title: Reactive nitrogen species block cell cycle re-entry through sustained production of hydrogen peroxide.
abstract: Endogenous sources of reactive nitrogen species (RNS) act as second messengers in a variety of cell signaling events, whereas environmental sources of RNS like nitrogen dioxide (NO2) inhibit cell survival and growth through covalent modification of cellular macromolecules. To examine the effects of RNS on cell cycle progression, murine type II alveolar C10 cells arrested in G0 by serum deprivation were exposed to either NO2 or SIN-1, a generator of RNS, during cell cycle re-entry. In serum-stimulated cells, RNS did not prevent the immediate early gene response by AP-1, but rather blocked cyclin D1 gene expression, resulting cell cycle arrest at the boundary between G0 and G1. Dichlorofluorescin diacetate (DCF) fluorescence indicated that RNS induced sustained production of intracellular hydrogen peroxide (H2O2), which normally is produced only transiently in response to serum growth factors. Loading cells with catalase did not diminish the formation of 3-nitrotyrosine on the cell surface, but rather prevented enhanced DCF fluorescence and rescued cyclin D1 expression and S phase entry. These studies indicate environmental RNS interfere with cell cycle re-entry through an H2O2-dependent mechanism that influences expression of cyclin D1 and progression from G0 to the G1 phase of the cell cycle.
authors.affiliation: Department of Pathology, University of Vermont College of Medicine, Burlington VT 05465, USA.
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Yuan
authors.forename: Harriet
authors.initials: H
authors.lastname: Schellekens
authors.forename: Loraine
authors.initials: L
authors.lastname: Warner
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Janssen-Heininger
authors.forename: Peter
authors.initials: P
authors.lastname: Burch
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Heintz
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000187:drug effects / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005452:Fluoresceins / Q000032:analysis / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009585:Nitrogen Dioxide / Q000378:metabolism / Q000494:pharmacology*; D016877:Oxidants / Q000378:metabolism* / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D005452:Fluoresceins; D020030:Nitric Oxide Donors; D016877:Oxidants; D018808:Transcription Factor AP-1; D019938:Cyclin D1; C029569:diacetyldichlorofluorescein; C002744:3-nitrotyrosine; D014443:Tyrosine; C002385:linsidomine; D006861:Hydrogen Peroxide; D008981:Molsidomine; D002374:Catalase; D013482:Superoxide Dismutase; D009585:Nitrogen Dioxide