Redox Regulation of Cell Survival

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play important roles in regulation of cell survival. In general, moderate levels of ROS/RNS may function as signals to promote cell proliferation and survival, whereas severe increase of ROS/RNS can induce cell death. Under physiologic conditions, the balance between generation and elimination of ROS/RNS maintains the proper function of redox-sensitive signaling proteins. Normally, the redox homeostasis ensures that the cells respond properly to endogenous and exogenous stimuli. However, when the redox homeostasis is disturbed, oxidative stress may lead to aberrant cell death and contribute to disease development. This review focuses on the roles of key transcription factors, signal-transduction pathways, and cell-death regulators in affecting cell survival, and how the redox systems regulate the functions of these molecules. The current understanding of how disturbance in redox homeostasis may affect cell death and contribute to the development of diseases such as cancer and degenerative disorders is reviewed. We also discuss how the basic knowledge on redox regulation of cell survival can be used to develop strategies for the treatment or prevention of those diseases.Antioxid. Redox Signal. 10, 1343–1374. Redox Biology and Regulatory Mechanisms Redox homeostasis: ROS production and elimination Oxidative stress and its consequences Redox-mediated mechanisms in regulation of cellular processes Transcriptional regulation Direct oxidative modification Regulation of redox-sensitive interacting proteins Regulation of redox-sensitive modifying enzymes Regulation of protein turnover Redox Regulation of Signaling Proteins Affecting Cell Death and Survival Redox regulation of cell survival at the transcription level NF-κB Role of NF-κB in cell survival Redox regulation of NF-κB Redox regulation of nuclear NF-κB Cytoplasmic regulation of NF-κB AP-1 Role of AP-1 in cell survival Redox regulation of AP-1 Nrf2 Role of Nrf2 in cell survival Redox regulation of Nrf2 HIF Role of HIF in cell survival Redox regulation of HIF Redox regulation of cell survival at the signal-transduction level Mitogen-activated protein kinase Role of MAPK for cell survival under oxidative stress Redox regulation of MAPK PI3K/Akt pathway Role of PI3K/Akt in cell survival Redox regulation of PI3K/Akt Redox regulation of cell survival at the cell death–execution level Caspases Role of caspases in cell death and survival Redox regulation of caspases Bcl-2 Role of Bcl-2 in cell survival Redox regulation of Bcl-2 Cytochrome c Role of cytochrome c in cell survival Redox regulation of cytochrome c Integration of redox-sensitive signaling pathways in the regulation of cell survival Crosstalk between signaling pathways Role of p53 P53 serves as an antioxidant to maintain redox homeostasis and normal cell survival Role of p53 in cell death Redox regulation of p53 Role of Redox Regulation of Cell Survival in Pathogenesis of Diseases Aberrant prolonged cell survival leads to cancer Oncogene activation Ras c-Myc Bcr-Abl Loss of functional p53 Aberrant expression of antioxidant enzymes Superoxide dismutase (SOD) Glutathione peroxidase (GPX) and peroxiredoxin (Prx) Diseases with excessive cell death: aging and degenerative disorders Therapeutic Strategies Based on Redox Regulation of Cell Survival Manipulating redox homeostasis Pro-oxidants as a therapeutic strategy for cancer Antioxidants for prevention of degenerative diseases Modulating redox-sensitive signaling molecules Concluding Remarks