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GENISTEIN AS MODULATOR OF ANTIOXIDANT PROTEIN EXPRESSION

染料木黄酮作为抗氧化蛋白表达的调节剂

基本信息

批准号：
6523745
负责人：
SHIU-MING KUO
金额：
$ 16.1万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-08-01 至 2004-07-31
项目状态：
已结题

项目摘要

Flavonoids represent a family of phytochemicals found in many human food items. Among them, genistein (Gn) is found especially at high concentration in soybeans, an important element of Oriental diet. Epidemiological studies, in vivo animal studies and in vitro cell studies all suggested that Gn could play a role in the prevention of cancer. More work at the molecular level is needed to define the mechanism. This proposal addresses one potential mechanism: the ability of Gn to increase the expression of an antioxidant protein, metallothionein (MT). We have found that Gn increased the levels of MT protein and mRNA in human intestinal cells, Caco-2. The induction was synergistic with the stimulatory effect of zinc. Based on these observations, the proposal is designed to determine the physiological significance of MT induction; and the mode of Gn-MT gene interaction. We will compare the level of oxidative byproduct after tert- butylhydroperoxide challenge in cells with and without Gn treatment. In addition, animal study will be conducted to show that Gn feeding leads to an increase in the organ MT level and a decrease in the organ oxidative byproduct level. The mode of Gn-MT gene interaction will be investigated indirectly through the combination treatment of cells with Gn and other inducers of MT expression like copper, cadmium or cytokines. We will also perform nuclear run-on experiment and mRNA stability analysis in cells to directly confirm the effect of Gn at the transcriptional level. Reporter gene assays will then be conducted to determine the site of Gn-MT gene interaction on the cloned sequence of human MTIIA promoter. The results from the proposed studies will help to assess the essentiality of Gn in the human diet for reduction of cancer risk. These studies may also lead to the identification of a previous unknown pathway for Gn to regulate mammalian genes.

风味素代表在许多人类食物中发现的植物化学物质家族。其中，染料木黄酮（Gn）在大豆中的浓度特别高，大豆是东方饮食的重要元素。流行病学研究、体内动物研究和体外细胞研究均表明，Gn可能在预防癌症方面发挥作用。需要在分子水平上做更多的工作来确定机制。这一提议解决了一个潜在的机制：Gn增加抗氧化蛋白金属硫蛋白（MT）表达的能力。我们已经发现，Gn增加MT蛋白和mRNA在人类肠细胞，Caco-2的水平。这种诱导作用与锌的刺激作用有协同作用。基于这些观察结果，该建议旨在确定MT诱导的生理意义;以及Gn-MT基因相互作用的模式。我们将比较有和没有Gn处理的细胞中叔丁基过氧化氢激发后氧化副产物的水平。此外，将进行动物研究，以表明Gn喂养导致器官MT水平的增加和器官氧化副产物水平的降低。 Gn-MT基因相互作用的模式将通过用Gn和其他MT表达诱导剂如铜、镉或细胞因子联合处理细胞来间接研究。我们还将在细胞中进行核运行实验和mRNA稳定性分析，以直接证实Gn在转录水平上的作用。然后进行报告基因测定，以确定人MTIIA启动子克隆序列上Gn-MT基因相互作用的位点。拟议研究的结果将有助于评估Gn在人类饮食中降低癌症风险的必要性。这些研究也可能导致以前未知的Gn调节哺乳动物基因的途径的鉴定。