Genetic and Pharmacological Suppression of Oncogenic Mutations in <i>RAS</i> Genes of Yeast and Humans

TLDR

Cholesterol biosynthesis intermediates are required for the post‑translational modification of yeast a‑factor and Ras proteins. Inhibiting mevalonate biosynthesis blocks Ras activation and a‑factor processing, demonstrating that isoprenoid attachment is essential for Ras membrane association and function and suggesting a pharmacological strategy to control ras‑driven malignancies.

Abstract

The activity of an oncoprotein and the secretion of a pheromone can be affected by an unusual protein modification. Specifically, posttranslational modification of yeast a-factor and Ras protein requires an intermediate of the cholesterol biosynthetic pathway. This modification is apparently essential for biological activity. Studies of yeast mutants blocked in sterol biosynthesis demonstrated that the membrane association and biological activation of the yeast Ras2 protein require mevalonate, a precursor of sterols and other isoprenes such as farnesyl pyrophosphate. Furthermore, drugs that inhibit mevalonate biosynthesis blocked the in vivo action of oncogenic derivatives of human Ras protein in the Xenopus oocyte assay. The same drugs and mutations also prevented the posttranslational processing and secretion of yeast a-factor, a peptide that is farnesylated. Thus, the mevalonate requirement for Ras activation may indicate that attachment of a mevalonate-derived (isoprenoid) moiety to Ras proteins is necessary for membrane association and biological function. These observations establish a connection between the cholesterol biosynthetic pathway and transformation by the ras oncogene and offer a novel pharmacological approach to investigating, and possibly controlling, ras -mediated malignant transformations.