Redox sensing: Orthogonal control in cell cycle and apoptosis signaling

• Type of Material: Article
• Authors: Dean P Jones, Emory University
• Language: English
• Date: 2010-11
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 The Association for the Publication of the Journal of Internal Medicine
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2010.02268.x/abstract;jsessionid=5BCDED6BF2E1F51F69953C664098BE6A.d03t02
• Title of Journal or Parent Work: Journal of Internal Medicine
• ISSN: 0954-6820
• Volume: 268
• Issue: 5
• Start Page: 432
• End Page: 448
• Grant/Funding Information: Research support in the author’s laboratory was provided by the National Institute of Environmental Health Sciences grants ES009047 and ES011195.
• Keywords: thioredoxin; Redox signaling; apoptosis; glutathione; oxidative stress; cell cycle
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Living systems have three major types of cell signaling systems that are dependent upon high-energy chemicals, redox environment and transmembranal ion gating mechanisms. Development of integrated systems biology descriptions of cell signaling require conceptual models incorporating all three. Recent advances in redox biology show that thiol/disulfide redox systems are regulated under dynamic, non-equilibrium conditions, progressively oxidized with the life cycle of cells and distinct in terms of redox potentials among subcellular compartments. The present article uses these observations as a basis to distinguish “redox-sensing” mechanisms, which are more global biologic redox control mechanisms, from “redox signaling”, which involves conveyance of discrete activating or inactivating signals. Both redox sensing and redox signaling use sulfur switches, especially cysteine (Cys) residues in proteins which are sensitive to reversible oxidation, nitrosylation, glutathionylation, acylation, sulfhydration or metal binding. Unlike specific signaling mechanisms, the redox-sensing mechanisms provide means to globally affect the rates and activities of the high-energy, ion gating and redox-signaling systems by controlling sensitivity, distribution, macromolecular interactions and mobility of signaling proteins. Effects mediated through Cys residues not directly involved in signaling means redox-sensing control can be orthogonal to the signaling mechanisms. This provides a capability to integrate signals according to cell cycle and physiologic state without fundamentally altering the signaling mechanisms. Recent findings that thiol/disulfide pools in humans are oxidized with age, environmental exposures and disease risk suggest that redox-sensing thiols could provide a central mechanistic link in disease development and progression.