Oxysterols are naturally-occurring oxygenated derivatives of cholesterol and its precursors with potent regulatory powers. Their functional roles as normal controllers of growth and metabolic processes are unknown, although several have been proposed. This project proposes to study the growth inhibitory effects of oxysterols in several distinctive clones of CEM cells, a line of human leukemic T lymphoblasts. Extensive preliminary studies have shown that these cells are growth inhibited by oxysterols, that in them the rate-limiting enzyme of cholesterol synthesis, 3-hydroxy- 3-methyglutaryl CoA reductase, is down regulated, and that they possess a classic oxysterol binding protein/receptor (OBP/R). Glucocorticoids are lethal for some of these clones; others are resistant. A line of oxysterol-resistant cells also has been isolated.
Three specific aims will be pursued: one, to test the hypothesis that there is a mechanistic correlation between oxysterol inhibition of the reductase and of growth; two, to test the hypothesis that the OBP/R is involved in growth regulation; and three, to see whether the paths by which oxysterols and glucocorticoids block the leukemic cell growth are overlapping. To achieve these aims, a combination of cell biological, biochemical and molecular biological techniques will be employed. Interactions with other projects occur at several levels.
