Ras farnesyltransferase inhibitors suppress the phenotype resulting from an activated ras mutation in Caenorhabditis elegans.
Attachment of Ras protein to the membrane, which requires farnesylation at its C terminus, is essential for its biological activity. A promising pharmacological approach of antagonizing oncogenic Ras activity is to develop inhibitors of farnesyltransferase. We use Caenorhabditis elegans vulval differentiation, which is controlled by a Ras-mediated signal transduction pathway, as a model system to test previously identified farnesyltransferase inhibitors. We show here that two farnesyltransferase inhibitors, manumycin and gliotoxin, suppress the Multivulva phenotype resulting from an activated let-60 ras mutation, but not the Multivulva phenotype resulting from mutations in the lin-1 gene or the lin-15 gene, which act downstream and upstream of let-60 ras, respectively, in the signaling pathway. These results are consistent with the idea that the suppression of the Multivulva phenotype of let-60 ras by the two inhibitors is specific for Ras protein and that the mutant Ras protein might be more sensitive than wild-type Ras to the farnesyltransferase inhibitors. This work suggests that C. elegans vulval development could be a simple and effective in vivo system for evaluation of farnesyltransferase inhibitors against Ras-activated tumors.
Hara
M
M
Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder 80309-0347, USA.
Han
M
M
D019883:Alkyl and Aryl Transferases; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D051231:Farnesyltranstransferase; D005260:Female; D017238:Genes, Helminth / Q000235:genetics; D011905:Genes, ras / Q000235:genetics*; D005912:Gliotoxin / Q000494:pharmacology; D009154:Mutation; D010641:Phenotype; D011090:Polyenes / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D017368:Protein Prenylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014166:Transferases / Q000037:antagonists & inhibitors*; D014844:Vulva / Q000187:drug effects / Q000254:growth & development; D018631:ras Proteins / Q000378:metabolism*
D011090:Polyenes; D053284:Polyunsaturated Alkamides; D005912:Gliotoxin; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins; C054474:manumycin