PROTEIN KINASE MEDIATED REGULATION OF THE AH RECEPTOR

AH受体(AhR)已被证明在很大程度上对 2，3，7，8-四氯二苯并对苯二酚的毒性和促癌作用 二恶英(TCDD)，特别是在啮齿动物中。而人类人口却是 暴露在低水平的TCDD和相关化合物中，实际长 足月对健康的影响(S)仍有待阐明。人们对此知之甚少 参与激活和调节的生化过程 这个配体激活的螺旋-环-螺旋/碱性区域转录 因素。我们的基本假设是物种间的差异 毒性方面的差异是由于生物化学和 AhR及其受体核转录调控途径的研究 转运蛋白(ARNT)。在本应用程序中，多个 本课程将探讨蛋白激酶调节AhR的机制， 包括以下目的：1)研究蛋白质的作用机制(S) 激酶C调节AhR介导的基因表达，2)检测 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和 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结构， 瞬时转基因技术，蛋白激酶抑制剂，蛋白激酶显性基因- 负性、结构性活性和野生型的激酶结构。 总而言之，这些研究将发展对能力的理解 调节ah受体途径的活性的蛋白激酶。 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.