Redox Regulation of Metastasis by Sod2

描述(由申请者提供)：这些研究将评估 线粒体锰超氧化物歧化酶(Sod2)在细胞周期调控中的作用 基质金属蛋白酶(MMPs)表达与肿瘤转移我们有 确定依赖于Sod2的H202生产是足够和必需的 用于基质金属蛋白酶-1的表达。Sod2过表达对基质金属蛋白酶的调节作用 表达似乎依赖于通过RAS和ERK1/2的信号转导 卡斯卡德。这种信令级联可以在各种条件下使用 Sod2水平升高的地方。我们还证实了入侵， 在H202依赖的方式下，转移和基质金属蛋白酶的表达增强 Sod2基因过度表达。这些观察结果可以解释一些报告。 提示Sod2的过度表达与转移癌的增加有关 癌症。更重要的是，我们已经证明了Sod2和MMP-1在功能上 互动。后一种观察结果非常具有挑衅性，因为这两个基因中的任何一个 这些蛋白质已经独立地与增加的发病率有关。 各种形式的癌症。已有研究提出Sod2基因的多态 增加了它的活动。我们的发现表明，Sod2活性的增加 可以提高原生和多态基因的转录活性 基质金属蛋白酶-1启动子。此外，只需要对Sod2级别进行细微的更改 调节基质金属蛋白酶-1的表达。建议的研究将会：(1)确立 Sod2、MMPs与肿瘤转移的关系：(2)明确分子机制 调节基质金属蛋白酶的表达，以响应依赖于Sod2的过氧化氢的产生， (3)确定Sod2和MMP1水平或多态之间是否存在协同作用 存在，以及(4)开发以氧化还原为基础的针对转移的腺病毒载体 等着销毁肿瘤细胞。

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.