Molecular identification of novel aryl hydrocarbon receptor modulators.
Published: 2004
Language: eng
Number of pages: 215
Description: The Aryl hydrocarbon Receptor (AhR) is a ligand dependent basic helix-loop-helix Per-ARNT-Sim transcription factor that regulates the expression of genes in a wide range of species and tissues. The best-characterized AhR ligands are environmental contaminants, which include polycyclic and halogenated aromatic hydrocarbons (dioxin). The molecular mechanism of AhR signaling has been extensively investigated in the induction of drug metabolizing enzymes. However, the involvement of AhR in biological processes remains obscure. The objective of this thesis was to identify novel endogenous modulators that may influence the mechanism of AhR action. Competitive binding assays performed with a panel of the most frequent oxysterols in blood revealed that 7-ketocholesterol displaced radiolabeled-dioxin from AhR. The search for additional partners of AhR was further pursued using a yeast two-hybrid screen where Nedd8 and Ubc9 were identified as potential AhR-interacting proteins. Initially the three novel, yet distinct modulators were validated for their independent interaction with AhR. Each modulator was found within an AhR multi-protein complex; however 7-ketocholesterol and Ubc9 independently functioned to attenuate the transactivational properties of the receptor, while Nedd8 augmented AhR signaling. These findings provided novel evidence for interactions between AhR and important cell signaling molecules. The molecular mechanism of AhR action within a specific cell type, organ or tissue as well as developmental stage may be dependent on the presence or absence of these specific modulators. Alteration of the AhR signaling pathway with these modulators may serve as potential therapeutic targets to inhibit the toxicity of dioxin and dioxin-like compounds. Additionally, the identification of these proteins may reveal the importance of AhR signaling in a non-toxicological context.
Notes: Advisers:  T. J. Brown; R. F. Casper.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2234.