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). In an effort to better understand the mechanism of TCDD action, we will investigate the molecular mechanism of the AhR signaling pathway. The working hypothesis is as follows: Upon TCDD binding, nuclear translocation of the receptor occurs and the AhR forms the AhR/Arnt/DRE complex in the nucleus, leading to activation of gene transcription. We discovered that p23 and CyP40 potentiate the formation of this AhR ternary complex in vitro (Refs: 1. Shetty, P. V., Wang, X., and Chan, W. K. (2004) Arch. Biochem. Biophys. 429, 42-9;2. Shetty, P. V., Bhagwat, B. Y., and Chan, W. K. (2003) Biochem. Pharmacol. 65, 941-8) and these proteins appear to affect the AhR signaling in cell culture studies. This proposal focuses on the endogenous roles of p23 and CyP40 in the AhR signaling.
Four specific aims have been proposed as follows: We will use p23 and CyP40 knockdown and overexpressed cells to determine whether (1) the heterodimerization of AhR and Arnt and the binding of the heterodimer to the DRE are affected by p23 and CyP40 in intact cells (Aim 1);the assembly of the AhR complex to the enhancer region prior to activation of gene transcription is affected by p23 and CyP40 in intact cells (Aim 2) and (3) the fate of the nuclear AhR is affected by p23 and CyP40. We will also examine the requirements of p23 and CyP40 in the AhR signaling (Aim 4). Deletion and mutation studies will be performed to map out the minimal structural requirement of p23 and CyP40 for the AhR function. Interactions between CyP40 and AhR will be examined and characterized. CyP40-interacting proteins that are essential for the full CyP40 effect on the AhR function will be identified and characterized.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES014050-04
Application #
7660422
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Chadwick, Lisa
Project Start
2006-09-29
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$208,441
Indirect Cost
Name
University of the Pacific-Stockton
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
625948831
City
Stockton
State
CA
Country
United States
Zip Code
95211
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