 Checkpoint The Restriction Point and Therapy DNA Damage, Cell Cycle Control and Cancer Jens Oliver Funk, Temesgen Samuel and H. Oliver Weber Abstract Introduction Origins of DNA Damage DNA Damage of Intrinsic Origin DNA Damage of External Origin Upstream DNA Damage Signaling ATM-Dependent Signaling Pathways CHK2 The Next Line of Defense p53 The Core of the DNA Damage Pathways Regulatory Effects Converging on p The G1/S Checkpoint p21cip1 A Two-Tailed Cell Cycle Regulator The G2/M Checkpoint Control of the Unperturbed G2/M Transition Regulation of the CDC25C Phosphatase DNA Damage and the G2/M Transition Links to Cancer and Genetic Instability DNA-Damage-Independent Checkpoints from Yeast to Man Duncan J. Clarke, Adrian P.L. Smith and Juan F. Giménez-Abián Abstract Budding Yeast versus Higher Eukaryotes S-Phase Checkpoint Topoisomerase II-Dependent Checkpoint... 86

3 Checkpoint Control in Prophase Spindle Assembly Checkpoint Checkpoint Control of Mitotic Exit Oncological Implications of Mitotic Checkpoint Homologs The Regulation of p53 Growth Suppression Ronit Vogt Sionov, Igal Louria Hayon and Ygal Haupt Abstract Introduction Regulation of p Regulation of Intracellular Distribution of p p53-mediated Growth Regulatory Functions The Choice Between Growth Arrest and Apoptosis Cell Type-Dependence Functional Interactions Between BRCA1 and the Cell Cycle Timothy K. MacLachlan and Wafik El-Deiry Introduction BRCA1 Protein and mrna during the Cell Cycle Subcellular Localization Activity at Cell Cycle Checkpoints Interactions with Cell Cycle Proteins Transcription of Cell Cycle Genes Conclusion The Role of FHIT in Carcinogenesis Yuri Pekarsky, Kay Huebner and Carlo M. Croce Abstract Chromosomal Changes in Cancer FHIT Loci is the Target of Chromosomal Abnormalities at 3p Inactivation of FHIT mrna and Protein Expression in Cancer The Tumor Suppressor Activity of FHIT Toward Fhit Function Conclusions Hypoxia and Cell Cycle Rachel A. Freiberg, Susannah L. Green and Amato J. Giaccia Introduction Cell Cycle and Check Points Hypoxia-Induced Arrest Mechanisms Underlying Cell Cycle Arrest By Hypoxia Hypoxia-Induced Inhibition of CDK2 Activity and Resistance to Chemotherapy Acknowledgments

4 10. G2 Checkpoint and Anticancer Therapy Zoe A. Stewart and Jennifer A. Pietenpol Abstract Introduction G2 Checkpoint Activation G2 Checkpoint Maintenance Modulation of the G2 Checkpoint Therapeutic Implications Future Directions Acknowledgments p53, Apoptosis and Cancer Therapy Rosandra Kaplan and David E. Fisher Abstract Introduction p53 s Emergence as a Key Death Regulator Clinical Aspects of p Cell Cycle Arrest Apoptosis Regulating p53 Activation in the Stress Response Cell Cycle Arrest vs Death Therapy Non-Apoptotic Responses to Anticancer Agents: Mitotic Catastrophe, Senescence and the Role of p53 and p Igor B. Roninson, Bey-Dih Chang and Eugenia V. Broude Abstract Can Apoptosis Account for Tumor Cell Response to Anticancer Agents? p53 as a Negative Regulator of Mitotic Catastrophe Induction of Senescence by DNA-Damaging Agents Role of p53 and p21 in Damage-Induced Senescence and Abnormal Mitosis Paracrine Activities of Senescent Cells: Implications for Treatment Outcome and Side Effects of Cancer Therapy Mitotic Catastrophe and Senescence as Target Responses in Cancer Treatment Small Molecule Inhibitors of Cyclin-Dependent Kinases Geoffrey I. Shapiro Introduction Flavopiridol The Paullones Purine Derivatives UCN Novel Selective Cdk Inhibitors Conclusion

5 14. Cell Cycle Molecular Targets and Drug Discovery John K. Buolamwini Abstract Introduction Events in Cell Cycle Progression Regulatory Pathways Oncogenic Cell Cycle Targets Cell Cycle Molecular Target-Based Cancer Drug Discovery Cancer Drug Development of Small Molecule CDK Inhibitors Other Targets Index

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