Abstract
In order to assess the relative contributions of farnesylated and/or geranylgeranylated proteins on cell cycle progression from G1 to S phase we designed potent and selective farnesyltransferase (FTI-277) and geranylgeranyltransferase-I (GGTI-298) inhibitors. Flow cytometry studies showed that treatment of NIH3T3 cells with GGTI-298 or lovastatin, which inhibits both protein farnesylation and geranylgeranylation, arrested cells in G0/G1 whereas cells treated with FTI-277 progressed normally through the cell cycle. [3H]thymidine incorporation studies showed that mevalonate and geranylgeraniol, but not farnesol, released the lovastatin G1 block. Furthermore, mevalonate release of the lovastatin G1 block was inhibited by GGTI-298 but not by FTI-277. These results demonstrate that geranylgeranylated proteins are required for cells to proceed from G1 to S phase, and that farnesylated proteins do not play an essential role in the G1 to S phase transition
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Actins / drug effects
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Actins / ultrastructure
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Alkyl and Aryl Transferases*
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Animals
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Benzamides / pharmacology
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Cell Cycle / drug effects
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Cell Cycle / physiology
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Cell Division / drug effects
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Cell Division / physiology
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Cell Transformation, Neoplastic / genetics
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Cells, Cultured
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Cytoskeleton / drug effects
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Cytoskeleton / ultrastructure
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DNA / biosynthesis
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DNA / drug effects
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Diterpenes / metabolism
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Enzyme Inhibitors / pharmacology
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Farnesol / metabolism
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Fibroblasts / cytology
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Fibroblasts / metabolism
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G1 Phase / drug effects
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G1 Phase / physiology*
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GTP-Binding Proteins / drug effects
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GTP-Binding Proteins / metabolism
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Genes, ras
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Lovastatin / pharmacology
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Methionine / analogs & derivatives
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Methionine / pharmacology
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Mevalonic Acid / pharmacology
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Mice
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Protein Prenylation / drug effects
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Protein Prenylation / physiology*
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Protein Serine-Threonine Kinases / genetics
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-raf
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Resting Phase, Cell Cycle / drug effects
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Resting Phase, Cell Cycle / physiology
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S Phase / drug effects
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S Phase / physiology*
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Transferases / antagonists & inhibitors
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rap GTP-Binding Proteins
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ras Proteins / drug effects
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ras Proteins / metabolism
Substances
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Actins
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Benzamides
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Diterpenes
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Enzyme Inhibitors
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FTI 277
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GGTI 297
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GGTI 298
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Proto-Oncogene Proteins
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Farnesol
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DNA
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Lovastatin
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Methionine
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geranylgeraniol
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Transferases
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Alkyl and Aryl Transferases
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geranylgeranyltransferase type-I
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p21(ras) farnesyl-protein transferase
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf
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GTP-Binding Proteins
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rap GTP-Binding Proteins
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ras Proteins
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Mevalonic Acid