AH RECEPTOR SIGNALING MECHANISM

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DESCRIPTION: (Adapted from the Investigator's Abstract) Dioxins, generated both commercially and naturally, are chlorinated polycyclic aromatic hydrocarbons that are highly toxic environmental contaminants. These agents are known to be potent rodent carcinogens and suspected human carcinogens. The best known prototype of this group of agents is 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD). It has been well-documented that most, if not all, of the TCDD effects are mediated through the Ah receptor (AHR). Thus, in an effort to better understand the mechanism of dioxin action, the investigator proposes to investigate the molecular mechanism of the AHR signaling pathway using the overexpressed AHR and ARNT proteins. The investigator's working hypothesis is as follows: Upon ligand binding, the AHR undergoes conformational changes resulting in alteration of a number of AHR-protein interactions, which subsequently leads to a cascade of biologic events to occur. In addition to AHR-protein interactions, other interactions involving ARNT and other proteins also contribute to the action of dioxins mediated by the AHR. This proposal contains specific aims investigating the protein factors and ARNT-associated proteins involved in the AHR signaling pathway. Not only do these studies provide important information and reagents to further the study of the PAH action mediated by the AHR, but they also provide mechanistic insights on how the AHR regulates its target genes by understanding what other proteins are involved in the AHR signaling pathway. Three specific aims have been proposed: Aim 1) purification and functional characterization of baculovirus expressed human AHR; Aim 2) identification and characterization of protein factors required for AHR and ARNT (Ah receptor nuclear translocator) function and Aim 3) investigation of ARNT-associated protein using Far-Western blot analysis.