Abstract
The p16INK4a cyclin-dependent kinase inhibitor1 is implicated in replicative senescence, the state of permanent growth arrest provoked by cumulative cell divisions or as a response to constitutive Ras–Raf–MEK signalling in somatic cells2,3,4,5,6,7,8. Some contribution to senescence presumably underlies the importance of p16INK4a as a tumour suppressor9 but the mechanisms regulating its expression in these different contexts remain unknown. Here we demonstrate a role for the Ets1 and Ets2 transcription factors10 based on their ability to activate the p16INK4a promoter through an ETS-binding site and their patterns of expression during the lifespan of human diploid fibroblasts. The induction of p16INK4a by Ets2, which is abundant in young human diploid fibroblasts, is potentiated by signalling through the Ras–Raf–MEK kinase cascade and inhibited by a direct interaction with the helix–loop–helix protein Id1 (ref. 11). In senescent cells, where the Ets2 levels and MEK signalling decline, the marked increase in p16INK4a expression is consistent with the reciprocal reduction of Id1 and accumulation of Ets1.
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Acknowledgements
We thank C. A. Hauser, K. E. Boulukos, N. G. Ahn, Y. de Launoit, Y. Nagamine and J. Ghysdael for providing useful materials. We are also grateful to N. Jones, R. Treisman, J. Campisi, I. Palmero and M. Serrano for helpful discussions, and to M. Hughes and J. Barry for help in FACS. We also thank T. Tanaka for his useful suggestion in ChIP assay and S. Bagley and T. D. Allen for help in using the microscope. This work was supported by the Cancer Research Campaign, Imperial Cancer Research Fund and Nihon Schering KK.
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Ohtani, N., Zebedee, Z., Huot, T. et al. Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 409, 1067–1070 (2001). https://doi.org/10.1038/35059131
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DOI: https://doi.org/10.1038/35059131
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