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Table of Contents
                            Front Cover
Regulation of Organelle and Cell Compartment Signaling
Copyright Page
Editorial Advisory Board
Contents
Preface
Contributors
Section A: Overview
	Chapter 1: Organelle Signaling
		Origins of Cell Signaling Research
		Receptors and Intracellular Signaling
		Transcriptional Responses
		Organelle Signaling
		Focus and Scope of this Volume
		References
Section B: Nuclear Signaling
	Part 1: Transcription
		Chapter 2: Signaling at the Nuclear Envelope
			Introduction
			Lamins and Lamin Associated Proteins in Cell Signaling
			The Npc in Cell Signaling
			Conclusions
			Acknowledgements
			References
		Chapter 3: Nuclear Receptor Coactivators
			Introduction
			Ligand-Dependent Interaction between Nuclear Receptors and Coactivators
			Posttranslational Modifications Performed by Coactivator Complexes
			Conclusions
			References
		Chapter 4: Corepressors in Mediating Repression by Nuclear Receptors
			Introduction
			Corepressors Bound to Unliganded Receptor
			Transrepression Strategies
			Corepressors as Metabolic Sensors
			Disease Mechanisms of Nuclear Receptor Dependent Transrepression
			Future Directions
			References
		Chapter 5: Steroid Hormone Receptor Signaling
			Introduction
			Activation by the Hormone
			Hormone Independent Activation
			Cross-Talk with Other Transcription Factors
			Non-Genomic Action of Steroid Hormones
			The Errs
			Selective Steroid Hormone Receptor Modulators
			Acknowledgements
			References
		Chapter 6: FOXO Transcription Factors: Key Targets of the PI3K-Akt Pathway that Regulate Cell Proliferation, Survival,and Organismal Aging
			Introduction
			Identification of the Foxo Subfamily of Transcription Factors
			Regulation of Foxo Transcription Factors by the PI3K-Akt Pathway
			Other Regulatory Phosphorylation Sites in Foxos
			Mechanism of the Exclusion of Foxos from the Nucleus in Response to Growth Factor Stimulation
			Transcriptional Activator Properties of Foxos
			Foxos and the Regulation of Apoptosis
			Foxos are Key Regulators of Several Phases of the Cell Cycle
			Foxos in Cancer Development: Potential Tumor Suppressors
			Role of Foxos in the Response to stress and Organismal Aging
			Foxos and the Regulation of Metabolism in Relation to Organismal Aging
			Conclusion
			Acknowledgements
			References
		Chapter 7: The Multi-Gene Family of Transcription Factor AP-1
			Introduction
			General Structure of the AP-1 Subunits
			Transcriptional And posttranslational Control of AP-1 Activity
			Function of Mammalian AP-1 Subunits During Embryogenesis and Tissue Homeostasis: Lessons From Loss-of-Function and Gain-of-Function Approaches in Mice
			Function of Mammalian AP-1 Subunits During Cancer Development and Progression
			Conclusion
			Acknowledgements
			References
		Chapter 8: NFκB: A Key Integrator of Cell Signaling
			References
		Chapter 9: Ubiquitin-mediated Regulation of Protein Kinases in NFκB Signaling
			Introduction
			The Ubiquitin Pathway
			NFκB Signaling
			Ubiquitin-Mediated Activation of Protein Kinases in the IL-1R and TLR Pathways
			Ubiquitin-Mediated Regulation of NFκB and Apoptosis in the TNFα Pathway
			De-Ubiquitination Enzymes Prevent Protein Kinases Activation in The NFκB Pathway
			Polyubiquitination Regulates Protein Kinase Activation in Diverse NFκB Pathways
			Conclusions And Perspectives
			Acknowledgements
			References
		Chapter 10: Transcriptional Regulation via the cAMP Responsive Activator CREB
			The Creb Family of Transcription Factors
			Domain Structure and Function
			Overview of CREB Activation
			Key Phosphorylation Events
			CREB Target Genes
			CBP and P300
			TORC
			Other Coactivators and Interacting Proteins
			Questions to be Addressed
			Acknowledgements
			References
		Chapter 11: The NFAT Family: Structure, Regulation, and Biological Functions
