Regulation of proliferation and Ras localization in transformed cells by products of mevalonate metabolism.

摘要: Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl (HMG) CoA reductase, and 6-fluoromevalonate (Fmev), diphosphomevalonate decarboxylase, blocked the synthesis downstream mevalonate products, including prenyl-derived lipids, prevented membrane localization Ras in myeloid cell line U-937. In contrast to lovastatin, which induced cytosol U-937 cells, Fmev failed increase cytosolic also completely proliferation cells. Growth cells was restored by addition lovastatin Fmev-blocked These results implied that a product metabolism proximal isopentenyl diphosphate responsible for suppression proliferation. To delineate action this endogenous determine relationship between its impact on proliferation, effect variety leukemia- lymphoma-derived examined. Whereas growth these lines, there were more than 50-fold differences concentrations required inhibit individual lines 90%. Regardless biochemical similar. Thus, uniformly conversion radiolabeled other sterol nonsterol lipids prenylation proteins. A correlation noted higher intrinsic rates susceptibility inhibition Fmev. sensitivity associated with markedly increased HMG reductase activity further incubation depleted cellular levels prenylated protein sensitive U-937, no depletion resistant EL-4, but rather, shift from cytosol, as expected prenylation. suggest leukemic produce mevalonate-derived leads growth. As result, transformed might be specifically accomplished