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International Review of Cell and Molecular Biology

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Contents

Contributors

Chapter One: New Insights Into the Roles of Retinoic Acid Signaling in Nervous System Development and the Establishment o ...

1. Introduction

2. Developmental Signaling

3. Retinoids as Morphogens, Teratogens, and Drugs

4. RA Signaling Pathway

5. Major Functions of RA Signaling

6. RA Signaling During Nervous System Development

6.1. Posteriorizing Neural Plate

6.2. Setting Up RA Signaling System and Boundaries of Neural Tube

6.3. Patterning Neural Tube Along the Anterior-Posterior Axis

6.3.1. Hindbrain and Anterior Spinal Cord

6.3.2. Spinal Cord

6.4. Patterning Neural Tube Along Dorsal-Ventral Axis

6.5. Orchestrating Proliferation, Differentiation, and Survival of Neural Progenitors

6.6. Inducing and Coordinating Neural Crest Development

6.7. Inducing and Coordinating Cranial Placode Development

6.8. Regulating Formation of Neural Crest and Cranial Placode Derivatives

7. RA Signaling and the Establishment of Neurotransmitter Systems

7.1. Natural Neuroactive Substances: Neurotransmitters, Neuromodulators, and Neurohormones

7.2. Catecholaminergic Neurons

7.3. Serotonergic Neurons

7.4. Glutamate and GABAergic Neurons

8. RA Signaling Outside Vertebrates: Evolutionary Considerations

9. Concluding Remarks

Acknowledgments

References

Chapter Two: AMBRA1, a Novel BH3-Like Protein: New Insights Into the AMBRA1-BCL2-Family Proteins Relationship

1. Introduction

2. AMBRA1 in Autophagy, Selective Autophagy, and Beyond

2.1. AMBRA1 in Autophagy

2.2. AMBRA1 in Mitophagy

2.3. AMBRA1 in Apoptosis, Development, Differentiation, Viral Infection, and Proliferation

2.4. AMBRA1 in Diseases

3. Autophagy and Apoptosis Cross-Talk

3.1. The Antiapoptotic BCL2 Proteins Control the Autophagy Process

3.2. AMBRA1 Contains a BH3 Domain Necessary for BCL2 Binding

4. Autophagy Inhibition by the Oncogenic Function of BCL2

4.1. Autophagy Pathway as a Tumor Suppressor

4.2. BCL2 Inhibits AMBRA1-Dependent Autophagy: Could It Be a Novel Mechanism to Regulate Tumorigenesis?

5. BCL2-AMBRA1 Interaction as a Novel Therapeutic Target

5.1. Autophagy Induction Through BCL2-AMBRA1 Dissociation

5.2. Is AMBRA1-Mediated Mitophagy Regulated by BCL2 Family Proteins?

6. Conclusion

Acknowledgments

References

Chapter Three: Rationale for the Combination of Dendritic Cell-Based Vaccination Approaches With Chemotherapy Agents

1. Introduction

2. Immunological Aspects of Anticancer Chemotherapy With Regards to DC Functions

2.1. Direct DC Stimulatory Effects of Anticancer Agents

2.2. Chemotherapeutic Agents Affecting DC Functions by Inducing ICD in Tumor Cells

2.2.1. Concept of ICD

2.2.2. Anthracyclines (Doxorubicin, Idarubicin, Epirubicin) and Mitoxantrone

2.2.3. Cyclophosphamide

2.2.4. Oxaliplatin

2.2.5. Bortezomib

2.2.6. Bleomycin

2.2.7. Modulating DC Functions by Immunogenic Chemotherapy-Induced DAMPs

2.2.7.1. Sensing ICD-Associated Danger Signals by DCs

2.2.7.2. Recognition and Phagocytosis of Tumor Cells by DCs

2.2.7.3. DC Activation

2.2.7.4. Antigen Processing and Presentation

3. Clinical Trials of Combined DC-Based Immunotherapy and Chemotherapy Affecting DC Functions

4. Conclusions

Acknowledgments

References

Chapter Four: Smac Mimetics to Therapeutically Target IAP Proteins in Cancer

1. Introduction

2. IAP Proteins

3. Mechanisms of Action of Smac Mimetics

4. Smac Mimetics as Single Agents

5. Smac Mimetic-Based Combination Therapies

6. Conclusions

Acknowledgments

References

Chapter Five: Consequences of Keratin Phosphorylation for Cytoskeletal Organization and Epithelial Functions

