PROTEIN KINASE MEDIATED REGULATION OF THE AH RECEPTOR

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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.