Our objective is to understand the AHR's role in liver development, as well as the mechanism by which 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD)-receptor interactions are related to tumor promotion organ toxicity and birth defects. We propose to use the power of murine genetics, embryonic stem (ES) cell technology and gene targeting to understand the molecular details of this signaling pathways. Our experiments are derived from recent gene targeting of the murine Ahr and Arnt loci. The surprising phenotypes of these animals have left us with a number of important questions, such as: What is the AHR's role in normal liver growth and development and is the related to the mechanism of TCDD carcinogenicity/toxicity? What receptor domains are involved in toxic endpoints? Given that homozygous Arnt null alleles are embryonic lethal, how can we characterize ARNT's role in TCDD toxicity and carcinogenesis? To address these questions, we have proposed to generate informative allelic series at both the Ahr and Arnt loci and define the molecular basis for their phenotypes. In addition, we propose that these mutant strains will provide insights into the roles of the corresponding proteins in liver development, toxicity and hepatocarcinogenesis.
Our specific aims are as follows:
AIM #1 : Characterize the Ahr null allele and understand the variable that affect expression of phenotype.
AIM#2 : Generate an allelic series at the Ahr locus to delineate the roles of the AHR and its subdomains on liver development, TCDD-induced hepatotoxicity and carcinogenesis.
AIM#3 : Generate an allelic series at the Arnt locus to delineate the role of the ARNT protein in TCDD-induced toxicity, teratogenesis and carcinogenesis.
AIM#4 : Determine the AHR' role in modulating liver size and in hepatotoxicity and carcinogenicity of compounds like TCDD.

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National Cancer Institute (NCI)
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University of Wisconsin Madison
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Xia, Chuanwu; Rwere, Freeborn; Im, Sangchoul et al. (2018) Structural and Kinetic Studies of Asp632 Mutants and Fully Reduced NADPH-Cytochrome P450 Oxidoreductase Define the Role of Asp632 Loop Dynamics in the Control of NADPH Binding and Hydride Transfer. Biochemistry 57:945-962
Oberley, Christopher C; Bilger, Andrea; Drinkwater, Norman R (2015) Genetic background determines if Stat5b suppresses or enhances murine hepatocarcinogenesis. Mol Carcinog 54:959-70
Kennedy, Gregory D; Nukaya, Manabu; Moran, Susan M et al. (2014) Liver tumor promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxin is dependent on the aryl hydrocarbon receptor and TNF/IL-1 receptors. Toxicol Sci 140:135-43
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Figueiredo, Marxa L; Stein, Timothy J; Jochem, Adam et al. (2012) Mutant Hras(G12V) and Kras(G12D) have overlapping, but non-identical effects on hepatocyte growth and transformation frequency in transgenic mice. Liver Int 32:582-91
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Copp, Richard R; Peebles, Daniel D; Fahl, William E (2011) Synthesis and growth regulatory activity of a prototype member of a new family of aminothiol radioprotectors. Bioorg Med Chem Lett 21:7426-30
Stein, Timothy J; Bowden, Margaret; Sandgren, Eric P (2011) Minimal cooperation between mutant Hras and c-myc or TGF? in the regulation of mouse hepatocyte growth or transformation in vivo. Liver Int 31:1298-305
Xia, Chuanwu; Hamdane, Djemel; Shen, Anna L et al. (2011) Conformational changes of NADPH-cytochrome P450 oxidoreductase are essential for catalysis and cofactor binding. J Biol Chem 286:16246-60
Figueiredo, Marxa L; Wentworth, Kristin M; Sandgren, Eric P (2010) Quantifying growth and transformation frequency of oncogene-expressing mouse hepatocytes in vivo. Hepatology 52:634-43

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