title: Signaling and stress: The redox landscape in NOS2 biology.
abstract: Nitric oxide (NO) has a highly diverse range of biological functions from physiological signaling and maintenance of homeostasis to serving as an effector molecule in the immune system. However, deleterious as well as beneficial roles of NO have been reported. Many of the dichotomous effects of NO and derivative reactive nitrogen species (RNS) can be explained by invoking precise interactions with different targets as a result of concentration and temporal constraints. Endogenous concentrations of NO span five orders of magnitude, with levels near the high picomolar range typically occurring in short bursts as compared to sustained production of low micromolar levels of NO during immune response. This article provides an overview of the redox landscape as it relates to increasing NO concentrations, which incrementally govern physiological signaling, nitrosative signaling and nitrosative stress-related signaling. Physiological signaling by NO primarily occurs upon interaction with the heme protein soluble guanylyl cyclase. As NO concentrations rise, interactions with nonheme iron complexes as well as indirect modification of thiols can stimulate additional signaling processes. At the highest levels of NO, production of a broader range of RNS, which subsequently interact with more diverse targets, can lead to chemical stress. However, even under such conditions, there is evidence that stress-related signaling mechanisms are triggered to protect cells or even resolve the stress. This review therefore also addresses the fundamental reactions and kinetics that initiate signaling through NO-dependent pathways, including processes that lead to interconversion of RNS and interactions with molecular targets.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Thomas
authors.affiliation: Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Heinecke
authors.affiliation: Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ridnour
authors.affiliation: Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Robert Y
authors.initials: RY
authors.lastname: Cheng
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Aparna H
authors.initials: AH
authors.lastname: Kesarwala
authors.affiliation: Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Switzer
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: McVicar
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
authors.affiliation: Prostate Cancer Institute, NUI Galway, Ireland, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Glynn
authors.affiliation: Department of Chemistry, Sonoma State University, Rohnert Park, CA 94928, USA.
authors.forename: Jon M
authors.initials: JM
authors.lastname: Fukuto
authors.affiliation: Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: wink@mail.nih.gov.
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.affiliation: Department of Chemistry, University of Arizona, 1306 E. University Blvd., Tucson, AZ 85721, USA. Electronic address: kmiranda@email.arizona.edu.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Miranda
mesh_terms: D017209:Apoptosis / Q000235:genetics; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D026361:Reactive Nitrogen Species / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D005609:Free Radicals; D026361:Reactive Nitrogen Species; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II
keywords: Breast cancer; Cancer biology; Cell signaling; Free radicals; Nitric oxide; Nitric oxide synthase