Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Nov 21;92(24):10919–10923. doi: 10.1073/pnas.92.24.10919

Activated Drosophila Ras1 is selectively suppressed by isoprenyl transferase inhibitors.

R C Kauffmann 1, Y Qian 1, A Vogt 1, S M Sebti 1, A D Hamilton 1, R W Carthew 1
PMCID: PMC40542  PMID: 7479910

Abstract

Ras CAAX (C = cysteine, A = aliphatic amino acid, and X = any amino acid) peptidomimetic inhibitors of farnesyl protein transferase suppress Ras-dependent cell transformation by preventing farnesylation of the Ras oncoprotein. These compounds are potential anticancer agents for tumors associated with Ras mutations. The peptidomimetic FTI-254 was tested for Ras1-inhibiting activity in whole animals by injection of activated Ras1val12 Drosophila larvae. FTI-254 decreased the ability of Ras1val12 to form supernumerary R7 photoreceptor cells in the compound eye of transformed flies. In contrast, it had no effect on the related supernumerary R7 phenotypes of flies transformed with either the activated sevenless receptor tyrosine kinase, Raf kinase, or a chimeric Ras1val12 protein that is membrane associated through myristylation instead of isoprenylation. Therefore, FTI-254 acts as an isoprenylation inhibitor to selectively inhibit Ras1val12 signaling activity in a whole-animal model system.

