Abstract

The major aim of this project is to examine the mechanism by which cholesterogenesis is articulated with DNA replication. Previous studies have demonstrated that mevalonic acid is required for the synthesis of DNA, specifically during the S phase of the cell cycle. We have further shown that the isoprenoid purine, isopentenyl adenine, is approximately 100 times more effective in regulating DNA replication than mevalonic acid itself. During the coming year, we shall study the biochemical pathway of isopentenyl adenine synthesis in animal tissues. The various classes of DNA polymerase will be isolated from normal and malignant tissues of various growth rates. We will then determine whether the inhibition of mevalonic acid synthesis inhibits the activity of these polymerases, and if so, whether mevalonic acid and isopentenyl adenine can restore polymerase activity. By this approach, we hope to determine the mechanism by which isopentenyl adenine or related isoprene derivatives regulate DNA replication and thereby the rate of cell replication in normal and cancerous cells. (B)

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA015979-15
Application #
3164305
Study Section
Metabolism Study Section (MET)
Project Start
1976-12-03
Project End
1991-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
15
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Silber, J R; Galick, H; Wu, J M et al. (1992) The effect of mevalonic acid deprivation on enzymes of DNA replication in cells emerging from quiescence. Biochem J 288 ( Pt 3):883-9
Erickson, S K; Lear, S R; Barker, M E et al. (1990) Regulation of cholesterol metabolism in the ethionine-induced premalignant rat liver. J Lipid Res 31:933-45
Erickson, S K; Jaeckle, S; Lear, S R et al. (1989) Regulation of hepatic cholesterol and lipoprotein metabolism in ethinyl estradiol-treated rats. J Lipid Res 30:1763-71
Erickson, S K; Cooper, A D; Barnard, G F et al. (1988) Regulation of cholesterol metabolism in a slow-growing hepatoma in vivo. Biochim Biophys Acta 960:131-8
Feingold, K R; Soued, M; Grunfeld, C (1988) Tumor necrosis factor stimulates DNA synthesis in the liver of intact rats. Biochem Biophys Res Commun 153:576-82
Hughes-Fulford, M; Feingold, K R; Searle, G L et al. (1986) Role of the kidneys in the metabolism of circulating mevalonate in humans. J Clin Endocrinol Metab 62:1227-31
Feingold, K R; Moser, A H (1986) The effect of substrates and competitive inhibitors on the phosphatase-dependent activation of hepatic hydroxymethylglutaryl CoA reductase. Arch Biochem Biophys 249:46-52
Golper, T A; Feingold, K R; Fulford, M H et al. (1986) The role of circulating mevalonate in nephrotic hypercholesterolemia in the rat. J Lipid Res 27:1044-51
Hughes-Fulford, M; Wu, J; Kato, T et al. (1985) Inhibition of DNA synthesis and cell cycle by prostaglandins independent of cyclic AMP. Adv Prostaglandin Thromboxane Leukot Res 15:401-4
Williams, M L; Hughes-Fulford, M; Elias, P M (1985) Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and sterol synthesis by cholesterol sulfate in cultured fibroblasts. Biochim Biophys Acta 845:349-57

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