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Farnesylation of Cenp-F is required for G2/M progression and degradation after mitosis

School of Biological Sciences, University of Manchester, 2.205 Stopford Building, Oxford Road, Manchester M13 9PT, UK

^* Author for correspondence (e-mail: stephen.taylor{at}man.ac.uk)

Accepted 8 June 2002

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.

Key words: Mitosis, Kinetochore, Cenp-F, Protein farnesylation, Farnesyl transferase inhibitor

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