1. Introduction

2. Characteristics of Keratin Phosphorylation

2.1. Keratin Phosphorylation Is Complex, Fast, and Linked to Other Posttranslational Modifications

2.2. Phosphorylation Occurs Preferentially in the Keratin End Domains

2.3. Phosphorylation Increases Keratin Solubility

2.4. Common Guidelines Determine Keratin Phosphorylation

3. Regulation of Protein Binding to Keratins by Phosphorylation

3.1. Phosphorylation-Dependent Keratin-14-3-3 Protein Association Enhances Keratin Solubility and Affects mTOR Signaling

3.2. Sequestration of Raf Kinase Is Regulated by Keratin Phosphorylation

3.3. Association of Cytolinkers With Keratin Is Influenced by Phosphorylation

3.4. Phosphorylation-Dependent Association of the Ubiquitin Ligase Pirh2 With Keratin Affects Cell Survival

4. Role of Keratin Phosphorylation in Cell Physiology

4.1. Mitosis Is Linked to Keratin Phosphorylation and Keratin Network Remodeling

4.2. The Epithelial Stress Response Is Coupled to Altered Keratin Phosphorylation

4.2.1. Chemical Stress and Keratin Phosphorylation Contribute to Mallory-Denk Body Formation

4.2.2. Chemical Stress and Phosphorylation Alter the Assembly State of Keratins

4.2.3. Heat Stress Leads to Recruitment of Chaperones to Phosphorylated Keratin Resulting in Keratin Aggregate Formation

4.2.4. Mechanical Stress Is Linked to Keratin Phosphorylation and Keratin Network Reorganization

4.2.5. Osmotic Stress Induces Kinase-Dependent Alterations of the Keratin Cytoskeleton

4.2.6. Microbes Elicit Keratin Phosphorylation Leading to Keratin Network Reorganization

4.3. Keratin Phosphorylation Protects Against Ubiquitin-Dependent Degradation and Reduces Sensitivity to Apoptosis

5. Disease Relevance of Keratin Phosphorylation

5.1. Keratin Phosphorylation Affects Keratin Network Organization and Function in Simple Epithelia

5.1.1. Altered Keratin Phosphorylation Affects Keratin Network Organization and Stress Resilience in Hepatocytes

5.1.2. The Pancreas Is Sensitive to Changes in Keratin Expression Levels Leading to Altered Keratin Phosphorylation

5.1.3. Keratin Phosphorylation Is Linked to Liver Disease Progression

5.1.4. Keratin Phosphorylation Affects Keratin Network Organization and Function of Intestinal Epithelial Cells

5.2. Keratin Phosphorylation Is Altered in Skin Diseases

5.2.1. Increased Keratin Phosphorylation Is Related to Keratin Network Dynamics in Skin Disease

5.2.2. Keratin Phosphorylation Is Increased in Stressed Keratinocytes Producing Mutant Keratins

5.2.3. Increased Keratin Phosphorylation Is Observed in Hyperkeratotic Skin Diseases

5.3. Keratin Phosphorylation Is Altered in Cancer

5.3.1. Phosphorylation-Dependent Keratin Network Plasticity Correlates With Tumor Cell Migration

5.3.2. Keratin Dephosphorylation Is Linked to Tumor Progression

5.3.3. Keratin Phosphorylation Is Linked to Epithelial-Mesenchymal Transition

5.3.4. Keratin Hyperphosphorylation Is a Consequence of Altered Growth Control in Cancer Cells

6. Concluding Remarks: Significance of Keratin Phosphorylation

Acknowledgments

References

Chapter Six: Plastid Protein Targeting: Preprotein Recognition and Translocation

1. Introduction

2. Origin of Plastids

3. Plastid Protein Targeting Routes

3.1. General Import Pathway

3.2. Roles of General Import Pathway Components

3.2.1. TPs and Interacting Domains

3.2.2. Cytosolic and Lipid Modulators of Plastid Targeting

3.2.3. TOC Apparatus

3.2.3.1. Core Complex

3.2.3.2. Identification of TOC Core Components

3.2.3.3. GTPase Cycle of TOC Receptors: TOC34 and TOC159

3.2.3.4. Models of TOC Receptor Function

3.2.3.5. Preprotein Recognition by TOC GTPases

3.2.3.6. Protein Conducting Channel: TOC75

3.2.3.7. TOC Complex Assembly

3.2.4. TIC Apparatus

3.2.5. Stromal Motors

3.2.6. Peptidases

3.3. Noncanonical Trafficking

3.3.1. Vesicle-Mediated Trafficking

3.3.2. SA and TA Proteins

3.4. Dual Targeting to Plastids and Mitochondria

4. Regulation of Plastid Protein Import

4.1. Organism-Specific Recognition of TPs

4.1.1. Evolution of Translocon Subunits

4.1.2. Evolution of TP of Small Subunit of RuBisCO

4.1.3. Comparative Nuclear-Encoded Plastid Proteomes

4.2. Expression Control

4.3. Precursor-Specific Import Pathways

4.3.1. Photosynthetic and Nonphotosynthetic Precursors

4.3.2. Age-Specific Precursors

4.4. Redox Regulation

4.5. Phosphorylation Regulation

4.6. Potential Role of Proline Isomerization

4.7. Regulation by Ubiquitin-Proteasome System

5. Concluding Remarks

Acknowledgments

References

Chapter Seven: Immunomodulatory Activity of VEGF in Cancer

1. Introduction

2. The VEGF Family

2.1. Properties of VEGF Family Members

2.2. Isoforms of VEGF-A and Their Particularities

2.3. Production of VEGF-A

3. VEGF Receptors

4. The VEGF-A/VEGFR Axis

5. Antitumor Immunity

5.1. Tumor Immunosurveillance

5.1.1. Basic Principles

5.1.2. Main Effectors of the Antitumor Immune Response

5.2. Escape From the Antitumor Immune Response

5.2.1. Cytokines

5.2.2. Maturation of DCs

5.2.3. Accumulation of MDSCs

5.2.4. Tumor-Associated Macrophages

5.2.5. Increase in Tregs

5.2.6. Immune Checkpoints and T-Cell Exhaustion

6. Immunosuppressive Roles of VEGF

6.1. Inhibition of DC Maturation

6.2. Accumulation of MDSCs

6.3. Development of Tumor-Induced Macrophages

6.4. Increase in Tregs

6.5. Effector T Cells

7. Immunomodulatory Properties of Therapeutics Targeting VEGF

7.1. Development of Major Antiangiogenic Molecules

7.2. Immunomodulatory Activity of Antiangiogenic Therapies in Animals

7.3. Immunomodulatory Activity of Antiangiogenic Therapies in Humans

7.3.1. Bevacizumab

7.3.2. Sorafenib

7.3.3. Sunitinib

8. Medical Applications

8.1. Antiangiogenic Drugs as Ideal Companions for Anticancer Immunotherapy: Preclinical Studies

8.2. First Clinical Results

8.3. Other Potential Applications

9. Concluding Remarks

Acknowledgments

References

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