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Journal of Lipid Research, Vol. 44, 1209-1215, June 2003
Copyright © 2003 by Lipid Research, Inc.

Monoterpene regulation of Ras and Ras-related protein expression

Sarah A. Holstein^* and Raymond J. Hohl^1,*,

^* Departments of Pharmacology, University of Iowa, Iowa City, IA 52242
Internal Medicine, University of Iowa, Iowa City, IA 52242

¹ To whom correspondence should be addressed. e-mail: raymond-hohl{at}uiowa.edu

Monoterpenes, derived primarily from plants, are products of the isoprenoid biosynthetic pathway and function as chemical messengers with diverse functions. The biochemical bases for these activities are largely undefined. The Ras small GTPase superfamily of proteins consists of isoprenylated proteins that play key roles in signal transduction pathways known to regulate diverse cellular functions. In these studies, we have examined the effects of the monoterpenes on expression of Ras and Ras-related proteins, in the absence and presence of mevalonate depletion. Although prior studies have suggested that monoterpenes inhibit isoprenyl transferases, our studies clearly show that select monoterpenes inhibit up-regulation of Ras and the Ras-related proteins. A structure-activity relationship model for these effects was defined. The ability of monoterpenes to regulate the expression of the Ras-related proteins was found to be independent of effects on cell proliferation or total cellular protein synthesis/degradation.

This regulatory function of monoterpenes suggests a role for these plant-derived compounds in altering signal transduction elements.

Abbreviations: FPP, farnesyl pyrophosphate; GGPP, geranylgeranyl pyrophosphate; HRP, horseradish peroxidase; LOV, lovastatin; PA, perillyl alcohol; TCA, trichloroacetic acid

Supplementary key words Rap1a • RhoA • RhoB • perillyl alcohol • down-regulation

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