Elevation of alpha2(I) collagen, a suppressor of Ras transformation, is required for stable phenotypic reversion by farnesyltransferase inhibitors.
Farnesyltransferase inhibitors (FTIs) are a novel class of anticancer drugs that can reverse Ras transformation. One of the intriguing aspects of FTI biology is that continuous drug exposure is not necessary to maintain phenotypic reversion. For example, after a single exposure to FTIs, Ha-Ras-transformed fibroblasts revert to a flat and anchorage-dependent phenotype that persists for many days after processed Ras has returned to pretreatment levels. In this study, we show that persistence of the reverted state is mediated by elevated expression of the collagen isoform alpha2(I), a suppressor of Ras transformation the transcription of which is repressed by activated Ras and derepressed by FTI treatment. To our knowledge, this is the first report identifying an FTI-regulated gene which is linked to phenotypic reversion. The finding that extracellular matrix alterations can influence the kinetics of reversion supports our assertion that Rho-regulated cell adhesion parameters are a crucial determinant of the cellular response to FTIs.
Du
W
W
The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Lebowitz
P F
PF
Prendergast
G C
GC
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002448:Cell Adhesion; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D024042:Collagen Type I; D016373:DNA, Antisense / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D005347:Fibroblasts / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D011905:Genes, ras; D010641:Phenotype; D017368:Protein Prenylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*
D024042:Collagen Type I; D016373:DNA, Antisense; D004791:Enzyme Inhibitors; D003094:Collagen; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D016283:Proto-Oncogene Proteins p21(ras)