This research provides an integrated approach to an understanding of the carcinogenic process and its step-wise nature. The studies in the laboratory of Drs. J. A. and E. C. Miller are directed toward further characterization of the electrophilic metabolites of chemical carcinogens, the identification of the reaction products of these metabolites with cellular macromolecules, and correlations of specific reactions with the likelihood of tumor initiation. Dr. Kasper's research is focused on a molecular understanding of the biochemical regulation of the activities of certain enzymes (cytochrome P-450, NADPH-cytochrome c (P-450) oxidoreductase, and epoxide hydratase) which are important in the metabolic activation and/or deactivation of a variety of chemical carcinogens. cDNA probes for these enzymes will be used to determine the effects of xenobiotic chemicals on nuclear and cytoplasmic events related to the induction of these enzymes. The research in Dr. Boutwell's laboratory is directed toward the elucidation of the events involved in tumor promotion that are elicited in mouse skin by application of the tumor promoter 12-0-tetradecanoylphorbol-13-acetate. Of particular importance are studies on the isolation from mouse epidermis of receptors for specific uptake of the phorbol esters and the characterization of these receptors. He is also analyzing the modulation of ornithine decarboxylase activity; induction of this enzyme is an early event after the administration of the phorbol ester and is closely correlated with tumor promotion. Dr. Poland's group is analyzing the biological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin, which are mediated through its cytosolic receptor. This agent induces epidermal hyperplasia and hyperkeratosis and promotes skin tumor formation in HRS/J (hr/hr) mice, but not in their haired littermates. Dr. Pitot is analyzing the relationship of the enzyme-altered foci of hepatic parenchymal cells in carcinogen-treated liver to the eventual development of hepatic carcinomas. He is also examining the stability of the phenotypes and the cell biology of the foci cells. This group is also studying the regulation of the synthesis and the stabilization of mRNA for serine dehydratase and ornithine aminotransferase, as an approach to a better understanding of the molecular bases for the differences between normal liver and hepatic carcinomas.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA022484-08
Application #
3092993
Study Section
(SRC)
Project Start
1978-04-01
Project End
1988-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
8
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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
Copp, Richard R; Peebles, Daniel D; Soref, Cheryl M et al. (2013) Radioprotective efficacy and toxicity of a new family of aminothiol analogs. Int J Radiat Biol 89:485-92
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
Stein, Timothy J; Jochem, Adam; Holmes, Katie E et al. (2011) Effect of mutant ?-catenin on liver growth homeostasis and hepatocarcinogenesis in transgenic mice. Liver Int 31:303-12
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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