HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 36, 25984-25993, September 8, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/36/25984    most recent M602242200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thomas, D. D. Articles by Wink, D. A. Search for Related Content PubMed PubMed Citation Articles by Thomas, D. D. Articles by Wink, D. A. Social Bookmarking                      What's this?

Superoxide Fluxes Limit Nitric Oxide-induced Signaling^*

Douglas D. Thomas¹, Lisa A. Ridnour, Michael Graham Espey, Sonia Donzelli, Stefan Ambs, S. Perwez Hussain, Curtis C. Harris, William DeGraff, David D. Roberts^¶, James B. Mitchell, and David A. Wink²

From the Tumor Biology Section, Radiation Biology Branch, the ^¶Laboratory of Pathology, and the Laboratory of Human Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892

Independently, superoxide () and nitric oxide (NO) are biologically important signaling molecules. When co-generated, these radicals react rapidly to form powerful oxidizing and nitrating intermediates. Although this reaction was once thought to be solely cytotoxic, herein we demonstrate using MCF7, macrophage, and endothelial cells that when nanomolar levels of NO and were produced concomitantly, the effective NO concentration was established by the relative fluxes of these two radicals. Differential regulation of sGC, pERK, HIF-1, and p53 were used as biological dosimeters for NO concentration. Introduction of intracellular- or extracellular-generated during NO generation resulted in a concomitant increase in oxidative intermediates with a decrease in steady-state NO concentrations and a proportional reduction in the levels of sGC, ERK, HIF-1, and p53 regulation. NO responses were restored by addition of SOD. The intermediates formed from the reactions of NO with were non-toxic, did not form 3-nitrotyrosine, nor did they elicit any signal transduction responses. H₂O₂ in bolus or generated from the dismutation of by SOD, was cytotoxic at high concentrations and activated p53 independent of NO. This effect was completely inhibited by catalase, suppressed by NO, and exacerbated by intracellular catalase inhibition. We conclude that the reaction of with NO is an important regulatory mechanism, which modulates signaling pathways by limiting steady-state levels of NO and preventing H₂O₂ formation from .

Received for publication, March 9, 2006 , and in revised form, June 1, 2006.

^* This work was supported in part by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence may be addressed: Radiation Biology Branch, NCI, National Institutes of Health, Bldg. 10, Rm. B3-B69, Bethesda, MD 20892. Tel.: 301-496-7511; Fax: 301-480-2238; E-mail: thomasdo{at}mail.nih.gov. ² To whom correspondence may be addressed: Radiation Biology Branch, NCI, National Institutes of Health, Bldg. 10, Rm. B3-B69, Bethesda, MD 20892. E-mail: wink{at}mail.nih.gov.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. P. Jones Radical-free biology of oxidative stress Am J Physiol Cell Physiol, October 1, 2008; 295(4): C849 - C868. [Abstract] [Full Text] [PDF]

				G. Martin-Manso, S. Galli, L. A. Ridnour, M. Tsokos, D. A. Wink, and D. D. Roberts Thrombospondin 1 Promotes Tumor Macrophage Recruitment and Enhances Tumor Cell Cytotoxicity of Differentiated U937 Cells Cancer Res., September 1, 2008; 68(17): 7090 - 7099. [Abstract] [Full Text] [PDF]

				Q. Zhang, P. Malik, D. Pandey, S. Gupta, D. Jagnandan, E. B. de Chantemele, B. Banfi, M. B. Marrero, R. D. Rudic, D. W. Stepp, et al. Paradoxical Activation of Endothelial Nitric Oxide Synthase by NADPH Oxidase Arterioscler. Thromb. Vasc. Biol., September 1, 2008; 28(9): 1627 - 1633. [Abstract] [Full Text] [PDF]

				A. Diet, K. Abbas, C. Bouton, B. Guillon, F. Tomasello, S. Fourquet, M. B. Toledano, and J.-C. Drapier Regulation of Peroxiredoxins by Nitric Oxide in Immunostimulated Macrophages J. Biol. Chem., December 14, 2007; 282(50): 36199 - 36205. [Abstract] [Full Text] [PDF]

				B. Brune and J. Zhou Nitric oxide and superoxide: Interference with hypoxic signaling Cardiovasc Res, July 15, 2007; 75(2): 275 - 282. [Abstract] [Full Text] [PDF]