Activated Drosophila Ras1 is selectively suppressed by isoprenyl transferase inhibitors

Rachele C. Kauffmann, Yimin Qian, Andreas Vogt, Said M. Sebti, Andrew Hamilton, Richard W. Carthew

Research output: Contribution to journalArticle

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 Ras1(val12) Drosophila larvae. FTI-254 decreased the ability of Ras1(val12) 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 Ras1(val12) protein that is membrane associated through myristylation instead of isoprenylation. Therefore, FTI-254 acts as an isoprenylation inhibitor to selectively inhibit Ras1(val12) signaling activity in a whole-animal model system.

Original languageEnglish (US)
Pages (from-to)10919-10923
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number24
DOIs
StatePublished - Nov 21 1995

Fingerprint

Prenylation
Transferases
Drosophila
Peptidomimetics
Diptera
raf Kinases
Amino Acids
Photoreceptor Cells
Oncogene Proteins
Receptor Protein-Tyrosine Kinases
Antineoplastic Agents
Cysteine
Larva
Membrane Proteins
Fatty Acids
Animal Models
Phenotype
Mutation
Injections
Neoplasms

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Activated Drosophila Ras1 is selectively suppressed by isoprenyl transferase inhibitors. / Kauffmann, Rachele C.; Qian, Yimin; Vogt, Andreas; Sebti, Said M.; Hamilton, Andrew; Carthew, Richard W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 92, No. 24, 21.11.1995, p. 10919-10923.

Research output: Contribution to journalArticle

Kauffmann, Rachele C. ; Qian, Yimin ; Vogt, Andreas ; Sebti, Said M. ; Hamilton, Andrew ; Carthew, Richard W. / Activated Drosophila Ras1 is selectively suppressed by isoprenyl transferase inhibitors. In: Proceedings of the National Academy of Sciences of the United States of America. 1995 ; Vol. 92, No. 24. pp. 10919-10923.
@article{7bfb661a43f346459412976f6ccb58fa,
title = "Activated Drosophila Ras1 is selectively suppressed by isoprenyl transferase inhibitors",
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 Ras1(val12) Drosophila larvae. FTI-254 decreased the ability of Ras1(val12) 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 Ras1(val12) protein that is membrane associated through myristylation instead of isoprenylation. Therefore, FTI-254 acts as an isoprenylation inhibitor to selectively inhibit Ras1(val12) signaling activity in a whole-animal model system.",
author = "Kauffmann, {Rachele C.} and Yimin Qian and Andreas Vogt and Sebti, {Said M.} and Andrew Hamilton and Carthew, {Richard W.}",
year = "1995",
month = "11",
day = "21",
doi = "10.1073/pnas.92.24.10919",
language = "English (US)",
volume = "92",
pages = "10919--10923",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "24",

}

TY - JOUR

T1 - Activated Drosophila Ras1 is selectively suppressed by isoprenyl transferase inhibitors

AU - Kauffmann, Rachele C.

AU - Qian, Yimin

AU - Vogt, Andreas

AU - Sebti, Said M.

AU - Hamilton, Andrew

AU - Carthew, Richard W.

PY - 1995/11/21

Y1 - 1995/11/21

N2 - 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 Ras1(val12) Drosophila larvae. FTI-254 decreased the ability of Ras1(val12) 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 Ras1(val12) protein that is membrane associated through myristylation instead of isoprenylation. Therefore, FTI-254 acts as an isoprenylation inhibitor to selectively inhibit Ras1(val12) signaling activity in a whole-animal model system.

AB - 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 Ras1(val12) Drosophila larvae. FTI-254 decreased the ability of Ras1(val12) 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 Ras1(val12) protein that is membrane associated through myristylation instead of isoprenylation. Therefore, FTI-254 acts as an isoprenylation inhibitor to selectively inhibit Ras1(val12) signaling activity in a whole-animal model system.

UR - http://www.scopus.com/inward/record.url?scp=0028868945&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028868945&partnerID=8YFLogxK

U2 - 10.1073/pnas.92.24.10919

DO - 10.1073/pnas.92.24.10919

M3 - Article

C2 - 7479910

AN - SCOPUS:0028868945

VL - 92

SP - 10919

EP - 10923

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 24

ER -