PROTEIN KINASE MEDIATED REGULATION OF THE AH RECEPTOR

已显示Ah受体（AhR）在很大程度上负责 2，3，7，8-四氯二苯并-对- 二恶英（TCDD），特别是在啮齿动物中。 当人类人口 暴露于低水平的TCDD和相关化合物， 术语健康影响仍有待阐明。 知之甚少 参与激活和调节的生物化学过程 该配体激活的螺旋-环-螺旋/碱性区转录 因子我们的基本假设是物种间的差异 在毒性的结果，从不同的生化和 AhR和Ah受体核转录调控途径 转运蛋白（ARNT）。 在本申请中， 将检查蛋白激酶调节AhR的机制， 包括以下目标：1）研究蛋白质的作用机制 激酶C调节Ah受体介导的基因表达，2）检查 MAP激酶改变Ah受体介导的基因表达的能力， 3)表征其他蛋白激酶途径的能力， 受体系统影响Ah受体介导的基因表达。 我们 将利用各种技术，包括AhR和ARNT构建体， 瞬时转染技术，激酶抑制剂，激酶显性- 阴性、组成型活性和野生型激酶构建体。 总的来说，这些研究将有助于理解 蛋白激酶来调节Ah受体途径的活性。 这些信息可以用来探索发育，组织， 以及TCDD介导的毒性的物种特异性差异。

The Ah receptor (AhR) has been shown to be largely responsible for the toxic and tumor promotional properties of 2,3,7,8- tetrachlorodibenzo-p- dioxin (TCDD), especially in rodents. While the human population is exposed to low levels of TCDD and related compounds, the actual long term health effect(s) remain to be elucidated. Little is known about the biochemical processes involved in the activation and regulation of this ligand-activated helix-loop-helix/basic region transcriptional factor. It is our underlying hypothesis that interspecies differences in toxicity results from differences in the biochemical and transcriptional regulatory pathways for the AhR and Ah receptor nuclear translocator protein (ARNT). In this application the multiple mechanisms of AhR regulation by protein kinases will be examined, including the following aims; 1) Examine the mechanism(s) of protein kinase C regulation Ah receptor-mediated gene expression, 2) Examine the ability of MAP kinases to alter Ah receptor-mediated gene expression, 3) Characterize the ability of other protein kinase pathways and receptor systems to influence Ah receptor-mediated gene expression. We will utilize a variety of techniques, including AhR and ARNT constructs, transient transfection techniques, kinase inhibitors, kinase dominant- negative, constitutively-active and wild-type kinase constructs. Collectively, these studies will develop an understanding of the ability of protein kinases to regulate the activity of the Ah receptor pathway. This information can then be used to explore developmental-, tissue-, and species-specific differences in TCDD-mediated toxicity.