Gadd45 Stress Sensor Genes (Advances in Experimental Medicine and Biology, 1360)

This second edition is fully updated throughout and covers the emerging evidence that indicates that the Gadd45 family of proteins plays a unique and critical role as sensors of stress, including genotoxic, physiological, and oncogenic stress. It sheds light on the complex cellular stress response, encompassing myriad molecular pathways with a plethora of regulators and effectors. The GADD45 stress response genes encode small (18 kd) nuclear/cytoplasmic proteins. These genes are rapidly induced by a wide variety of endogenous and exogenous stress stimuli. Despite marked similarities, Gadd45 genes are regulated differentially and exhibit functional diversity. Gadd45 proteins respond to physiological and oncogenic stress, and are implicated in cell cycle arrest, DNA demethylation and repair, apoptosis, cell survival, genomic stability, and inflammation. The purpose of this book is to provide a comprehensive overview of the unique global role that Gadd45proteins play as stress sensors and the molecular pathways involved. Introduction Contents 1: GADD45 in Stress Signaling, Cell Cycle Control, and Apoptosis 1.1 Overview 1.2 GADD45 Regulation in Growth Arrest and Apoptosis 1.2.1 Transcriptional Regulation of GADD45 1.2.2 Post-transcriptional Regulation of GADD45 1.2.3 GADD45 and NF-κB 1.2.4 GADD45A Reporter as an Assessor of Genotoxicity 1.3 GADD45A Effectors in Growth Arrest and Apoptosis 1.3.1 GADD45A Effectors in Growth Arrest 1.3.2 GADD45A Effectors in Apoptosis 1.3.3 Other Notable GADD45A Effectors 1.4 Roles for GADD45B and GADD45G 1.4.1 GADD45B and GADD45G in p38 and JNK Signaling 1.4.2 Notable Roles of GADD45G Only 1.5 Involvement of GADD45 in Tumorigenesis 1.5.1 GADD45 Expression in Clinical Studies References 2: Roles for GADD45 in Development and Cancer 2.1 Introduction 2.2 GADD45 in Development and Homeostasis: Insights from Model Organisms 2.2.1 Drosophila melanogaster (Fly) 2.2.2 Danio rerio (Zebrafish) 2.2.3 Xenopus laevis (Frog) 2.2.4 Oryctolagus cuniculus (Rabbit) 2.2.5 Mus musculus (Mouse) 2.2.6 Summary 2.3 GADD45 in Cancer 2.3.1 Expression of GADD45 Family Members in Human Cancer 2.3.2 Tumor Suppressive Roles for GADD45 Family Members 2.3.3 Tumor Promoting Roles for GADD45 Family Members 2.3.4 GADD45 Family Members in Cancer Therapy 2.3.5 Summary 2.4 Concluding Remarks References 3: Gadd45 in Normal Hematopoiesis and Leukemia 3.1 Gadd 45 Functions and Mode of Action 3.2 Each of the Gadd45 Genes Is Regulated Independently in Myeloid Cells in Response to Cytokine Stimulation 3.3 Loss of Gadd45 Impairs Terminal Differentiation and Survival of Myeloid Cells in Response to Acute Stimulation with Cytokines 3.4 Role of Gadd45 in Maintaining the Quiescent Stem Cell Pool 3.5 Loss of Gadd45 Reduces the Response of the Myeloid Compartment to Acute Inflammatory Stress 3.6 Loss of Gadd45a and Gadd45b Sensitizes Hematopoietic Cells to Genotoxic-Stress Induced Apoptosis 3.7 Gadd45a and Gadd45b Mediate the Protective Effects from UV in Hematopoietic Cells by Separate Signaling Pathways Involving Either p38 Activation or JNK Inhibition 3.8 Gadd45 in Leukemia 3.9 Gadd45 as a Target for Therapy 3.10 Concluding Remarks References 4: Gadd45 in DNA Demethylation and DNA Repair 4.1 Introduction and Overview 4.2 DNA Methylation and Demethylation 4.3 Mechanisms of Active DNA Demethylation 4.4 DNA Demethylation Mediated by Gadd45 4.5 DNA Repair-Mediated DNA