			Introduction
			Structure and DNA Binding
			Regulation
			Transcriptional Functions
			Biological Programs Regulated By NFAT
			The Primordial Family Member: NFAT5
			Perspectives
			References
		Chapter 12: JAK-STAT Signaling
			Abbreviations
			Introduction
			The JAK-STAT Paradigm
			The JAK Family
			The STAT Family
			A Bright Future
			References
	Part 2: Chromatin Remodeling
		Chapter 13: Histone Acetylation Complexes
			Introduction
			KAT Classification and Diversity
			Bromodomains and Other Interpreters of Histone Modifications
			Kats and Disease
			Conclusion and Future Directions
			Acknowledgements
			References
		Chapter 14: Regulation of Histone Deacetylase Activities and Functions by Phosphorylation and Dephosphorylation
			Introduction
			Reversible Phosphorylation of Mammalian Class I Hdacs
			Reversible Phosphorylation of Mammalian Class II Hdacs
			Conclusion and Perspectives
			References
		Chapter 15: Histone Methylation: Chemically Inert but Chromatin Dynamic
			Introduction
			Historical Perspective of Chromatin and Histone Methylation
			Enzymes Regulating Arginine and Lysine Methylation States
			Histone Lysine Methyltransferases
			Histone Demethylase Enzymes
			Degree and Location Matter
			References
		Chapter 16: Histone Phosphorylation: Chromatin Modifications that Link Cell Signaling Pathways to Nuclear Function Regulation
			Introduction
			Histone Phosphorylation and Transcriptional Regulation
			Downstream Effects of Transcription Associated H3 Phosphorylation
			Histone Phosphorylation in Response to DNA Damage
			Histone Phosphorylation and Mitosis
			Histone Phosphorylation During Apoptosis
			Histone Phosphorylation and Human Diseases
			Conclusions and Perspectives
			References
		Chapter 17: Histone Variants: Signaling or Structural Modules?
			Introduction
			H2A.Bbd in Search of a Function
			H2A.X: DNA Damage and Beyond
			H2A.Z Function at a Flip of a Coin
			Macro H2A: Phosphorylation Matters
			H2B Variance and Unknown Partners
			H3.3 Providing Transcriptional Memory
			CENP-A: Splitting Nucleosomes in Drosophila
			Histone H1: The Microheterogeneity of Specialized Function
			Concluding Remarks
			Acknowledgements
			References
		Chapter 18: Histone Ubiquitination
			The Mechanism of Ubiquitination
			Histone Ubiquitination
			Mono-Ubiquitination of H2A
			Ubiquitination of Histone H2A Variants
			De-Ubiquitination of Ubh2A
			How does UbH2A Repress Transcription?
			The Role of UbH2A in DNA Repair
			Mono-Ubiquitination of H2B
			H2B Ubiquitination Requires Factors Involved in Transcription Initiation and Elongation
			H2B Ubiquitination is Required for Processive Lys-4 H3 and Lys-79 H3 Methylation
			The 19S Proteasome and the Ccr4-not Complex Link H2B Ubiquitination to Lys-4 and Lys-79 H3 Methylation
			De-Ubiquitination of UbH2B
			De-Ubiquitination of UbH2B is Required for Later Stages of Transcription Elongation
			Conclusion
			Acknowledgements
			References
		Chapter 19: Chromatin Mediated Control of Gene Expression in Innate Immunity and Inflammation
			Introduction
			Inflammation as a Kinetically Complex Transcriptional Response
			Chromatin and the Kinetic Control of Inflammatory Responses
			Genetic Dissection of Chromatin Remodeling at Inflammatory Genes
			Binding of Inflammatory Transcription Factors to Nucleosomal DNA
			Conclusions
			References
	Part 3: Stress Responses
		Chapter 20: Complexity of Stress Signaling
			Abbreviations
			Introduction
			Origin of Stress Response Signals
			Signal Transduction
			Systems Level Deductions of Stress Response Networks
			Acknowledgements
			References
		Chapter 21: Oxidative Stress and Free Radical Signal Transduction
			Introduction: Redox Biology
			Oxidative Stress Responses in Bacteria: Some Well-Defined Models of Redox Signal Transduction
			Response to Superoxide Stress and Nitric Oxide: SoxR Protein
