Cited by 977Nitric Oxide and Endothelin EffectsRedox biology and oxidative stressHemoglobin structure and function

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The chemical biology of nitric oxide: Implications in cellular signaling

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Thomas, Douglas D., Ridnour, Lisa A., Isenberg, Jeffrey S., Flores-Santana, Wilmarie, Switzer, Christopher H., Donzelli, Sonia, Hussain, Perwez, Vecoli, Cecilia, Paolocci, Nazareno, Ambs, Stefan, Colton, Carol A., Harris, Curtis C., Roberts, David D., Wink, David A.·2008·Free Radical Biology and Medicine

DOI 10.1016/j.freeradbiomed.2008.03.020PMC PMC2572721

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Abstract

Nitric oxide (NO) has earned the reputation of being a signaling mediator with many diverse and often opposing biological activities. The diversity in response to this simple diatomic molecule comes from the enormous variety of chemical reactions and biological properties associated with it. In the past few years, the importance of steady-state NO concentrations has emerged as a key determinant of its biological function. Precise cellular responses are differentially regulated by specific NO concentration. We propose five basic distinct concentration levels of NO activity: cGMP-mediated processes ([NO]<1-30 nM), Akt phosphorylation ([NO] = 30-100 nM), stabilization of HIF-1alpha ([NO] = 100-300 nM), phosphorylation of p53 ([NO]>400 nM), and nitrosative stress (1 microM). In general, lower NO concentrations promote cell survival and proliferation, whereas higher levels favor cell cycle arrest, apoptosis, and senescence. Free radical interactions will also influence NO signaling. One of the consequences of reactive oxygen species generation is to reduce NO concentrations. This antagonizes the signaling of nitric oxide and in some cases results in converting a cell-cycle arrest profile to a cell survival profile. The resulting reactive nitrogen species that are generated from these reactions can also have biological effects and increase oxidative and nitrosative stress responses. A number of factors determine the formation of NO and its concentration, such as diffusion, consumption, and substrate availability, which are referred to as kinetic determinants for molecular target interactions. These are the chemical and biochemical parameters that shape cellular responses to NO. Herein we discuss signal transduction and the chemical biology of NO in terms of the direct and indirect reactions.

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Authors: Thomas, D. D., Ridnour, L. A., Isenberg, J. S., Flores-Santana, W., Switzer, C. H., Donzelli, S., Hussain, P., Vecoli, C., Paolocci, N., Ambs, S., Colton, C. A., Harris, C. C., Roberts, D. D., & Wink, D. A.
Affiliations: University of Illinois Chicago (US)
National Institutes of Health (US)
Johns Hopkins University (US)
Duke University (US)
Corresponding author: Wink, David A.
ORCID: Thomas, Douglas D.
Ridnour, Lisa A.
Isenberg, Jeffrey S.
Switzer, Christopher H.
Vecoli, Cecilia
Paolocci, Nazareno
Ambs, Stefan
Colton, Carol A.
Harris, Curtis C.
Roberts, David D.
Wink, David A.
Venue: Free Radical Biology and Medicine
Publisher: Elsevier BV
Published: 2008-07
Volume: 45
Issue: 1
Pages: 18-31
ISSN: 0891-5849 (ISSN-L)
DOI: 10.1016/j.freeradbiomed.2008.03.020
PMC: PMC2572721
OpenAlex: W1980458823
Cited by: 975
References: 166
Citations by year: 2026: 33 · 2025: 44 · 2024: 37 · 2023: 54 · 2022: 57 · 2021: 73 · 2020: 58 · 2019: 55 · 2018: 54 · 2017: 45 · 2016: 53 · 2015: 63 · 2014: 67 · 2013: 50 · 2012: 69
FWCI: 5.87
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Free Radical Biology and Medicine (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Cancer Institute (K22CA113315, Z01BC010033)
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
Keywords: nitric oxide, signal transduction, NO concentration, cGMP signaling, Akt phosphorylation, HIF-1α stabilization, p53 phosphorylation, nitrosative stress, reactive oxygen species, reactive nitrogen species, oxidative stress, cell cycle arrest, apoptosis, senescence
MeSH terms: Animals, Diffusion, Humans, Kinetics, Nitric Oxide, Signal Transduction

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