Manganese Superoxide Dismutase Signals Matrix Metalloproteinase Expression via H2O2-dependent ERK1/2 Activation

Abstract

Manganese-superoxide dismutase (Sod2) removes mitochondrially derived superoxide (O 2 . ) at near-diffusion limiting rates and is the only antioxidant enzyme whose expression is regulated by numerous stimuli. Here it is shown that Sod2 also serves as a source of the intracellular signaling molecule H 2 O 2 . Sod2-dependent increases in the steady-state levels of H 2 O 2 led to ERK1/2 activation and subsequent downstream transcriptional increases in matrix metalloproteinase-1 (MMP-1) expression, which were reversed by expression of the H 2 O 2 -detoxifying enzyme, catalase. In addition, a single nucleotide polymorphism has recently been identified (1G/2G) at base pair ؊1607 that creates an Ets site adjacent to an AP-1 site at base pair ؊1602 and has been shown to dramatically enhance transcription of the MMP-1 promoter. Luciferase promoter constructs containing either the 1G or 2G variation were 25-or 1000-fold more active when transiently transfected into Sod2-overexpressing cell lines, respectively. The levels of MMP-2, -3, and -7 were also increased in the Sod2-overexpressing cell lines, suggesting that Sod2 may function as a "global" redox regulator of MMP expression. In addition, Sod2 ؊/؉ mouse embryonic fibroblasts failed to respond to the cytokine-mediated induction of the murine functional analog of MMP-1, MMP-13. This study provides evidence that the modulation of Sod2 activity by a wide array of pathogenic and inflammatory stimuli may be utilized by the cell as a primary signaling mechanism leading to matrix metalloproteinase expression.

Importance of mitochondrial superoxide dismutase expression in insulin-producing cells for the toxicity of reactive oxygen species and proinflammatory cytokines

“…Through overexpression of catalase within the mitochondrial compartment, we were able to protect insulin-producing cells against cytokine-induced toxicity and thus demonstrate the deleterious effects of mitochondrially accumulated H 2 O 2 [10]. Enhanced toxicity due to increased MnSOD protein expression was also observed in MnSOD-overexpressing fibroblasts [7,30,31], in skeletal muscle cells [32], in fibroblasts and in brain of patients suffering from neuronal ceroid lipofuscinosis type 6 [33], in the ovarian cancer cell line SK-OV-3 [34] and in transformed human bronchial epithelial cells [35].…”

Potent Anti-tumor Effects of an Active Site Mutant of Human Manganese-Superoxide Dismutase

“…2D) or prior overexpression of catalase to overcome the anti-proliferative effects of H30N overexpression (Fig. 3), the slow growth phenotype observed with elevated Mn-SOD activity documented by other investigators has also been rescued by the overexpression of catalase, either in the cytosol or targeted to the mitochondrion (23,24). It therefore appears that overexpression of the more efficient H30N Mn-SOD must generate H 2 O 2 levels approaching 200 M based on its anti-proliferative and anti-tumor effects.…”

“…In addition, in mammals, Mn-SOD has been postulated to function as a tumor suppressor gene (16 -19), with its expression and activity being significantly reduced in many cancers (20,21). Overexpression of Mn-SOD in several human cancer cell lines leads to reversion of the malignant phenotype with a decrease in cell proliferation (16 -19), which is thought to be mediated by H 2 O 2 , a potential signaling molecule (22)(23)(24) and primary product of Mn-SOD catalysis (2). An inference, therefore, derived from the active site structure, catalytic mechanism, and the signaling properties of H 2 O 2 , would be that specific alterations in active site residues may alleviate the inherent inefficiency associated with the product-inhibited complex, thus increasing the anti-proliferative effects through elevated levels of H 2 O 2 .…”

Determinação da atividade antioxidante e do teor total de polifenol em amostras de chá de ervas comercializadas em sachets

“…Em níveis elevados de concentração, H 2 O 2 induz à apoptose em células de mamíferos 17 e acredita-se que esteja envolvido na metástase tumoral 18 . Por isso, a capacidade de consumo (scavenging) de H 2 O 2 pelas mesmas amostras de chás também foi avaliada.…”