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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 et al. (Sun,) studied this question.