Reduced transcriptional activity in the p53 pathway of senescent cells revealed by the MDM2 antagonist nutlin-3
Reduced transcriptional activity in the p53 pathway of senescent cells revealed by the MDM2 antagonist nutlin-3
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DOI：
10.18632/aging.100091
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发表时间：
2009-10-01
期刊：
影响因子：
5.2
通讯作者：
Vassilev, Lyubomir T.
中科院分区：
文献类型：
--
作者：
Huang, Baoying;Vassilev, Lyubomir T.
p53肿瘤抑制因子在细胞衰老的诱导和维持中起着关键作用，但对p53调节衰老细胞对应激的反应知之甚少。在这里，我们使用小分子MDM 2拮抗剂nutlin-3a，选择性激活p53和探测衰老的人成纤维细胞WI-38中p53通路的功能。我们的实验揭示了nutlin诱导的9个p53靶基因和4个p53调节的microRNA的转录活性的总体降低，表明不仅p53蛋白水平，而且其激活转录的能力在衰老过程中发生了改变。此外nutlin恢复阿霉素诱导的p53蛋白和转录活性在衰老细胞的水平在早期传代细胞，但只有部分恢复其凋亡活性，这表明在衰老过程中的上游和下游p53信号的变化是负责衰减响应遗传毒性应激。
The p53 tumor suppressor plays a key role in induction and maintenance of cellular senescence but p53-regulated response to stress in senescent cells is poorly understood. Here, we use the small-molecule MDM2 antagonist, nutlin-3a, to selectively activate p53 and probe functionality of the p53 pathway in senescent human fibroblasts, WI-38. Our experiments revealed overall reduction in nutlin-induced transcriptional activity of nine p53 target genes and four p53 regulated microRNAs, indicating that not only p53 protein levels but also its ability to activate transcription are altered during senescence. Addition of nutlin restored doxorubicin-induced p53 protein and transcriptional activity in senescent cells to the levels in early passage cells but only partially restored its apoptotic activity, suggesting that changes in both upstream and downstream p53 signaling during senescence are responsible for attenuated response to genotoxic stress.