Opposing effects of Ets and Id proteins on p16(INK4a) expression during cellular senescence

The p16(INK4a) cyclin-dependent kinase inhibitor(1) is implicated in replic ative senescence, the state of permanent growth arrest provoked by cumulati ve cell divisions or as a response to constitutive Ras-Raf-MEK signalling i n somatic cells(2-8). Some contribution to senescence presumably underlies the importance of p16(INK4a) as a tumour suppressor(9) but the mechanisms r egulating its expression in these different contexts remain unknown. Here w e demonstrate a role for the Ets1 and Ets2 transcription factors(10) based on their ability to activate the p16(INK4a) promoter through an ETS-binding site and their patterns of expression during the lifespan of human diploid fibroblasts. The induction of p16(INK4a) by Ets2, which is abundant in you ng 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 level s and MEK signalling decline, the marked increase in p16(INK4a) expression is consistent with the reciprocal reduction of Id1 and accumulation of Ets1 .