Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules

J Biol Chem. 2000 Sep 29;275(39):30451-7. doi: 10.1074/jbc.M003469200.


Human tumor cell lines that are sensitive to the effects of farnesyl transferase inhibitors accumulate in G(2) --> M (except for cells with an activated Ha-ras that accumulate in G(1)). A search for CAAX box proteins from Swiss-Prot revealed more than 300 peptides. Of these, the centromeric proteins CENP-E and CENP-F are preferentially expressed during mitosis and are implicated as mediators of the G(2) --> M checkpoint. Experiments performed here show that peptides from the COOH-terminal CAAX box of CENP-E and CENP-F are substrates for farnesyl transferase but not geranylgeranyl transferase-I. Although both proteins are prenylated in the human tumor cell line DLD-1, their prenylation is completely inhibited by the farnesyl transferase inhibitor, SCH 66336. Immunohistochemical data with the lung carcinoma cell line, A549, showed that preventing the farnesylation of CENP-E and CENP-F by treatment with the farnesyl transferase inhibitor SCH 66336 does not affect their localization to the kinetochores. However, the presence of farnesyl transferase inhibitors alters the association between CENP-E and the microtubules. Our results imply that the inhibition of CENP-E farnesylation results in the alteration of the microtubule-centromere interaction during mitosis and results in the accumulation of cells prior to metaphase.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Cell Cycle / drug effects
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Mevalonic Acid / metabolism
  • Microfilament Proteins
  • Microtubule-Associated Proteins / metabolism*
  • Microtubules / metabolism*
  • Piperidines / pharmacology
  • Protein Prenylation*
  • Pyridines / pharmacology
  • Substrate Specificity
  • Tumor Cells, Cultured


  • Chromosomal Proteins, Non-Histone
  • Enzyme Inhibitors
  • Microfilament Proteins
  • Microtubule-Associated Proteins
  • Piperidines
  • Pyridines
  • centromere protein E
  • centromere protein F
  • Alkyl and Aryl Transferases
  • p21(ras) farnesyl-protein transferase
  • lonafarnib
  • Mevalonic Acid