The primary focus of this research project is the identification and characterization of specific genes that control the susceptibility of inbred mice to hepatocarcinogenesis. This project will aid in elucidating general mechanisms of cancer susceptibility that will be of value in understanding genetic variation in human populations in risk for cancer development. Previous studies resulted in the identification of the Hcs locus, which is responsible for the high susceptibility of C3H mice to liver tumor induction, and the demonstration that this gene regulates the proliferation of preneoplastic and normal hepatocytes. The first two aims of the present application are directed toward the molecular characterization of the Hcs gene using a reverse genetic approach. The chromosomal location of the Hcs gene will be determined by analysis of animals from crosses between C3H/HeJ mice and resistant inbred mice for cosegregation between carcinogen sensitivity and DNA- based genetic markers, including endogenous nonectropic murine leukemia viruses, restriction fragment length polymorphisms, and microsatellites. A physical map of the chromosomal region containing the Hcs locus will be constructed by analysis of a mouse genomic library of yeast artificial chromosomes. Candidate sequences from the region that are expressed at the RNA level in mouse liver will be evaluated in order to identify a cDNA encoding the Hcs gene.
The third aim i s to investigate the interaction between mouse liver cancer susceptibility genes and the initiation of hepatocarcinogenesis by mutations induced in the c-Ha-ras proto-oncogene. tumors induced by treatment with vinyl carbamate in 10 inbred strains of varying susceptibilities to hepatocarcinogenesis will be analyzed for the presence of mutant c-Ha-ras alleles. Fourth, the biological and genetic basis for the high susceptibility of DBA/2J male mice will be investigated by studying the development of preneoplastic hepatic lesions in carcinogen-treated animals, and by attempting to genetically map the major gene responsible for the sensitivity of this strain to liver tumor induction by using methods similar to those used in Aim 1. Finally, the hormonal regulation of liver tumor induction will be investigated by directly studying the inhibitory effects of estrogen on hepatocarcinogenesis in C57BL/6J, C3H/HeJ, and C57BR/cdJ mice and by genetic studies of the basis for the unusually high susceptibility of female C57BR/cdJ mice to liver tumor induction.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA022484-20
Application #
6236480
Study Section
Project Start
1997-02-01
Project End
1998-01-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
20
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
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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