The long range goal of this project is to enlarge our understanding of the genetic regulation of enzymes in cholesterol biosysnthesis. Such studies derive their scientific significance both from some unusual opportunities in this system to study transcriptional control of gene expession and the utilization of insights derived from these studies to increase our understanding of the pathogenesis and eventual chemotherapy of atherosclerotic cardiovascular disease. Specifically, this project describes studies directed at cloning the human gene for the enzyme 3-hydroxy-3-methyglutaryl coenzyme A synthases by the technique of DNA mediated gene transfer. The methodology proposed provides a vehicle not only for cloning informational elements of the gene, but for cloning regulatory sequences involved in its epxression as well. We also proposed to determine where within such cloned DNA sequences the regulatory sequences lie, the construction of restriction maps on both the functional gene and its regulatory component, and finally the identification and activity of specific DNA sequences which determine the regulated expression of this gene.
| Panini, S R; Schnitzer-Polokoff, R; Spencer, T A et al. (1989) Sterol-independent regulation of 3-hydroxy-3-methylglutaryl-CoA reductase by mevalonate in Chinese hamster ovary cells. Magnitude and specificity. J Biol Chem 264:11044-52 |
| von Gunten, C F; Sinensky, M (1989) Treatment of CHO-K1 cells with 25-hydroxycholesterol produces a more rapid loss of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity than can be accounted for by enzyme turnover. Biochim Biophys Acta 1001:218-24 |
| Sinensky, M; Logel, J; Phirwa, S et al. (1987) Requirement for 24(S),25-epoxycholesterol for the viability of cultured fibroblasts. Exp Cell Res 171:492-7 |
| Leonard, S; Arbogast, D; Geyer, D et al. (1986) Localization of the gene encoding 3-hydroxy-3-methylglutaryl-coenzyme A synthase to human chromosome 5. Proc Natl Acad Sci U S A 83:2187-9 |
