Farnesylation of Cenp-F is required for G2/M progression and degradation after mitosis.
Farnesyl transferase inhibitors induce G2/M cell cycle delays that cannot be explained by inhibition of the Ras GTPase. Recently, the kinetochore protein Cenp-F has been shown to be farnesylated. Here, we show that ectopic expression of the kinetochore targeting domain of Cenp-F delays progression through G2/M. Significantly, this is dependent on the CAAX farnesylation motif. We also show that localisation of Cenp-F to the nuclear envelope at G2/M and kinetochores in prometaphase is dependent both on its CAAX motif and farnesyl transferase activity. Strikingly, farnesyl transferase activity is also required for Cenp-F degradation after mitosis. Thus, these observations suggest that farnesylation of Cenp-F is required not only for its localisation to the nuclear envelope and kinetochores but also for timely progression through G2/M and its degradation after mitosis. In addition, these observations raise the possibility that the anti-proliferative effects induced by farnesyl transferase inhibitors may be due to inhibition of Cenp-F function and/or turnover.
Hussein
Deema
D
School of Biological Sciences, University of Manchester, 2.205 Stopford Building, Oxford Road, Manchester M13 9PT, UK.
Taylor
Stephen S
SS
D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D020090:Chromosome Segregation; D051231:Farnesyltranstransferase; D005434:Flow Cytometry; D016195:G2 Phase / Q000502:physiology*; D006801:Humans; D018386:Kinetochores / Q000378:metabolism; D008840:Microfilament Proteins; D008938:Mitosis / Q000502:physiology*; D009685:Nuclear Envelope / Q000378:metabolism; D017368:Protein Prenylation
D002868:Chromosomal Proteins, Non-Histone; D008840:Microfilament Proteins; C094772:centromere protein F; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase