Redox Regulation of Metastasis by Sod2

描述（由申请人提供）：这些研究将评价 线粒体锰超氧化物歧化酶（SOD 2）在调节 基质金属蛋白酶（MMP）表达和转移性侵袭。 我们有 确定了依赖于Sod 2的H2 O2生产是足够的并且是必需的， MMP-1的表达。 Sod 2过表达调节MMP的能力 表达似乎依赖于通过Ras和ERK 1/2的信号传导， 级联。 这种信号级联可以在多种条件下使用 其中SOD 2水平升高。 我们还证实了这次入侵， 转移和MMP表达以H2 O2依赖的方式增强， Sod 2被过度表达。 这些观察可以解释一些报告 这表明Sod 2过表达与转移性肝癌的增加有关， 癌的 更重要的是，我们已经表明，SOD 2和MMP-1在功能上， 互动.后一种观察结果是相当具有挑衅性的，因为 这些蛋白质独立地与增加的 各种癌症。 有人提出，Sod 2多态性 增加其活性。 我们的研究结果表明，SOD 2活性的增加 可以增加天然的和多态性的转录活性， MMP-1启动子。 此外，仅需要Sod 2水平的细微变化 调节MMP-1的表达。 拟议的研究将：（1）建立 探讨Sod 2、MMPs与肿瘤转移的关系;（2）明确肿瘤转移的分子机制 其调节MMP表达以响应H2 O2的Sod 2依赖性产生， (3)确定Sod 2和MMP-1水平或多态性之间的协同作用 存在，和（4）开发基于氧化还原的腺病毒载体， 肿瘤细胞的破坏。

DESCRIPTION (provided by applicant): These studies will evaluate the role of the mitochondrial manganese superoxide dismutase (Sod2) in the regulation of matrix metalloproteinase (MMP) expression and metastatic invasion. We have established that the Sod2-dependent H202 production is sufficient and required for MMP-1 expression. The ability of Sod2 overexpression to modulate MMP expression appears to be dependent on signaling through Ras and the ERK1/2 cascade. This signaling cascade may be utilized under a variety of conditions where Sod2 levels are elevated. We have also established that invasion, metastasis and MMP expression are enhanced in an H202-dependent fashion when Sod2 is overexpressed. These observations may explain a number of reports suggesting that Sod2 overexpression is linked to an increase in metastatic cancers. More importantly we have shown that Sod2 and MMP-1 functionally interact. This latter observation is quite provocative, as SNPs in either of these proteins have independently been linked to increased incidence of various forms of cancer. It has been proposed that the Sod2 polymorphism increases its activity. Our findings indicate that increases in Sod2 activity can increase the transcriptional activity of both the native and polymorphic MMP-1 promoter. Furthermore, only subtle changes in Sod2 levels are required to modulate MMP-1 expression. The proposed studies will: (1) establish the link between Sod2, MMPs and metastasis, (2) define the molecular mechanisms that modulate MMP expression in response to Sod2-dependent production of H2O2, (3) determine if a synergy between the Sod2 and MMP-1 levels or polymorphisms exist, and (4) develop redox-based adenoviral vectors that target metastatic tumor cells for destruction.