Bischof Oliver, Schwamborn Klaus, Martin Nadine, Werner Andreas, Sustmann Claudio, Grosschedl Rudolf, Dejean Anne
Nuclear Organisation and Oncogenesis Unit, INSERM U579, Institut Pasteur, 75724 Paris Cedex 15, France.
Max-Planck-Institute of Immunobiology, D-79108 Freiburg, Germany.
Mol Cell. 2006 Jun 23;22(6):783-794. doi: 10.1016/j.molcel.2006.05.016.
Cellular senescence and apoptosis have evolved to restrain unwarranted proliferation of potentially tumorigenic cells. Here we show that overexpression of the E3 SUMO ligase PIASy in normal human fibroblasts recruits the p53 and Rb tumor suppressor pathways to provoke a senescence arrest. By contrast, in Rb-deficient fibroblasts, expression of PIASy leads to p53-dependent apoptosis. Induction of senescence requires PIASy E3 activity and is specific for this member of the PIAS ligase family. PIASy stimulates sumoylation and transcriptional activity of p53 and increases Rb-dependent corepression through recruitment to E2F-responsive promoters. Viral oncoprotein E6 suppresses both PIASy-induced senescence and sumoylation of PIASy substrates. Finally, we show that fibroblasts lacking PIASy exhibit a highly reduced propensity to undergo senescence in response to a prosenescence stimulus. Altogether, these data provide the first evidence for a direct role of an E3 SUMO ligase, and by implication of the SUMO pathway, in cellular senescence and apoptosis.
细胞衰老和凋亡的进化是为了抑制潜在致瘤细胞的过度增殖。我们在此表明，在正常人成纤维细胞中过表达E3 SUMO连接酶PIASy会募集p53和Rb肿瘤抑制途径，从而引发衰老停滞。相比之下，在Rb缺陷的成纤维细胞中，PIASy的表达会导致p53依赖性凋亡。衰老的诱导需要PIASy的E3活性，并且对PIAS连接酶家族的该成员具有特异性。PIASy刺激p53的SUMO化和转录活性，并通过募集到E2F反应性启动子来增加Rb依赖性共抑制。病毒癌蛋白E6抑制PIASy诱导的衰老和PIASy底物的SUMO化。最后，我们表明缺乏PIASy的成纤维细胞在对促衰老刺激作出反应时经历衰老的倾向大大降低。总之，这些数据首次证明了E3 SUMO连接酶以及SUMO途径在细胞衰老和凋亡中的直接作用。
