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AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1

Abstract

The Forkhead transcription factors AFX, FKHR and FKHR-L1 are orthologues of DAF-16, a Forkhead factor that regulates longevity in Caenorhabditis elegans1,2,3. Here we show that overexpression of these Forkhead transcription factors causes growth suppression in a variety of cell lines, including a Ras-transformed cell line and a cell line lacking the tumour suppressor PTEN. Expression of AFX blocks cell-cycle progression at phase G1, independent of functional retinoblastoma protein (pRb) but dependent on the cell-cycle inhibitor p27kip1. Indeed, AFX transcriptionally activates p27kip1, resulting in increased protein levels. We conclude that AFX-like proteins are involved in cell-cycle regulation and that inactivation of these proteins is an important step in oncogenic transformation.

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Figure 1: Expression of AFX causes arrest at the G1 phase of the cell cycle.
Figure 2: AFX expression induces up-regulation of p27kip1.
Figure 3: AFX-induced cell-cycle arrest occurs independent of pRb but is dependent on p27kip1.
Figure 4: AFX regulates p27kip1 transcription.

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Acknowledgements

We thank B. van Oirschot, R. Klompmaker, V. Smits and L. de Vries-Smits for technical assistance, M. Greenberg, A. Brunet, T. Unterman, R. Bernards, I. Touw, D. Peeper and B. Scheien for providing useful reagents, and K. Reedquist for critical reading of the manuscript.

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Correspondence to Boudewijn M. T. Burgering.

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Medema, R., Kops, G., Bos, J. et al. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782–787 (2000). https://doi.org/10.1038/35008115

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