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

Abstract

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.

• Authors: H R Ashar, L James, K Gray, D Carr, S Black, L Armstrong, W R Bishop, P Kirschmeier
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 275 Issue 39 Pg. 30451-7 (Sep 29 2000) ISSN: 0021-9258 [Print] United States
• PMID: 10852915 (Publication Type: Journal Article)

Chemical References

• 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

Topics

• 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