Ohtani N, Zebedee Z, Huot T J, Stinson J A, Sugimoto M, Ohashi Y, Sharrocks A D, Peters G, Hara E
Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
Nature. 2001 Feb 22;409(6823):1067-70. doi: 10.1038/35059131.
The p16INK4a cyclin-dependent kinase inhibitor 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 cells. Some contribution to senescence presumably underlies the importance of p16INK4a as a tumour suppressor but the mechanisms regulating its expression in these different contexts remain unknown. Here we demonstrate a role for the Ets1 and Ets2 transcription factors 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.
p16INK4a细胞周期蛋白依赖性激酶抑制剂与复制性衰老有关，复制性衰老是一种由累积细胞分裂引发的永久性生长停滞状态，或是体细胞对组成型Ras-Raf-MEK信号传导的一种反应。p16INK4a作为肿瘤抑制因子的重要性可能部分归因于其对衰老的作用，但在这些不同情况下调节其表达的机制仍不清楚。在这里，我们基于Ets1和Ets2转录因子通过ETS结合位点激活p16INK4a启动子的能力以及它们在人二倍体成纤维细胞寿命期间的表达模式，证明了它们的作用。Ets2在年轻的人二倍体成纤维细胞中含量丰富，它对p16INK4a的诱导作用通过Ras-Raf-MEK激酶级联信号增强，并通过与螺旋-环-螺旋蛋白Id1的直接相互作用而受到抑制（参考文献11）。在衰老细胞中，Ets2水平和MEK信号传导下降，p16INK4a表达的显著增加与Id1的相互减少和Ets1的积累一致。
