Genetic and pharmacological suppression of oncogenic mutations in ras genes of yeast and humans.
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.
Schafer
W R
WR
Department of Biochemistry, University of California, Berkeley 94720.
Kim
R
R
Sterne
R
R
Thorner
J
J
Kim
S H
SH
Rine
J
J
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004330:Drosophila; D004591:Electrophoresis, Polyacrylamide Gel; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D011905:Genes, ras; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics; D015151:Immunoblotting; D000072235:Mating Factor; D008798:Mevalonic Acid / Q000096:biosynthesis; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011233:Precipitin Tests; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins; D013489:Suppression, Genetic; D014981:Xenopus; D018631:ras Proteins
D005656:Fungal Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D029701:Saccharomyces cerevisiae Proteins; D000072235:Mating Factor; D006903:Hydroxymethylglutaryl CoA Reductases; D006904:Hydroxymethylglutaryl-CoA Synthase; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); C489015:RAS2 protein, S cerevisiae; D018631:ras Proteins; D008798:Mevalonic Acid