Control of RAS mRNA level by the mevalonate pathway.
The ability of Ras proteins to initiate eukaryotic cell proliferation requires the post-translational attachment of a farnesyl group, an isoprenoid lipid moiety derived from mevalonate, to the carboxyl-terminus of the protein. This modification is essential for the subsequent processing and intracellular targeting of the Ras protein. Here we report that mevalonate is also required for the efficient synthesis of Ras proteins in Saccharomyces cerevisiae. Depletion of intracellular mevalonate resulted in decreased steady-state levels of Ras1p and Ras2p, an effect that was mediated at the level of mRNA accumulation. The sequences controlling the response of RAS2 mRNA level to mevalonate availability, mapped to the coding region of the RAS2 gene. Mevalonate starvation also had a significant effect on the expression of some, but not all, genes encoding prenylated proteins. The regulatory effect on RAS2 mRNA did not require a functional farnesyl transferase. These results uncover a novel regulatory role for mevalonate-derived products and expand the potential for inhibitors of mevalonate metabolism as anti-cancer agents.
Dimster-Denk
D
D
Department of Molecular and Cell Biology, University of California, Berkeley 94720, USA.
Schafer
W R
WR
Rine
J
J
D001483:Base Sequence; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism*; D008969:Molecular Sequence Data; D017368:Protein Prenylation; D011499:Protein Processing, Post-Translational; D012331:RNA, Fungal / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins; D018631:ras Proteins
D005656:Fungal Proteins; D012331:RNA, Fungal; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D006903:Hydroxymethylglutaryl CoA Reductases; C489015:RAS2 protein, S cerevisiae; D018631:ras Proteins; D008798:Mevalonic Acid