It has recently been reported that a precursor of p21ras (pro-p21ras) becomes modified by a metabolite of
mevalonic acid prior to conversion to mature p21ras. We have examined the effect of blocking
isoprenoid biosynthesis on this process. Fluoromevalonate, which inhibits the conversion of pyrophosphomevalonate to
isopentenyl pyrophosphate, blocks the incorporation of radioactive
mevalonate into pro-p21ras, demonstrating the
mevalonate must be converted to an
isoprenoid prior to such incorporation.
Starvation of CHO-K1 cells for
mevalonic acid by treatment with
mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl (
HMG)-CoA reductase, or
mevalonate deprivation in a
mevalonate auxotroph defective in
HMG-CoA synthase activity results in the accumulation of pro-p21ras. The precursor, accumulated due to either of these treatments, is converted through an intermediate form to the mature p21ras by incubation of cells with
mevalonate. Incubation of cells with
25-hydroxycholesterol, the pleiotropic transcriptional down-regulator of
cholesterol biosynthesis does not, however, result in the accumulation of pro-p21ras. This result indicates that in contrast to the regulation of
cholesterol biosynthesis in mammalian cells, important regulatory control other than at the level of
HMG-CoA reductase is involved in the
isoprenoid biosynthesis required for protein isoprenylation.