Manganese superoxide dismutase signals matrix metalloproteinase expression via H2O2-dependent ERK1/2 activation
Manganese superoxide dismutase signals matrix metalloproteinase expression via H2O2-dependent ERK1/2 activation
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DOI：
10.1074/jbc.m100199200
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发表时间：
2001-04-27
影响因子：
4.8
通讯作者：
Melendez, JA
中科院分区：
文献类型：
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作者：
Ranganathan, AC;Nelson, KK;Melendez, JA
锰超氧化物歧化酶 (Sod2) 以接近扩散极限的速率去除线粒体衍生的超氧化物（O-2（自由基阴离子）），并且是唯一一种其表达受多种刺激调节的抗氧化酶。这里表明，Sod2 也是细胞内信号分子 H2O2 的来源。 Sod2 依赖性 H2O2 稳态水平增加导致 ERK1/2 激活，随后基质金属蛋白酶-1 (MMP-1) 表达下游转录增加，而 H2O2 解毒酶过氧化氢酶的表达可逆转这种情况。此外，最近在碱基对-1607处发现了一个单核苷酸多态性（1G/2G），它在碱基对-1602处创建了一个与AP-1位点相邻的Ets位点，并且已被证明可以显着增强MMP-1启动子的转录。当瞬时转染到 Sod2 过表达细胞系中时，含有 1G 或 2G 变异的荧光素酶启动子构建体的活性分别提高了 25 倍或 1000 倍。在 Sod2 过表达的细胞系中，MMP-2、-3 和 -7 的水平也增加，表明 Sod2 可能作为 MMP 表达的“全局”氧化还原调节剂。此外，Sod2(-/+)小鼠胚胎成纤维细胞未能对细胞因子介导的MMP-1、MMP-13的小鼠功能类似物的诱导作出反应。这项研究提供的证据表明，细胞可能利用多种致病性和炎症刺激对 Sod2 活性的调节作为导致基质金属蛋白酶表达的主要信号传导机制。
Manganese-superoxide dismutase (Sod2) removes mitochondrially derived superoxide (O-2(radical anion)) 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 H2O2. Sod2-dependent increases in the steady-state levels of H2O2 led to ERK1/2 activation and subsequent downstream transcriptional increases in matrix metalloproteinase-1 (MMP-1) expression, which were reversed by expression of the H2O2-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.