Full text

PDF

Images in this article

10921Fig. 2
on p.10921

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Basler K., Christen B., Hafen E. Ligand-independent activation of the sevenless receptor tyrosine kinase changes the fate of cells in the developing Drosophila eye. Cell. 1991 Mar 22;64(6):1069–1081. doi: 10.1016/0092-8674(91)90262-w. [DOI] [PubMed] [Google Scholar]
  2. Biggs W. H., 3rd, Zavitz K. H., Dickson B., van der Straten A., Brunner D., Hafen E., Zipursky S. L. The Drosophila rolled locus encodes a MAP kinase required in the sevenless signal transduction pathway. EMBO J. 1994 Apr 1;13(7):1628–1635. doi: 10.1002/j.1460-2075.1994.tb06426.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bos J. L. ras oncogenes in human cancer: a review. Cancer Res. 1989 Sep 1;49(17):4682–4689. [PubMed] [Google Scholar]
  4. Brunner D., Oellers N., Szabad J., Biggs W. H., 3rd, Zipursky S. L., Hafen E. A gain-of-function mutation in Drosophila MAP kinase activates multiple receptor tyrosine kinase signaling pathways. Cell. 1994 Mar 11;76(5):875–888. doi: 10.1016/0092-8674(94)90362-x. [DOI] [PubMed] [Google Scholar]
  5. Casey P. J., Solski P. A., Der C. J., Buss J. E. p21ras is modified by a farnesyl isoprenoid. Proc Natl Acad Sci U S A. 1989 Nov;86(21):8323–8327. doi: 10.1073/pnas.86.21.8323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cox A. D., Der C. J. Protein prenylation: more than just glue? Curr Opin Cell Biol. 1992 Dec;4(6):1008–1016. doi: 10.1016/0955-0674(92)90133-w. [DOI] [PubMed] [Google Scholar]
  7. Dickson B., Hafen E. Genetics of signal transduction in invertebrates. Curr Opin Genet Dev. 1994 Feb;4(1):64–70. doi: 10.1016/0959-437x(94)90092-2. [DOI] [PubMed] [Google Scholar]
  8. Dickson B., Sprenger F., Morrison D., Hafen E. Raf functions downstream of Ras1 in the Sevenless signal transduction pathway. Nature. 1992 Dec 10;360(6404):600–603. doi: 10.1038/360600a0. [DOI] [PubMed] [Google Scholar]
  9. Fortini M. E., Simon M. A., Rubin G. M. Signalling by the sevenless protein tyrosine kinase is mimicked by Ras1 activation. Nature. 1992 Feb 6;355(6360):559–561. doi: 10.1038/355559a0. [DOI] [PubMed] [Google Scholar]
  10. Garcia A. M., Rowell C., Ackermann K., Kowalczyk J. J., Lewis M. D. Peptidomimetic inhibitors of Ras farnesylation and function in whole cells. J Biol Chem. 1993 Sep 5;268(25):18415–18418. [PubMed] [Google Scholar]
  11. Gibbs J. B., Oliff A., Kohl N. E. Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell. 1994 Apr 22;77(2):175–178. doi: 10.1016/0092-8674(94)90308-5. [DOI] [PubMed] [Google Scholar]
  12. Gibbs J. B., Pompliano D. L., Mosser S. D., Rands E., Lingham R. B., Singh S. B., Scolnick E. M., Kohl N. E., Oliff A. Selective inhibition of farnesyl-protein transferase blocks ras processing in vivo. J Biol Chem. 1993 Apr 15;268(11):7617–7620. [PubMed] [Google Scholar]
  13. Gibbs J. B. Ras C-terminal processing enzymes--new drug targets? Cell. 1991 Apr 5;65(1):1–4. doi: 10.1016/0092-8674(91)90352-y. [DOI] [PubMed] [Google Scholar]
  14. Goldstein J. L., Brown M. S., Stradley S. J., Reiss Y., Gierasch L. M. Nonfarnesylated tetrapeptide inhibitors of protein farnesyltransferase. J Biol Chem. 1991 Aug 25;266(24):15575–15578. [PubMed] [Google Scholar]
  15. Hancock J. F., Magee A. I., Childs J. E., Marshall C. J. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell. 1989 Jun 30;57(7):1167–1177. doi: 10.1016/0092-8674(89)90054-8. [DOI] [PubMed] [Google Scholar]
  16. Hariharan I. K., Carthew R. W., Rubin G. M. The Drosophila roughened mutation: activation of a rap homolog disrupts eye development and interferes with cell determination. Cell. 1991 Nov 15;67(4):717–722. doi: 10.1016/0092-8674(91)90066-8. [DOI] [PubMed] [Google Scholar]
  17. Havel C. M., Fisher P., Watson J. A. Isopentenoid synthesis in embryonic Drosophila cells: prenylated protein profile and prenyl group usage. Arch Biochem Biophys. 1992 Jun;295(2):410–420. doi: 10.1016/0003-9861(92)90535-5. [DOI] [PubMed] [Google Scholar]
  18. James G. L., Goldstein J. L., Brown M. S., Rawson T. E., Somers T. C., McDowell R. S., Crowley C. W., Lucas B. K., Levinson A. D., Marsters J. C., Jr Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells. Science. 1993 Jun 25;260(5116):1937–1942. doi: 10.1126/science.8316834. [DOI] [PubMed] [Google Scholar]
  19. Kato K., Cox A. D., Hisaka M. M., Graham S. M., Buss J. E., Der C. J. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6403–6407. doi: 10.1073/pnas.89.14.6403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kawata M., Farnsworth C. C., Yoshida Y., Gelb M. H., Glomset J. A., Takai Y. Posttranslationally processed structure of the human platelet protein smg p21B: evidence for geranylgeranylation and carboxyl methylation of the C-terminal cysteine. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8960–8964. doi: 10.1073/pnas.87.22.8960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kimmel B. E., Heberlein U., Rubin G. M. The homeo domain protein rough is expressed in a subset of cells in the developing Drosophila eye where it can specify photoreceptor cell subtype. Genes Dev. 1990 May;4(5):712–727. doi: 10.1101/gad.4.5.712. [DOI] [PubMed] [Google Scholar]
