The goal of our research program is to understand the mechanisms by which specific gene control susceptibility of inbred mice to hepatocarcinogenesis. These studies will provide insights into the functions of critical regulatory pathways for multistage hepatocarcinogenesis and paradigms for understanding the action of risk- modifier genes in humans. We have identified and mapped three genes that determine the high susceptibilities of C3H, CBA and C57BR mice to liver tumor induction relative to C57BL/6 mice. The Hcs locus, carried by C3H and CBA is located on Chromosome 1. The Hcf1 locus, on Chromosome 17, and the Hcf2 locus, on Chromosome 1, are responsible for the uniquely high susceptibility of female C57BR mice to hepatocarcinogenesis. The goal of the first two aims of the present application is to determine the molecular identities of these genes by first mapping them to high resolution by analysis of congenic strains that carry the susceptible allele on a C57BL/6 background and then to use that positional information to molecularly clone the genes. In the third aim, we seek to understand the mechanistic basis for the sexual dimorphism observed in murine hepatocarcinogenesis. Specifically, we will test the hypothesis that sex- dependent differences in the growth hormone regulation are responsible for the increased sensitivity of male mice to liver tumor induction relative to female mice.
The fourth aim focuses on the genetic basis for strain variation in the biological consequences of one class initiating event for hepatocarcinogenesis, mutational activation of the Hras1 gene. We will attempt to map genes carried by SM mice that suppress this pathway and to determine whether these genes act by tissue specific or cell autonomous mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA022484-22
Application #
6101944
Study Section
Project Start
1999-02-01
Project End
2000-01-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
22
Fiscal Year
1999
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
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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
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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