Reactive oxygen species (ROS) are generated during mitochondrial oxidative metabolism as well as in cellularresponse to xenobiotics, cytokines, and bacterial invasion. Oxidative stress refers to the imbalance due toexcess ROS or oxidants over the capability of the cell to mount an effective antioxidant response. Oxidativestress results in macromolecular damage and is implicated in various disease states such as atherosclerosis,diabetes, cancer, neurodegeneration, and aging. Paradoxically, accumulating evidence indicates that ROSalso serve as critical signaling molecules in cell proliferation and survival. While there is a large body ofresearch demonstrating the general effect of oxidative stress on signaling pathways, less is known aboutthe initial and direct regulation of signaling molecules by ROS, or what we term the “oxidative interface.”Cellular ROS sensing and metabolism are tightly regulated by a variety of proteins involved in the redox(reduction/oxidation) mechanism. This review focuses on the molecular mechanisms through which ROSdirectly interact with critical signaling molecules to initiate signaling in a broad variety of cellular processes,such as proliferation and survival (MAP kinases, PI3 kinase, PTEN, and protein tyrosine phosphatases), ROShomeostasis and antioxidant gene regulation (thioredoxin, peroxiredoxin, Ref-1, and Nrf-2), mitochondrialoxidative stress, apoptosis, and aging (p66Shc), iron homeostasis through iron–sulfur cluster proteins(IRE–IRP), and ATM-regulated DNA damage response.
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