The CAAX peptidomimetic compound B581 specifically blocks farnesylated, but not geranylgeranylated or myristylated, oncogenic ras signaling and transformation.
Recently developed CAAX peptidomimetic compounds have been shown to be potent and specific inhibitors of farnesyl protein transferase activity and to block the growth of Ras-transformed cells. However, whether this growth inhibitory action is specifically a consequence of blocking oncogenic Ras signaling has not been determined. To address this question, we have utilized mutants of the normally farnesylated oncogenic Ras protein (Ras-F) that are modified by alternative lipids, a geranylgeranyl isoprenoid (Ras-GG) or the fatty acid myristate (Myr-Ras), to determine the specificity of the CAAX peptidomimetic compound, B581. Like Ras-F, both Ras-GG and Myr-Ras are membrane-associated and transforming. Unexpectedly, NIH 3T3 cells transformed by each of the three Ras mutants underwent morphological alteration to a less transformed, but not normal, morphology. However, B581 inhibited the ability of only Ras-F-transformed cells, but not Ras-GG- or Myr-Ras- (or Raf-) transformed cells, to grow in soft agar. Furthermore, although all three lipid-modified versions of Ras stimulated mitogen-activated protein kinase activation, and both Jun and Elk-1 transcriptional activity, B581 inhibited only farnesylated Ras activation of these three downstream components of Ras signaling. Therefore, B581 prevents the growth of Ras-transformed cells by specifically antagonizing Ras-mediated signaling.
Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 27599.
A D
AD
Cox
A M
AM
Garcia
J K
JK
Westwick
J J
JJ
Kowalczyk
M D
MD
Lewis
D A
DA
Brenner
C J
CJ
Der
D016475:3T3 Cells; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004268:DNA-Binding Proteins; D004224:Diterpenes / Q000378:metabolism; D005204:Farnesol / Q000378:metabolism; D051379:Mice; D019814:Myristic Acid; D009227:Myristic Acids / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D017368:Protein Prenylation; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors; D014158:Transcription, Genetic; D050807:ets-Domain Protein Elk-1
D004268:DNA-Binding Proteins; D004224:Diterpenes; C494113:Elk1 protein, mouse; D009227:Myristic Acids; D009842:Oligopeptides; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D015682:Retroviridae Proteins, Oncogenic; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D019814:Myristic Acid; C088459:B 581; D005204:Farnesol; C017338:geranylgeraniol; D015689:Oncogene Protein p21(ras)