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Ras-dependent and -independent regulation of reactive oxygen species by mitogenic growth factors and TGF-beta1.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2000 Sep; Vol. 14 (12), pp. 1741-8. - Publication Year :
- 2000
-
Abstract
- Mitogenic growth factors and transforming growth factor beta1 (TGF-beta1) induce the generation of reactive oxygen species (ROS) in nonphagocytic cells, but their enzymatic source(s) and regulatory mechanisms are largely unknown. We previously reported on the ability of TGF-beta1 to activate a cell surface-associated NADH:flavin:O(2) oxidoreductase (NADH oxidase) that generates extracellular H(2)O(2). In this study, we compared the ROS-generating enzymatic systems activated by mitogenic growth factors and TGF-beta1 with respect to the primary reactive species produced (O(2)(.-) vs. H(2)O(2)), the site of generation (intracellular vs. extracellular) and regulation by Ras. We find that the mitogenic growth factors PDGF-BB, FGF-2, and TGF-alpha (an EGF receptor ligand) are able to rapidly (within 5 min) induce the generation of intracellular O(2)(.-) without detectable NADH oxidase activity or extracellular H(2)O(2) release. In contrast, TGF-beta1 does not stimulate intracellular O(2)(.-) production and the delayed induction of extracellular H(2)O(2) release is not associated with O(2)(.-) production. Expression of dominant-negative Ras (N17Ras) protein by herpes simplex virus-mediated gene transfer blocks mitogen-stimulated intracellular O(2)(.-) generation but has no effect on TGF-beta1-induced NADH oxidase activation/H(2)O(2) production. These results demonstrate that there are at least two distinctly different ROS-generating enzymatic systems in lung fibroblasts regulated by mitogenic growth factors and TGF-beta1 via Ras-dependent and -independent mechanisms, respectively. In addition, these findings suggest that endogenous production of ROS by growth factors/cytokines may have different biological effects depending on the primary reactive species generated and site of production.
- Subjects :
- Cell Division drug effects
Cells, Cultured
Fibroblasts cytology
Fibroblasts drug effects
Fibroblasts metabolism
Humans
Hydrogen Peroxide metabolism
Lung cytology
Lung metabolism
Multienzyme Complexes metabolism
NADH, NADPH Oxidoreductases metabolism
Protein-Lysine 6-Oxidase metabolism
Signal Transduction
Tachykinins
Fibroblast Growth Factor 2 pharmacology
Lung drug effects
Reactive Oxygen Species metabolism
Transforming Growth Factor beta pharmacology
ras Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0892-6638
- Volume :
- 14
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 10973923
- Full Text :
- https://doi.org/10.1096/fj.99-0878com