BookMarc Laurence Mendillo, David Pincus, Ruth Scherz-Shouval, editors.
Summary: Protein homeostasis, or "Proteostasis", lies at the heart of human health and disease. From the folding of single polypeptide chains into functional proteins, to the regulation of intracellular signaling pathways, to the secreted signals that coordinate cells in tissues and throughout the body, the proteostasis network operates to support cell health and physiological fitness. However, cancer cells also hijack the proteostasis network and many of these same processes to sustain the growth and spread of tumors. The chapters in this book are written by world experts in the many facets of the proteostasis network. They describe cutting-edge insights into the structure and function of the major chaperone and degradation systems in healthy cells and how these systems are co-opted in cancer cells and the cells of the tumor microenvironment. The chapters also cover therapeutic interventions such as the FDA-approved proteasome inhibitors Velcade and Krypolis as well as other therapies currently under clinical investigation to disarm the ability of the proteostasis network to support malignancy. This compendium is the first of its kind and aims to serve as a reference manual for active investigators and a primer for newcomers to the field. This book is dedicated to the memory of Susan Lindquist, a pioneer of the proteostasis field and a champion of the power of basic scientific inquiry to unlock the mechanisms of human disease.
Contents:
Intro
Preface: Dedication to Susan Lindquist
Contents
Part I: Structure
1: Structural and Biochemical Properties of Hsp40/Hsp70 Chaperone System
1.1 Hsp70 Chaperone System
1.1.1 Hsp70 Domain Structure and Functional Cycle
1.1.2 Substrate Recognition and Remodeling by the Hsp70 Chaperones
1.2 Regulation of Hsp70 Function by Co-chaperones
1.2.1 J-Domain Proteins
1.2.2 Nucleotide Exchange Factors
1.2.2.1 Nucleotide Cycle Regulation Beyond JDPs and NEFs
1.3 Hsp70s Interaction with Other Cellular Chaperone Systems 1.3.1 Hsp70 Chaperones in Protein Disaggregation
1.4 Conclusion and Perspectives
References
2: The TRiC/CCT Chaperonin and Its Role in Uncontrolled Proliferation
2.1 Introduction
2.2 The Structure of CCT
2.3 CCT Substrates and Specificity
2.4 Conformational Changes and Nucleotide Hydrolysis
2.5 CCT and Cancer
2.6 CCT as Key Regulator of Cell Cycle
2.7 Is CCT a Possible Antiproliferation Target?
References
3: Regulation of Hsf1 and the Heat Shock Response
3.1 Introduction: The HSR in Health and Disease 3.2 Defining the Transcriptional Response to Heat Shock
3.3 What Activates the HSR?
3.4 Hsp70 and Hsf1 Constitute a Negative Feedback Loop That Controls the HSR
3.5 Hsp90 Negatively Regulates Hsf1 Orthogonally to Hsp70
3.6 Phosphorylation Is Dispensable for Hsf1 Activity During Heat Shock
3.7 Coordination of the HSR Across Tissues
3.8 Conclusion
References
Part II: Function
4: Challenging Proteostasis: Role of the Chaperone Network to Control Aggregation-Prone Proteins in Human Disease
4.1 Introduction 5: The Multifaceted Role of HSF1 in Tumorigenesis
5.1 Introduction
5.2 HSF1 Structure and Function
5.2.1 HSF1 Regulation by Post Translational Modification
5.3 HSF1 in Carcinogenesis
5.4 How Is HSF1 Activated in Cancer?
5.5 How Does HSF1 Support the Malignant State in Cancer?
5.5.1 HSF1 Regulation of Cancer Cell Proteostasis
5.5.2 HSF1 Regulation of mRNA Processing and Protein Synthesis
5.5.3 HSF1 Regulation of DNA Repair
5.5.4 HSF1 Regulation of Energy Metabolism
5.5.5 HSF1 Regulation of Cell Motility, Migration and Adhesion