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.
Dr. Ruth Scherz-Shouval is the daughter of Prof. Avigdor Scherz, a pioneer in the field of photo-dynamic therapy in the Department of Plant and Environmental Sciences at the Weizmann Institute. She earned a BSc in the life sciences with honors at the Hebrew University of Jerusalem in 2002 and a PhD in biological chemistry at the Weizmann Institute of Science in 2008 (with Prof. Zvulun Elazar). She conducted postdoctoral research in Prof. Moshe Oren's laboratory at the Weizmann Institute and at the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology (MIT), and will join the Weizmann Institute's Department of Biological Chemistry in October 2015.
Dr. Marc Mendillo is an Assistant Professor of Biochemistry and Molecular Genetics at the Northwestern University. His PhD was obtained from the University Of California-San Diego in Biomedical Sciences followed by a Postdoctoral Fellowship at the Ludwig Institute for Cancer Research in San Diego and another at the Whitehead Institute. Currently, he runs a lab in the Department of Biochemistry and Molecular Genetics and the Robert H. Lurie Comprehensive Cancer Center.
Dr. David Pincus is a fellow at the Whitehead Institute where he tries to reveal the underlying mechanisms cells employ to maintain homeostasis in inherently fluctuating environments.
Preface: Dedication to Susan Lindquist
Part I: Structure
Chapter 1: "Structural and Biochemical properties of Hsp40/Hsp70 chaperone system".
Chapter 2: "The TRiC/CCT chaperonin and its role in uncontrolled proliferation
Chapter 3: "Regulation of Hsf1 and the heat shock response"
Part II: Function
Chapter 4: "Challenging proteostasis: Role of the chaperone network to control aggregation-prone proteins in human disease"
Chapter 5: "The multifaceted role of HSF1 in tumorigenesis
Chapter 6: "Chaperome networks - redundancy and implications for cancer treatment"
Chapter 7: "Chaperones in the tumor microenvironment"
Chapter 8: "The impact of the ER unfolded protein response on cancer initiation and progression: Therapeutic implications"
Part III: Therapies
Chapter 9: "The right tool for the job: an overview of Hsp90 inhibitors"
Chapter 10: "Lessons learned from proteasome inhibitors, the paradigm for targeting
protein homeostasis in cancer"
Chapter 11: "Reflections and outlook on targeting HSP90, HSP70 and HSF1 in cancer: A personal perspective"