			Response to H2O2 and Nitrosothiols:Oxyr Protein
			Parallels in Redox and Free Radical Sensing
			Themes in Redox Sensing
			Acknowledgements
			References
		Chapter 22: Double-Strand Break Recognition and its Repair by Non-Homologous End-Joining
			Overview of Non-Homologous End-Joining (NHEJ)
			Kinase Activation and Autophosphorylation of DNA-PK
			DNA-PK May Influence the Balance of HR and NHEJ during S Phase
			Local Chromatin Structure at Sites of NHEJ
			References
		Chapter 23: ATM Mediated Signaling Defends the Integrity of the Genome
			Introduction
			Sensing Radiation Damage in DNA
			Atm Activation and Recruitment of DNA Damage Response Proteins to DNA DSB
			ATM Mediated Downstream Signaling
			Cell Cycle Checkpoint Activation
			Concluding Remarks
			References
		Chapter 24: Signaling to the p53 Tumor Suppressor through Pathways Activated by Genotoxic and Non-Genotoxic Stresses
			Introduction
			p53 Protein Structure
			Posttranslational Modifications to p53
			Regulation of p53 Activity
			p53 Stabilization
			p53 Activation
			Activation of p53 by Genotoxic Stresses
			DNA Doubled-Strand Breaks
			Replication Stress and Singlestranded DNA
			Replicative Senescence
			Oncogene Activation
			Other Genotoxic Agents
			Activation of p53 by Non-Genotoxic Stresses
			The Unfolded Protein Response – ER Stress
			Hypoxia
			Glucose Deprivation – Nutritional Stress
			Ribonucleotide Pool Imbalance
			Nucleolar and Ribosomal Stress
			Microtubule Disruption
			Setting Thresholds and Resetting Activation – p53 Phosphatases
			Conclusions
			Acknowledgements
			References
		Chapter 25: The p53 Master Regulator and Rules of Engagement with Target Sequences
			Introduction
			The p53 Induced Transcriptional Network: Genes, Biological Functions, and the Complexity of Target Selection
			Yeast as an in Vivo Test Tube to Study Wild-Type and Mutant p53 Transactivation Potential toward Defined Response Element Sequences
			Yeast as an in Vivo Test Tube to Study Wild-Type and Mutant p53 Transactivation Potential Toward Defined Response Element Sequences
			Rules of p53 Transactivation Revealed by Yeast-Based Assays
			Spacers Affect p53 Transactivation Potential in the Yeast-Based Assay
			Spacer Effects on p53 Binding and Transactivation in Mammalian Cell Assays
			Non-Canonical 3/4- and 1/2-Site Res Expand the p53 Transcriptional Network
			Impact of 1/2-Site res in the p53 Transcriptional Network
			Evolutionary Development of p53 Res
			Yeast Based Functional Classification of p53 Mutant Alleles Associated with Cancer
			Contributions to the Rules of Engagement by p53 Homologs and Other Sequence Specific Transcription Factors
			p53 Cofactors Contribute to Promoter Selectivity
			Conclusions
			Acknowledgements
			References
		Chapter 26: The Heat Shock Response and the Stressof Misfolded Proteins
			Introduction
			Transcriptional Regulation of the Heat Shock Response
			Chaperone Function in Normal and Disease States
			Acknowledgements
			References
		Chapter 27: Hypoxia Mediated Signaling Pathways
			Introduction
			HIF Regulation
			HIF Signaling and Metastasis
			Unfolded Protein Response
			Conclusions
			References
		Chapter 28: Regulation of mRNA Turnover by Cellular Stress
			Introduction
			RNA-Binding Proteins Controlling mRNA Turnover
			mRNA Decay Determinants and Degradation Machineries
			Stress-Activated Signaling Molecules that Regulate mRNA Turnover
			Concluding Remarks
			Acknowledgements
			References
		Chapter 29: Oncogenic Stress Responses
			Introduction
			Downstream Effectors of OIS
			p38Mapk Signaling and OIS
			DNA Damage Response and OIS
			Concluding Remarks
			References
		Chapter 30: Ubiquitin and FANC Stress Responses
			Introduction
			Components of the Fanconi Anemia Pathway
			The FA Core Complex and Activation of the FA Pathway
			Mono-Ubiquitylation of FANCD2 and FANCI
