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Ras farnesyltransferase inhibitors suppr ... ation in Caenorhabditis elegans
Ras farnesyltransferase inhibitors suppress the phenotype resulting from an activated ras mutation in Caenorhabditis elegans.
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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, Han M
Proceedings of the National Academy of Sciences of the United States of America
1995-04-11 00:00
92
8
3333-7
Alkyl and Aryl Transferases,Animals,Caenorhabditis elegans,Dose-Response Relationship, Drug,Farnesyltranstransferase,Female,Genes, Helminth,Genes, ras,Gliotoxin,Mutation,Phenotype,Polyenes,Polyunsaturated Alkamides,Protein Isoprenylation,Signal Transduction,Transferases,Vulva,ras Proteins,Polyenes,Polyunsaturated Alkamides,manumycin,Gliotoxin,Transferases,Alkyl and Aryl Transferases,Farnesyltranstransferase,ras Proteins
Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder 80309-0347, USA
Proc. Natl. Acad. Sci. U.S.A.
0027-8424
505
True
7536929
