Forkhead FOXO Transcription Factors in Development and Disease

Series Page
Copyright
Contributors
Preface
DAF-16: FOXO in the Context of C. elegans
Introduction
Identification of daf-16
Genetic
Molecular
Isoforms
Direct Phosphorylation
AKT-1/AKT-2/SGK-1
Jun Kinase
AMP Kinase
Cofactors/Interacting Proteins
NHL-1
SWI/SNF
14-3-3 Proteins
SMK-1
STK4/CST-1
Additional Inputs
Heat Shock Factor-1
Target Genes
Conclusion
Acknowledgments
References
Stem Cells Seen Through the FOXO Lens: An Evolving Paradigm
FOXO and Stem Cells
FOXO in Embryonic Stem Cells and Development
FOXO in Adult Tissue-Specific Stem Cells
FOXO in Hematopoietic Stem Cells
FOXO3, Reactive Oxygen Species, and Mitochondria in HSC
FOXO and Autophagy in HSC
FOXO and DNA Damage Response in HSC
FOXO, mTOR, and Myeloproliferation
FOXO and Leukemic Stem Cells
FOXO, HSC Longevity, and the Role of Sirtuins and miRNAs
FOXO and Neural Stem Cells
FOXO3 and Muscle Stem Cells
Concluding Remarks
Acknowledgments
References
FOXOs Maintaining the Equilibrium for Better or for Worse
Introduction: FOXO Regulation Getting up to Par
The PI3K/PKB(AKT)/FOXO Signaling Pathway and Cancer
FOXOs and the Hallmarks of Cancer
FOXOs and the Hallmarks: Sustaining Proliferative Signaling
FOXOs and the Hallmarks: Resisting Cell Death
FOXOs and the Hallmarks: Enabling Replicative Immortality
FOXOs and the Hallmarks: Inducing Angiogenesis
FOXOs and the Hallmarks: Activating Invasion and Metastasis
FOXOs Genuine or “Bona Fide” Tumor Suppressor
FOXOs: Tumor Suppressors or Promoters?
FOXOs as Rheostats in Homeostasis
Redox
DNA Damage Response
Protein Homeostasis
FOXOs and Resistance to Therapy
Quiescence as a Mechanism of Resistance
The Role of Feedback Signaling in Acquiring Resistance
Cross Talk With Other Pathways
Conclusion
References
Further Reading
FOXO in Neural Cells and Diseases of the Nervous System
Introduction
Neural Development and Stem Cell Maintenance
Neuronal Survival and Stress Responses
Phenotypic Consequences of FOXO Loss
Neurodegenerative Disease
Future Directions
References
Further Reading
Regulation of Hepatic Glucose Metabolism by FoxO Proteins, an Integrated Approach
Overview
Early Studies and Early Insights
Regulation of FoxO Function by Insulin/PI3K/Akt Signaling and Deacetylases
Effects on Gluconeogenic Gene Expression
Effects on Glycolysis and Glucose Utilization
Effects of Fatty Acid Oxidation on Glycolysis and Gluconeogenesis
Effects on Intra- and Extrahepatic Lipid Catabolism
Effects on Glucose Utilization
Hepatokines
Summary
Acknowledgments
References
The Role of FoxOs in Bone Health and Disease
Bone Growth, Remodeling, and Disease
FoxO Effects in Chondrocytes
Osteoarthritis
FoxO Effects in Osteoclasts
Bone Loss Caused by Estrogen Deficiency
FoxO Effects in Osteoblasts
Low Bone Mass in Type 1 Diabetes
Myeloid Leukemia
Age-Related Bone Loss
Future Considerations
Acknowledgments
References
Regulation of FOXO Factors in Mammalian Cells
Introduction: The FOXO Family
FOXO Domain Structure and Posttranslational Modifications
Regulation by Insulin/IGF Signaling and Other Growth Factors
Inhibition by AKT and Other Kinases
Regulation by Phosphatases
Nutrient Signaling and Metabolic Stress
Regulation by AMPK
Oxidative and Genotoxic Stress Stimuli
Regulation by the MAPK Family
Activation by Ste20-Like Kinase MST1
Ubiquitination/Deubiquitination in Response to Stress
Acetylation and Deacetylation Modulates FOXO Activity
Regulation by Cyclin-Dependent Kinases Under Genotoxic Stress
Regulation of FOXOs in Cancer and the Immune Response
AKT-Independent Regulation of FOXO Localization by IkB Kinase in Tumors
Regulation by T Cell Receptors, B Cell Receptors, and Cytokine Signaling
Other Inputs
Regulation by Methyltransferases
Regulation of Feeding Behavior by DYRK1A
Modification of FOXOs by Additional Protein Kinases
Regulation by miRNAs
Concluding Remarks
Acknowledgments
References
FOXO3 and Exceptional Longevity: Insights From Hydra to Humans
FoxO Genes as Determinants of Longevity
The Insulin Signaling Pathway and Life Span
Transcriptional Impacts of FoxO Genes Across Species
Extrinsic Influences and the Future of FoxO3-Mediated Longevity
References