The p16INK4A and p14ARF proteins, encoded by the INK4A-ARF locus, are key regulators of cellular senescence, yet the mechanisms triggering their up-regulation are not well understood. Here, we show that the ability of the oncogene BMI1 to repress the INK4A-ARF locus requires its direct association and is dependent on the continued presence of the EZH2-containing Polycomb-Repressive Complex 2 (PRC2) complex. Significantly, EZH2 is down-regulated in stressed and senescing populations of cells, coinciding with decreased levels of associated H3K27me3, displacement of BMI1, and activation of transcription. These results provide a model for how the INK4A-ARF locus is activated and how Polycombs contribute to cancer.

The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells / A.P. Bracken, D. Kleine-Kohlbrecher, N. Dietrich, D. Pasini, G. Gargiulo, C. Beekman, K. Theilgaard-Monch, S. Minucci, B.T. Porse, J.C. Marine, K.H. Hansen, K. Helin. - In: GENES & DEVELOPMENT. - ISSN 0890-9369. - 21:5(2007 Mar 01), pp. 525-530.

The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells

A.P. Bracken;G. Gargiulo;S. Minucci;
2007-03-01

Abstract

The p16INK4A and p14ARF proteins, encoded by the INK4A-ARF locus, are key regulators of cellular senescence, yet the mechanisms triggering their up-regulation are not well understood. Here, we show that the ability of the oncogene BMI1 to repress the INK4A-ARF locus requires its direct association and is dependent on the continued presence of the EZH2-containing Polycomb-Repressive Complex 2 (PRC2) complex. Significantly, EZH2 is down-regulated in stressed and senescing populations of cells, coinciding with decreased levels of associated H3K27me3, displacement of BMI1, and activation of transcription. These results provide a model for how the INK4A-ARF locus is activated and how Polycombs contribute to cancer.
epigenetic silencing ; polycomb proteins ; cancer ; senescence ;
Settore MED/04 - Patologia Generale
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/62967
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