FORUM REVIEW ARTICLE Hydrogen Peroxide as a Cell-Survival Signaling Molecule Gillian Groeger, Claire Quiney, and Thomas G. Cotter Abstract Reactive oxygen species (ROS) were seen as destructive molecules, but recently, they have been shown also to act as second messengers in varying intracellular signaling pathways. This review concentrates on hydrogen peroxide (H 2 O 2 ), as it is a more stable ROS, and delineates its role as a survival molecule. In the first part, the production of H 2 O 2 through the NADPH oxidase (Nox) family is investigated. Through careful examination of Nox proteins and their regulation, it is determined how they respond to stress and how this can be prosurvival rather than prodeath. The pathways on which H 2 O 2 acts to enable its prosurvival function are then examined in greater detail. The main survival pathways are kinase driven, and oxidation of cysteines in the active sites of various phosphatases can thus regulate those survival pathways. Regulation of transcription factors such as p53, NF-kB, and AP-1 also are reviewed. Finally, prodeath proteins such as caspases could be directly inhibited through their cysteine residues. A better understanding of the prosurvival role of H 2 O 2 in cells, from the why and how it is generated to the various molecules it can affect, will allow more precise targeting of therapeutics to this pathway. Antioxid. Redox Signal. 11, 2655–2671. Introduction R eactive oxygen species (ROS) are a group of molecules produced in cells when oxygen is metabolized. They were traditionally viewed as destructive molecules that re- sulted in cell death through damaging key cellular molecules such as DNA and lipids, but recently they have also been shown to contribute to cell proliferation, migration, and sur- vival [reviewed by (126)]. This group is made up of several members, including superoxide (O 2  ), nitric oxide (NO  ), hydrogen peroxide (H 2 O 2 ), and the hydroxyl anion (OH  ). This review is focused primarily on H 2 O 2 . It is formed as the end product of O 2  degeneration, which can be accom- plished either by a family of cellular enzymes, called super- oxide dismutase (SOD), or by its spontaneous breakdown. ROS, and O 2  in particular, are produced by a variety of enzymes, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox), xanthine oxidase [for review, see (25)], lipoxygenase [for reviews, see (80, 140)], and myeloperoxidase [for reviews, see (75, 98)]. ROS also are as- sociated with mitochondria, where they are seen mainly as a by-product of the high oxygen consumption of this organelle. This review focuses initially on Nox proteins, because they form the family of enzymes about which most is known in terms of the production of O 2  =H 2 O 2 . It is not just the source of H 2 O 2 that is important when considering its role as a survival molecule; it also is important to understand how it interacts with its targets molecules. The main way that H 2 O 2 affects cell-signaling pathways is through oxidation of specific target molecules. If the concen- tration of H 2 O 2 is high, then these oxidation processes may lead to irreversible damage, followed by cell death. However, this is not always the case, and H 2 O 2 at low concentrations is capable of reversible inhibition of many enzymes, including phosphatases, which are the second focus of this review. We examine Nox proteins as a source of H 2 O 2 and the oxidation of phosphatases to demonstrate how H 2 O 2 can act as a survival molecule. The Nox family Seven Nox family members in mammals are known with at least 101 orthologues across 25 species (71). The seven mem- bers are Nox1-5, and dual oxidases (Duoxs) 1 and 2. Nox2 is the prototype member of this family and originally was called gp91 phox . It is highly expressed in neutrophils and macro- phages, in which it produces an oxidative burst to destroy pathogens. This burst occurs when these cells engulf mi- crobes, containing them in a phagosome, and was character- ized first in the early 1960s (61). It was not until the mid-1980s that the gene responsible for the burst was cloned (128, 150). Activated Nox2 in the membrane of the phagosome produces high levels of O 2  , which is converted to H 2 O 2 , either through the action of SOD, or spontaneously at the low pH of this organelle (75). The O 2  =H 2 O 2 can be in the micromolar concentration range in the phagosome (57), which is lethal for Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland. ANTIOXIDANTS & REDOX SIGNALING Volume 11, Number 11, 2009 ª Mary Ann Liebert, Inc. DOI: 10.1089=ars.2009.2728 2655