			Downstream Effectors and Interactions with other DNA Repair Proteins
			De-Ubiquitylation of FANCD2 and FANCI
			Non-Repair Functions of the FA Pathway
			Conclusions
			References
		Chapter 31: Stress and γ-H2AX
			Introduction
			Stress Induces DNA DSB Damage and γ-H2AX Formation
			Role Of γ -H2AX In DNA Damage Repair Pathways
			γ -H2AX, a Marker to Monitor Cell Stress and a Protein Involved in Stress Signaling
			Conclusions
			Acknowledgements
			References
Section C: Signaling to/from Intracellular Compartments
	Chapter 32: Regulation of mRNA Turnover
		Introduction
		Current Model for MRNA Decay in Mammalian Cells
		Deadenylation: The First Major Step Triggering mRNA Decay
		Regulation of Deadenylation by a Protein that Interacts with Both Poly(A) Nuclease(S) and PABP
		A Mechanism for Translationally Coupled mRNA Turnover
		The Involvement of RNA Processing Bodies (P-Bodies) in Regulation of mRNA Turnover
		Concluding Remarks
		References
	Chapter 33: Signaling to Cytoplasmic Polyadenylation and Translation
		Introduction
		The Biochemistry of Cytoplasmic Polyadenylation
		Signaling to Polyadenylation
		A Hierarchy of Translation Control
		Polyadenylation in Mammalian Oocytes
		Signaling to Polyadenylation in the Brain
		Conclusions
		References
	Chapter 34: Translation Control and Insulin Signaling
		Introduction
		The Insulin Signaling Pathway
		Insulin Signaling and Regulation of Translation Initiation
		Insulin Signaling and Regulation of Translation Elongation
		Insulin Signaling and Ribosome Biogenesis
		Concluding Remarks
		Acknowledgements
		References
	Chapter 35: Signaling Pathways that Mediate Translational Control of Ribosome Recruitment to mRNA
		Introduction
		Translation Initiation
		The eIF4F Complex
		Regulation of Translation Initiation by mTOR
		Translation and Cancer
		Conclusions
		References
	Chapter 36: Nuclear and Cytoplasmic Functions of Abl Tyrosine Kinase
		Introduction
		Functional Domains of ABL
		Proteins that Interact with ABL
		ABL in Signal Transduction
		Future Prospects
		Acknowledgement
		References
	Chapter 37: The SREBP Pathway: Gene Regulation through Sterol Sensing and Gated Protein Trafficking
		SREBPS: Membrane Bound Transcription Factors
		Scap: Sterol Sensor and Escorter of SREBP from ER to Golgi
		Insig: Sterol Sensor and ER Retention Protein
		Scap and Insig: Two Sensors for Two Classes of Sterols
		Future Challenges
		Acknowledgements
		References
	Chapter 38: Ubiquitination/Proteasome
		Protein Degradation and the Ubiquitin/Proteasome System
		Regulation of Ubiquitination by Substrate Modification
		Regulation of Ubiquitin Ligase Activity
		Processing of TFS by the Ubiquitin System
		Modulation of Kinase Activity by Ubiquitination
		Role of Ubiquitination/Proteasome in TF Activity
		Conclusion
		Acknowledgements
		References
	Chapter 39: Regulating Endoplasmic Reticulum Function through the Unfolded Protein Response
		Introduction
		Molecular Sensors
		How Molecular Sensors Detect ER Stress
		Downregulating the UPR
		Cellular Effects of UPR Induction
		Physiological UPR
		Perspectives
		References
	Chapter 40: Protein Quality Control in the Endoplasmic Reticulum
		Introduction
		ER Quality Control
		Unique Environment of the ER
		Molecular Chaperones and Folding Enzyme
		Disposal of Unfolded and Misfolded Protein
		ER Subcompartments
		References
	Chapter 41: Protein Quality Control in Peroxisomes: Ubiquitination of the Peroxisomal Targeting Signal Receptors
		Introduction
		PTS (Co-) Receptor Ubiquitination: Conundrum and Confusion
		S. Cerevisiae PEX18P is Degraded in an Ubiquitin Dependent Manner
		S. Cerevisiae PEX5P, Two Distinct Ubiquitination Events, Two Distinct Functions
		The Ubiquitination of P. Pastoris PEX20P: Two Independent Ubiquitination Events?
		Involvement of the Ring Proteins in PTS (Co-) Receptor Ubiquitination
		AAA Protein Mediated (Co-) Receptor Recycling: an Ubiquitin Dependent Event?
