Abstract
Recent genetic investigations have established that RhoB gain-of-function is sufficient to mediate the antitransforming effects of farnesyltransferase inhibitors (FTIs) in H-Ras-transformed fibroblast systems. In this study, we addressed the breadth and mechanism of RhoB action in epithelial cells transformed by oncoproteins which are themselves insensitive to FTI inactivation. Rat intestinal epithelial (RIE) cells transformed by activated K-Ras or Rac1 were highly sensitive to FTI-induced actin reorganization and growth inhibition, despite the inability of FTI to block prenylation of either K-Ras or Rac1. Ectopic expression of the geranylgeranylated RhoB isoform elicited in cells by FTI treatment phenocopied these effects. Analysis of RhoB effector domain mutants pointed to a role for PRK, a Rho effector kinase implicated in the physiological function of RhoB in intracellular receptor trafficking, and these findings were supported further by experiments in a fibroblast system. We propose that FTIs recruit the antioncogenic RhoB protein in the guise of RhoB-GG to interfere with signaling by pro-oncogenic Rho proteins, possibly by sequestering common exchange factors or effectors such as PRK that are important for cell transformation.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Actin Cytoskeleton / drug effects
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Actin Cytoskeleton / ultrastructure
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Actins / analysis
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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Animals
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Bacterial Proteins / physiology*
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Cell Division / drug effects
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Cell Line, Transformed / drug effects
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Cell Line, Transformed / enzymology
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Cell Line, Transformed / ultrastructure
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Cell Transformation, Neoplastic / drug effects*
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Cell Transformation, Neoplastic / metabolism
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Cells, Cultured / drug effects
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Cells, Cultured / enzymology
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Cells, Cultured / ultrastructure
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DNA-Binding Proteins / physiology*
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Enzyme Inhibitors / pharmacology*
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Epithelial Cells / drug effects*
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Epithelial Cells / enzymology
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Epithelial Cells / ultrastructure
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Escherichia coli Proteins*
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Farnesyltranstransferase
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Fibroblasts / drug effects
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Fibroblasts / enzymology
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Fibroblasts / ultrastructure
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Genes, ras
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Intestinal Mucosa / cytology
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Methionine / analogs & derivatives*
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Methionine / pharmacology*
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Models, Biological
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Protein Isoforms / physiology
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Protein Kinase C / physiology*
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Protein Prenylation / drug effects
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Protein Processing, Post-Translational / drug effects
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Rats
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Signal Transduction
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rac1 GTP-Binding Protein / physiology
Substances
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Actins
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Bacterial Proteins
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DNA-Binding Proteins
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Enzyme Inhibitors
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Escherichia coli Proteins
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L 744832
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Protein Isoforms
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Rob protein, E coli
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Methionine
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Alkyl and Aryl Transferases
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Farnesyltranstransferase
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protein kinase N
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Protein Kinase C
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rac1 GTP-Binding Protein