  22. Kohl N. E., Mosser S. D., deSolms S. J., Giuliani E. A., Pompliano D. L., Graham S. L., Smith R. L., Scolnick E. M., Oliff A., Gibbs J. B. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science. 1993 Jun 25;260(5116):1934–1937. doi: 10.1126/science.8316833. [DOI] [PubMed] [Google Scholar]
  23. Kohl N. E., Wilson F. R., Mosser S. D., Giuliani E., deSolms S. J., Conner M. W., Anthony N. J., Holtz W. J., Gomez R. P., Lee T. J. Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):9141–9145. doi: 10.1073/pnas.91.19.9141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lowy D. R., Willumsen B. M. Function and regulation of ras. Annu Rev Biochem. 1993;62:851–891. doi: 10.1146/annurev.bi.62.070193.004223. [DOI] [PubMed] [Google Scholar]
  25. McGuire T. F., Qian Y., Blaskovich M. A., Fossum R. D., Sun J., Marlowe T., Corey S. J., Wathen S. P., Vogt A., Hamilton A. D. CAAX peptidomimetic FTI-244 decreases platelet-derived growth factor receptor tyrosine phosphorylation levels and inhibits stimulation of phosphatidylinositol 3-kinase but not mitogen-activated protein kinase. Biochem Biophys Res Commun. 1995 Sep 5;214(1):295–303. doi: 10.1006/bbrc.1995.2287. [DOI] [PubMed] [Google Scholar]
  26. Moores S. L., Schaber M. D., Mosser S. D., Rands E., O'Hara M. B., Garsky V. M., Marshall M. S., Pompliano D. L., Gibbs J. B. Sequence dependence of protein isoprenylation. J Biol Chem. 1991 Aug 5;266(22):14603–14610. [PubMed] [Google Scholar]
  27. Nigam M., Seong C. M., Qian Y., Hamilton A. D., Sebti S. M. Potent inhibition of human tumor p21ras farnesyltransferase by A1A2-lacking p21ras CA1A2X peptidomimetics. J Biol Chem. 1993 Oct 5;268(28):20695–20698. [PubMed] [Google Scholar]
  28. Perrimon N. The torso receptor protein-tyrosine kinase signaling pathway: an endless story. Cell. 1993 Jul 30;74(2):219–222. doi: 10.1016/0092-8674(93)90412-j. [DOI] [PubMed] [Google Scholar]
  29. Pompliano D. L., Schaber M. D., Mosser S. D., Omer C. A., Shafer J. A., Gibbs J. B. Isoprenoid diphosphate utilization by recombinant human farnesyl:protein transferase: interactive binding between substrates and a preferred kinetic pathway. Biochemistry. 1993 Aug 17;32(32):8341–8347. doi: 10.1021/bi00083a038. [DOI] [PubMed] [Google Scholar]
  30. Qian Y., Blaskovich M. A., Saleem M., Seong C. M., Wathen S. P., Hamilton A. D., Sebti S. M. Design and structural requirements of potent peptidomimetic inhibitors of p21ras farnesyltransferase. J Biol Chem. 1994 Apr 29;269(17):12410–12413. [PubMed] [Google Scholar]
  31. Reiss Y., Goldstein J. L., Seabra M. C., Casey P. J., Brown M. S. Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides. Cell. 1990 Jul 13;62(1):81–88. doi: 10.1016/0092-8674(90)90242-7. [DOI] [PubMed] [Google Scholar]
  32. Schaber M. D., O'Hara M. B., Garsky V. M., Mosser S. C., Bergstrom J. D., Moores S. L., Marshall M. S., Friedman P. A., Dixon R. A., Gibbs J. B. Polyisoprenylation of Ras in vitro by a farnesyl-protein transferase. J Biol Chem. 1990 Sep 5;265(25):14701–14704. [PubMed] [Google Scholar]
  33. Schafer W. R., Kim R., Sterne R., Thorner J., Kim S. H., Rine J. Genetic and pharmacological suppression of oncogenic mutations in ras genes of yeast and humans. Science. 1989 Jul 28;245(4916):379–385. doi: 10.1126/science.2569235. [DOI] [PubMed] [Google Scholar]
  34. Sun J., Qian Y., Hamilton A. D., Sebti S. M. Ras CAAX peptidomimetic FTI 276 selectively blocks tumor growth in nude mice of a human lung carcinoma with K-Ras mutation and p53 deletion. Cancer Res. 1995 Oct 1;55(19):4243–4247. [PubMed] [Google Scholar]
  35. Tomlinson A., Ready D. F. Cell fate in the Drosophila ommatidium. Dev Biol. 1987 Sep;123(1):264–275. doi: 10.1016/0012-1606(87)90448-9. [DOI] [PubMed] [Google Scholar]
  36. Trueblood C. E., Ohya Y., Rine J. Genetic evidence for in vivo cross-specificity of the CaaX-box protein prenyltransferases farnesyltransferase and geranylgeranyltransferase-I in Saccharomyces cerevisiae. Mol Cell Biol. 1993 Jul;13(7):4260–4275. doi: 10.1128/mcb.13.7.4260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Vogt A., Qian Y., Blaskovich M. A., Fossum R. D., Hamilton A. D., Sebti S. M. A non-peptide mimetic of Ras-CAAX: selective inhibition of farnesyltransferase and Ras processing. J Biol Chem. 1995 Jan 13;270(2):660–664. doi: 10.1074/jbc.270.2.660. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES