Ras farnesyltransferase inhibitors suppress the phenotype resulting from an activated ras mutation in Caenorhabditis elegans.

Abstract

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.

• Authors: M Hara, M Han
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 92 Issue 8 Pg. 3333-7 (Apr 11 1995) ISSN: 0027-8424 [Print] United States
• PMID: 7536929 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Polyenes
• Polyunsaturated Alkamides
• Gliotoxin
• Transferases
• Alkyl and Aryl Transferases
• Farnesyltranstransferase
• ras Proteins
• manumycin

Topics

• Alkyl and Aryl Transferases
• Animals
• Caenorhabditis elegans (drug effects, genetics, growth & development)
• Dose-Response Relationship, Drug
• Farnesyltranstransferase
• Female
• Genes, Helminth (genetics)
• Genes, ras (genetics)
• Gliotoxin (pharmacology)
• Mutation
• Phenotype
• Polyenes (pharmacology)
• Polyunsaturated Alkamides
• Protein Prenylation (drug effects)
• Signal Transduction (drug effects)
• Transferases (antagonists & inhibitors)
• Vulva (drug effects, growth & development)
• ras Proteins (metabolism)