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(Received for publication, January 4, 1995; and in revised form, April 26, 1995) From the Limonene and related monoterpenes have been shown to impair the
incorporation of mevalonic acid-derived isoprene compounds, that is
farnesyl pyrophosphate, into RAS and RAS-related proteins. As
farnesylation is critical for RAS's membrane localization and
function, the isoprenylation pathways have received attention as
potential targets of anti-RAS pharmacologic maneuvers. We have expanded
on these prior studies and demonstrate that one of limonene's
metabolic derivatives, perillyl alcohol, decreases the levels of
antigenic RAS in the human-derived myeloid THP-1 and lymphoid RPMI-8402
cell lines. Both limonene and perillyl alcohol decrease levels of
[
Volume 270,
Number 29,
Issue of July 21, pp. 17508-17512, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
S]methionine-labeled RAS proteins in cells that
have been pulsed with radiolabeled methionine for 4 h. In contrast,
lovastatin, which inhibits hydroxymethylglutaryl coenzyme A reductase
and thus depletes cells of farnesyl pyrophosphate, does not diminish
levels of total antigenic RAS but rather results in a shift in the RAS
protein; levels of farnesylated RAS decrease whereas levels of
unmodified/unfarnesylated RAS increase. As limonene and perillyl
alcohol do not induce such a shift, we conclude that these monoterpenes
decrease farnesylated RAS protein levels by a mechanism that is clearly
distinct from that of either depleting cells of farnesyl pyrophosphate
or inhibiting the enzyme farnesyl protein transferase that catalyzes
the post-translational farnesylation of RAS. Perillyl alcohol decreases
antigenic RAS levels but does not decrease levels of another
membrane-tethered protein, the
subunit of the heterotrimeric G
protein. Furthermore, perillyl alcohol decreases the levels of
radiolabeled methionine incorporated into immunoprecipitable RAS to a
greater extent than it decreases radiolabeled methionine incorporated
into total cellular protein. Thus there is some degree of specificity
for the activity of perillyl alcohol to depress RAS levels.
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