Front Cover

Forkhead FOXO Transcription Factors in Development and Disease

Copyright

Contents

Contributors

Preface

Chapter One: DAF-16: FOXO in the Context of C. elegans

1. Introduction

2. Identification of daf-16

2.1. Genetic

2.2. Molecular

3. Isoforms

4. Direct Phosphorylation

4.1. AKT-1/AKT-2/SGK-1

4.2. Jun Kinase

4.3. AMP Kinase

5. Cofactors/Interacting Proteins

5.1. NHL-1

5.2. SWI/SNF

5.3. 14-3-3 Proteins

5.4. SMK-1

5.5. STK4/CST-1

6. Additional Inputs

6.1. Heat Shock Factor-1

7. Target Genes

8. Conclusion

Acknowledgments

References

Chapter Two: Stem Cells Seen Through the FOXO Lens: An Evolving Paradigm

1. FOXO and Stem Cells

2. FOXO in Embryonic Stem Cells and Development

3. FOXO in Adult Tissue-Specific Stem Cells

4. FOXO in Hematopoietic Stem Cells

4.1. FOXO3, Reactive Oxygen Species, and Mitochondria in HSC

4.2. FOXO and Autophagy in HSC

4.3. FOXO and DNA Damage Response in HSC

4.4. FOXO, mTOR, and Myeloproliferation

4.5. FOXO and Leukemic Stem Cells

4.6. FOXO, HSC Longevity, and the Role of Sirtuins and miRNAs

5. FOXO and Neural Stem Cells

6. FOXO3 and Muscle Stem Cells

7. Concluding Remarks

Acknowledgments

References

Chapter Three: FOXOs Maintaining the Equilibrium for Better or for Worse

1. Introduction: FOXO Regulation Getting up to Par

2. The PI3K/PKB(AKT)/FOXO Signaling Pathway and Cancer

3. FOXOs and the Hallmarks of Cancer

3.1. FOXOs and the Hallmarks: Sustaining Proliferative Signaling

3.2. FOXOs and the Hallmarks: Resisting Cell Death

3.3. FOXOs and the Hallmarks: Enabling Replicative Immortality

3.4. FOXOs and the Hallmarks: Inducing Angiogenesis

3.5. FOXOs and the Hallmarks: Activating Invasion and Metastasis

3.6. FOXOs Genuine or "Bona Fide" Tumor Suppressor

3.7. FOXOs: Tumor Suppressors or Promoters?

4. FOXOs as Rheostats in Homeostasis

4.1. Redox

4.2. DNA Damage Response

4.3. Protein Homeostasis

5. FOXOs and Resistance to Therapy

5.1. Quiescence as a Mechanism of Resistance

5.2. The Role of Feedback Signaling in Acquiring Resistance

5.3. Cross Talk With Other Pathways

6. Conclusion

References

Further Reading

Chapter Four: FOXO in Neural Cells and Diseases of the Nervous System

1. Introduction

2. Neural Development and Stem Cell Maintenance

3. Neuronal Survival and Stress Responses

4. Phenotypic Consequences of FOXO Loss

5. Neurodegenerative Disease

6. Future Directions

References

Further Reading

Chapter Five: Regulation of Hepatic Glucose Metabolism by FoxO Proteins, an Integrated Approach

1. Overview

2. Early Studies and Early Insights

3. Regulation of FoxO Function by Insulin/PI3K/Akt Signaling and Deacetylases

4. Effects on Gluconeogenic Gene Expression

5. Effects on Glycolysis and Glucose Utilization

6. Effects of Fatty Acid Oxidation on Glycolysis and Gluconeogenesis

7. Effects on Intra- and Extrahepatic Lipid Catabolism

8. Effects on Glucose Utilization

9. Hepatokines

10. Summary

Acknowledgments

References

Chapter Six: The Role of FoxOs in Bone Health and Disease

1. Bone Growth, Remodeling, and Disease

2. FoxO Effects in Chondrocytes

2.1. Osteoarthritis

3. FoxO Effects in Osteoclasts

3.1. Bone Loss Caused by Estrogen Deficiency

4. FoxO Effects in Osteoblasts

4.1. Low Bone Mass in Type 1 Diabetes

4.2. Myeloid Leukemia

4.3. Age-Related Bone Loss

5. Future Considerations

Acknowledgments

References

Chapter Seven: Regulation of FOXO Factors in Mammalian Cells

1. Introduction: The FOXO Family

1.1. FOXO Domain Structure and Posttranslational Modifications

2. Regulation by Insulin/IGF Signaling and Other Growth Factors

2.1. Inhibition by AKT and Other Kinases

2.2. Regulation by Phosphatases

3. Nutrient Signaling and Metabolic Stress

3.1. Regulation by AMPK

4. Oxidative and Genotoxic Stress Stimuli

4.1. Regulation by the MAPK Family

4.2. Activation by Ste20-Like Kinase MST1

4.3. Ubiquitination/Deubiquitination in Response to Stress

4.4. Acetylation and Deacetylation Modulates FOXO Activity

4.5. Regulation by Cyclin-Dependent Kinases Under Genotoxic Stress

5. Regulation of FOXOs in Cancer and the Immune Response

5.1. AKT-Independent Regulation of FOXO Localization by IkB Kinase in Tumors

5.2. Regulation by T Cell Receptors, B Cell Receptors, and Cytokine Signaling

6. Other Inputs

6.1. Regulation by Methyltransferases

6.2. Regulation of Feeding Behavior by DYRK1A

6.3. Modification of FOXOs by Additional Protein Kinases

6.4. Regulation by miRNAs

7. Concluding Remarks

Acknowledgments

References

Chapter Eight: FOXO3 and Exceptional Longevity: Insights From Hydra to Humans

1. FoxO Genes as Determinants of Longevity

2. The Insulin Signaling Pathway and Life Span

3. Transcriptional Impacts of FoxO Genes Across Species

4. Extrinsic Influences and the Future of FoxO3-Mediated Longevity

References

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