Superoxide dismutase 1 (SOD1) is essential for H 2 O 2 -mediated oxidation and inactivation of phosphatases in growth factor signaling
| Autor: | Mari Manuia, David E. Shaw, Fernando Donate, Andrew P. Mazar, Nicholas K. Tonks, Oscar Betancourt, Benoit Boivin, Jose Juarez, Mark E. Burnett |
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| Rok vydání: | 2008 |
| Předmět: |
SOD1
Protein tyrosine phosphatase Protein oxidation Models Biological Superoxide dismutase chemistry.chemical_compound Superoxide Dismutase-1 Cell Line Tumor Humans Phosphorylation Molybdenum chemistry.chemical_classification Reactive oxygen species Multidisciplinary Neovascularization Pathologic biology Superoxide Dismutase Superoxide Hydrogen Peroxide Biological Sciences Phosphoric Monoester Hydrolases Oxygen Biochemistry chemistry biology.protein Intercellular Signaling Peptides and Proteins Endothelium Vascular Signal transduction Reactive Oxygen Species Oxidation-Reduction Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 105:7147-7152 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0709451105 |
| Popis: | Superoxide dismutase 1 (SOD1) is an abundant copper/zinc enzyme found in the cytoplasm that converts superoxide into hydrogen peroxide and molecular oxygen. Tetrathiomolybdate (ATN-224) has been recently identified as an inhibitor of SOD1 that attenuates FGF-2- and VEGF-mediated phosphorylation of ERK1/2 in endothelial cells. However, the mechanism for this inhibition was not elucidated. Growth factor (GF) signaling elicits an increase in reactive oxygen species (ROS), which inactivates protein tyrosine phosphatases (PTP) by oxidizing an essential cysteine residue in the active site. ATN-224-mediated inhibition of SOD1 in tumor and endothelial cells prevents the formation of sufficiently high levels of H 2 O 2 , resulting in the protection of PTPs from H 2 O 2 -mediated oxidation. This, in turn, leads to the inhibition of EGF-, IGF-1-, and FGF-2-mediated phosphorylation of ERK1/2. Pretreatment with exogenous H 2 O 2 or with the phosphatase inhibitor vanadate abrogates the inhibition of ERK1/2 phosphorylation induced by ATN-224 or SOD1 siRNA treatments. Furthermore, ATN-224-mediated SOD1 inhibition causes the down-regulation of the PDGF receptor. SOD1 inhibition also increases the steady-state levels of superoxide, which induces protein oxidation in A431 cells but, surprisingly, does not oxidize phosphatases. Thus, SOD1 inhibition in A431 tumor cells results in both prooxidant effects caused by the increase in the levels of superoxide and antioxidant effects caused by lowering the levels of H 2 O 2 . These results identify SOD1 as a master regulator of GF signaling and as a therapeutic target for the inhibition of angiogenesis and tumor growth. |
| Databáze: | OpenAIRE |
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