Linkage of the isoprenoid biosynthetic pathway with induction of DNA synthesis in mouse lymphocytes effects of compactin on mitogen-induced lymphocytes in serum-free medium

Abstract

Concanavalin A induction of DNA synthesis in mouse spleen lymphocytes cultured in serum-free medium was shown to be very sensitive to inhibition by compactin (ML-236B), a specific competitive inhibitor of hydroxymethylglutaryl-CoA reductase. As low as 0.1 μM compactin could give 98% inhibition of mitogen induction of a 5 · 10 6 cells/ml culture. This inhibition could be reversed completely by addition of exogenous mevalonate, but could not be reversed by either exogenous cholesterol or isopentenyladenine. Oxygenated sterol inhibition of mitogen-induced DNA synthesis could be reversed by cholesterol or by mevalonate, whereas cyclic AMP inhibition could not be reversed by either compound. These results suggest that endogenous cholesterol production is a necessary but not sufficient factor co-ordinated with mitogen-induced DNA synthesis, and that the presence of some additional product of mevalonate metabolism is involved also. Isopentenyladenine, though, did not have a significant effect on alleviating any of the above inhibitions. Since mevalonate could not relieve cyclic AMP inhibition, but could overcome compactin inhibition, cyclic AMP inhibition cannot be explained as due only to blockage of mevalonate production.