Protein geranylgeranylation, not farnesylation, is required for the G1 to S phase transition in mouse fibroblasts

Oncogene. 1996 Nov 7;13(9):1991-9.

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

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / drug effects
  • Actins / ultrastructure
  • Alkyl and Aryl Transferases*
  • Animals
  • Benzamides / pharmacology
  • Cell Cycle / drug effects
  • Cell Cycle / physiology
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cell Transformation, Neoplastic / genetics
  • Cells, Cultured
  • Cytoskeleton / drug effects
  • Cytoskeleton / ultrastructure
  • DNA / biosynthesis
  • DNA / drug effects
  • Diterpenes / metabolism
  • Enzyme Inhibitors / pharmacology
  • Farnesol / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • G1 Phase / drug effects
  • G1 Phase / physiology*
  • GTP-Binding Proteins / drug effects
  • GTP-Binding Proteins / metabolism
  • Genes, ras
  • Lovastatin / pharmacology
  • Methionine / analogs & derivatives
  • Methionine / pharmacology
  • Mevalonic Acid / pharmacology
  • Mice
  • Protein Prenylation / drug effects
  • Protein Prenylation / physiology*
  • Protein-Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-raf
  • Resting Phase, Cell Cycle / drug effects
  • Resting Phase, Cell Cycle / physiology
  • S Phase / drug effects
  • S Phase / physiology*
  • Transferases / antagonists & inhibitors
  • rap GTP-Binding Proteins
  • ras Proteins / drug effects
  • ras Proteins / metabolism

Substances

  • Actins
  • Benzamides
  • Diterpenes
  • Enzyme Inhibitors
  • FTI 277
  • GGTI 297
  • GGTI 298
  • Proto-Oncogene Proteins
  • Farnesol
  • DNA
  • Lovastatin
  • Methionine
  • geranylgeraniol
  • Transferases
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • p21(ras) farnesyl-protein transferase
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • GTP-Binding Proteins
  • rap GTP-Binding Proteins
  • ras Proteins
  • Mevalonic Acid