Prenylated proteins and lymphocyte proliferation: inhibition by d-limonene related monoterpenes.
The aim of the present study was to explore the role of post-translational isoprenoid modification of cellular proteins in the proliferation of human lymphocytes. We here report that treatment of phytohemagglutinin-stimulated peripheral blood mononuclear cells with monoterpenes including d-limonene, perillic acid and perillyl alcohol (0.5-5 mM) which selectively inhibit the isoprenylation of 21-26-kDa proteins resulted in a dose-dependent inhibition of DNA synthesis. Cell cycle analysis revealed that perillic acid arrested cells in G1 and prevented cells from entering S phase in a manner similar to that induced by the specific 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, compactin. However, unlike compactin, the perillic acid-induced effects on lymphocyte proliferation were not prevented by addition of mevalonate. We also examined the incorporation of [3H]mevalonate into proteins in resting and phytohemagglutinin-stimulated lymphocytes during the first 30 h of culture. While in unstimulated lymphocytes radioactivity was predominantly incorporated into a cluster of 21-26-kDa proteins, mitogenic stimulation was associated with a striking increase in [3H]mevalonate incorporation into a protein (approximately 68 kDa) with migration characteristics similar to that of nuclear lamin B. Treatment of phytohemagglutinin-stimulated lymphocytes with 5 mM d-limonene, 2.5 mM perillic acid or 1.25 mM perillyl alcohol strongly suppressed [3H]mevalonate-labeling of proteins to a degree that correlated with the level of DNA synthesis inhibition. These findings suggest that those mevalonate-derived products required for lymphocyte proliferation may include one or more isoprenylated proteins and that the isoprenylation of these proteins is required for cell cycle progression.
Schulz
S
S
Department of Medicine, Otto-von-Guericke-University, Magdeburg, FRG.
Bühling
F
F
Ansorge
S
S
D002453:Cell Cycle / Q000187:drug effects; D053138:Cyclohexenes; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D000077222:Limonene; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008213:Lymphocyte Activation; D008798:Mevalonic Acid / Q000378:metabolism; D039821:Monoterpenes; D017368:Protein Prenylation / Q000187:drug effects*; D013729:Terpenes / Q000494:pharmacology*
D053138:Cyclohexenes; D039821:Monoterpenes; D013729:Terpenes; C012258:mevastatin; C078706:perillic acid; D004247:DNA; D008148:Lovastatin; D000077222:Limonene; D008798:Mevalonic Acid