Demethylation by Gadd45 4.6 Determinants of Gadd45 Mediated Target Specificity and DNA Demethylation 4.7 Concluding Remarks References 5: Gadd45 Proteins in Immunity 2.0 5.1 Introduction into the Immune System 5.2 Some Background on Gadd45 Proteins 5.2.1 Functions of Gadd45 Proteins 5.3 Gadd45 Proteins in Immune Cells 5.3.1 Myeloid Cells 5.3.2 Lymphoid Cells 5.4 Gadd45 Proteins in Infection and Autoimmune Disease 5.4.1 Autoimmunity 5.4.2 Infection and Autophagy 5.5 Gadd45 Proteins and Tumor Immunity 5.6 Outlook References 6: Gadd45 in the Liver: Signal Transduction and Transcriptional Mechanisms 6.1 Introduction 6.2 Gadd45α and γ 6.3 Gadd45β in Liver 6.4 Gadd45 Proteins in HCC 6.5 Contradictory Effects on Hepatocyte Proliferation 6.6 Gadd45β Mutation Impairs Liver Regeneration 6.7 Gadd45β Impairs Rapid Growth During Hyperplasia 6.8 Gadd45β Is a Transcriptional Coactivator 6.9 Conclusions References 7: Gadd45 in Preeclampsia 7.1 Stress and Preeclampsia 7.1.1 Hypoxia 7.1.2 Immune Activation 7.1.3 Inflammatory Cytokines 7.1.3.1 TNF-α 7.1.3.2 IL-1 7.1.3.3 IL-6 7.1.4 Oxidative Stress 7.2 The Role of Gadd45 Stress Sensors in Preeclampsia 7.2.1 Hypoxia and Gadd45a in Preeclampsia 7.2.2 Oxidative Stress and Gadd45a in Preeclampsia 7.2.3 AT-1 AAs and Gadd45a in Preeclampsia 7.2.4 Inflammatory Cytokines and Gadd45a in Preeclampsia 7.3 Conclusions References 8: Gadd45 in Senescence 8.1 Gadd45 Family of Stress Response Genes 8.2 Cellular Senescence 8.3 Gadd45 Proteins in Cellular Senescence 8.3.1 Gadd45a Deficiency Results in Escape of Mouse Embryonic Fibroblasts from Senescence, Whereas Gadd45b Deficiency Promotes Premature Senescence and Skin Aging 8.3.2 Gadd45b Deficiency Promotes Senescence and Attenuates Hepatic Fibrosis, Whereas Gadd45a Exerts a Protective Effect Against It 8.4 Summary and Future Prospects References 9: Gadd45 in Neuronal Development, Function, and Injury 9.1 Introduction 9.2 Nervous System Development 9.2.1 Expression Patterns of the Gadd45 Genes in Neural Development 9.2.2 Regulation of Nervous System Development 9.2.3 Molecular Mechanisms in Neurodevelopment 9.3 Neuronal Lesions 9.3.1 Ischemia 9.3.2 Neuronal Injury 9.3.2.1 Physical Neuronal Lesions 9.3.2.2 Neuronal Injury by Non-physical Insults 9.3.2.3 Neuronal Injury by Drugs of Abuse 9.3.2.4 Neoplasia 9.3.2.5 Seizures 9.4 Cognitive Neuroepigenetics 9.4.1 Memory 9.4.2 Autism 9.4.3 Alzheimer’s Disease and Aging 9.4.4 Psychosis 9.5 Conclusions References Index This second edition is fully updated throughout and covers the emerging evidence that indicates that the Gadd45 family of proteins plays a unique and critical role as sensors of stress, including genotoxic, physiological, and oncogenic stress. It sheds light on the complex cellular stress response, encompassing myriad molecular pathways with a plethora of regulators and effectors. The GADD45 stress response genes encode small (18 kd) nuclear/cytoplasmic proteins. These genes are rapidly induced by a wide variety of endogenous and exogenous stress stimuli. Despite marked similarities, Gadd45 genes are regulated differentially and exhibit functional diversity. Gadd45 proteins respond to physiological and oncogenic stress, and are implicated in cell cycle arrest, DNA demethylation and repair, apoptosis, cell survival, genomic stability, and inflammation. The purpose of this book is to provide a comprehensive overview of the unique global role that Gadd45 proteins play as stress sensors and the molecular pathways involved