		Conclusions
		References
	Chapter 42: Mitochondrial Dynamics: Fusion and Division
		Introduction
		Mitochondrial Fusion
		Mitochondrial Division
		Conclusions
		Acknowledgements
		References
	Chapter 43: Signaling Pathways from Mitochondria to the Cytoplasm and Nucleus
		Introduction
		Small Molecules as Signals from Mitochondria
		Small Cations: NA+, K+, MG+2, CA+2, H+
		ATP, ADP, and AMP
		NADH and NAD+
		Glutathione (GSH and GSSG)
		Reactive Oxygen Species
		Iron Sulfur Clusters
		Sirtuins
		Mitochondrial Retrograde Signaling
		Conclusion
		References
	Chapter 44: Quality Control and Quality Assurance in the Mitochondrion
		Introduction
		Quality Assurance Mediated by Chaperones and the Protein Translocation Complex
		Quality Control of Protein Structure and Function Mediated by ATP Dependent Proteases
		Perspective
		Acknowledgements
		References
	Chapter 45: Mitochondria as Organizers of the Cellular Ca2+ Signaling Network
		Introduction
		Fundamentals
		The Plasticity of the Mitochondrial Ca2+ Handling Machinery
		Mitochondrial Ca2+ Handling in the Cellular Context
		CODA
		Acknowledgements
		References
	Chapter 46: Signaling during Organelle Division and Inheritance: Peroxisomes
		Introduction to Peroxisomes
		Peroxisome Division
		Peroxisome Inheritance
		Concluding Remarks
		Acknowledgements
		References
	Chapter 47: Bidirectional Crosstalk between Actin Dynamics and Endocytosis
		Introduction
		From Actin to Endocytosis
		Converging Molecular Machinery in Endocytosis and Actin Dynamics
		From Endocytosis to Actin Dynamics
		Outlook
		Acknowledgements
		References
	Chapter 48: Signaling in Autophagy Related Pathways
		Introduction
		Signaling Control of Autophagy
		Autophagy and Cell Death
		Acknowledgements
		References
Section D: Cell Cycle/Cell Death Signaling
	Chapter 49: Regulation of Cell Cycle Progression
		Introduction
		Cyclins Define Cell Cycle Phase
		Signals to Slow Progress: Regulation of CDKs by Inhibitory Proteins
		CDKs are Positively and Negatively Regulated by Phosphorylation
		Degradation: The Importance of Being Absent
		Checkpoint Signaling
		Lessons from Mice: Cell Division without CDKs
		Knockout Mouse Models: Cycling without Cyclins
		References
	Chapter 50: The Role of Rac and Rho in Cell Cycle Progression
		Introduction
		Regulation of G1 Progression
		The Function of RAC and RHO in Cell Cycle Progression and Transformation
		Cell Cycle Targets of RAC and RHO
		Future Perspectives
		Acknowledgement
		References
	Chapter 51: The Role of Alternative Splicing During the Cell Cycle and Programmed Cell Death
		Introduction
		Apoptosis and Splicing
		Cell Cycle and Splicing
		Conclusions
		References
	Chapter 52: Cell-Cycle Functions and Regulation of Cdc14 Phosphatases
		Introduction
		The CDC14 Phosphatase Subgroup of PTPs
		Budding Yeast CDC14 is Essential for Exit from Mitosis
		Fission Yeast CDC14 Coordinates Cytokinesis with Mitosis
		Potential Cell-Cycle Functions of Human CDC14A and B
		References
	Chapter 53: Caspases: Cell Signaling by Proteolysis
		Protease Signaling
		Apoptosis and Limited Proteolysis
		Caspase Activation
		Regulation by Inhibitors
		References
	Chapter 54: Apoptosis Signaling: A Means to an End
		Introduction
		The End of the Road
		Caspase-8 Activation via Death Receptors
		Mitochondria and the Activation of Caspase-9
		Mitochondrial Outer Membrane Permeabilization
		The BCL-2 Family
		Cell Cycle Versus Apoptosis
		Conclusions
		References
	Chapter 55: The Role of Ceramide in Cell Regulation
		Introduction
		Sphingolipid Metabolism
		Apoptosis
		Non-Apoptotic Ceramide Biology
		Conclusions
		References
Index
                        

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