Abstract
Extracellular superoxide dismutase (SOD3) gene transfer to tissue damage results in increased healing, increased cell proliferation, decreased apoptosis, and decreased inflammatory cell infiltration. At molecular level, in vivo SOD3 overexpression reduces superoxide anion (O2 −) concentration and increases mitogen kinase activation suggesting that SOD3 could have life-supporting characteristics. The hypothesis is further strengthened by the observations showing significantly increased mortality in conditional knockout mice. However, in cancer SOD3 has been shown to either increase or decrease cell proliferation and survival depending on the model system used, indicating that SOD3-derived growth mechanisms are not completely understood. In this paper, the author reviews the main discoveries in SOD3-dependent growth regulation and signal transduction.
Highlights
Extracellular superoxide dismutase (EC-SOD, SOD3) [1, 2], similar to cytosolic CuZn-SOD (SOD1) [3] and mitochondrial MnSOD (SOD2) [4, 5], catalyzes the dismutation of superoxide this review raenaicotniv(eOo2x−y)gienntospheycdieros greenferpetoroOxi2d−e (H2O2), which to date is the only reported physiological function of the enzyme
We have further demonstrated, using rat hind limb injury model, SOD3-dependent increases in tissue injury recovery that were mediated by activation of mitogen signal transduction with consequent increased satellite cell proliferation in muscles [24]; by activation of antiapoptotic signaling that involved increased extracellular signal regulated kinase 1/2 (ERK1/2), protein kinase B (AKT), and forkhead box O3a (FOXO3a) activation [39]; and by reduction of macrophage-specific inflammation, which was correlated with reduced expression of the inflammatory cytokines tumor necrosis factor α (TNFα), interleukin 1α (IL1α), interleukin 6 (IL6), macrophage inflammatory protein 2 (MIP2), and monocyte chemotactic protein 1 (MCP-1) and the adhesion molecules vascular adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), P-selectin, and E-selectin [36]
We have previously shown that RAS-BRAF-MEK1/2ERK1/2, a major signal transduction pathway in cancer, activates SOD3 mRNA expression and enzyme activity in vitro and in vivo, which increases GTP loading to RAS [24]
Summary
Extracellular superoxide dismutase (EC-SOD, SOD3) [1, 2], similar to cytosolic CuZn-SOD (SOD1) [3] and mitochondrial MnSOD (SOD2) [4, 5], catalyzes the dismutation of superoxide this review raenaicotniv(eOo2x−y)gienntospheycdieros greenferpetoroOxi2d−e (H2O2) (in and H2O2), which to date is the only reported physiological function of the enzyme. The data is supported by observations reporting that Arg-213-Gly mutation at C-terminal end of SOD3 reduces the affinity of the enzyme to heparan sulphate proteoglycans of endothelial cells increasing plasma SOD3 concentration by 10-fold [12, 13]. A number of reports have demonstrated tight regulation of SOD3 expression at the transcriptional, posttranscriptional, and posttranslational levels [12, 15,16,17,18,19,20,21,22,23] This regulation is influenced by various factors, most importantly by the level of O2− substrate and the reaction end product H2O2 [23,24,25]
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