Physical and functional interaction between PML and TBX2 in the establishment of cellular senescence
Physical and functional interaction between PML and TBX2 in the establishment of cellular senescence
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DOI：
10.1038/emboj.2011.370
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发表时间：
2012-01-04
期刊：
影响因子：
11.4
通讯作者：
Bischof, Oliver
中科院分区：
文献类型：
--
作者：
Martin, Nadine;Benhamed, Moussa;Bischof, Oliver
细胞衰老是肿瘤发生和发展的有效屏障。以前的研究表明，PML肿瘤抑制物促进衰老，尽管确切的机制仍未阐明。结合基因表达谱、染色质结合分析和启动子报告研究，我们确定Tbx2是一种在癌症中经常过表达的T-box转录因子，是一个新的、直接的PML可抑制的E2F靶基因，处于衰老而不是静止状态。PML在TBX2启动子上的募集依赖于一个功能性的p130/E2F4抑制物复合体，最终在TBX2启动子上实现转录不活跃的染色质环境。Tbx2抑制在细胞衰老过程中起着积极的作用，因为缺乏Tbx2的细胞会触发PML衰老功能(S)，从而进入衰老。反过来，升高的TBX2水平通过直接的蛋白质-蛋白质相互作用拮抗PML的促衰老功能。总体而言，我们的发现表明，PML和TBX2在一个自动调节环路中发挥作用，控制衰老程序的有效执行。EMBO期刊(2012)31，95-109。DOI：10.1038/Intemj.2011.370；2011年10月14日在线发布
Cellular senescence acts as a potent barrier for tumour initiation and progression. Previous studies showed that the PML tumour suppressor promotes senescence, although the precise mechanisms remain to be elucidated. Combining gene expression profiling with chromatin-binding analyses and promoter reporter studies, we identify TBX2, a T-box transcription factor frequently overexpressed in cancer, as a novel and direct PML-repressible E2F-target gene in senescence but not quiescence. Recruitment of PML to the TBX2 promoter is dependent on a functional p130/E2F4 repressor complex ultimately implementing a transcriptionally inactive chromatin environment at the TBX2 promoter. TBX2 repression actively contributes to senescence induction as cells depleted for TBX2 trigger PML prosenescence function(s) and enter senescence. Reciprocally, elevated TBX2 levels antagonize PML pro-senescence function through direct protein-protein interaction. Collectively, our findings indicate that PML and TBX2 act in an autoregulatory loop to control the effective execution of the senescence program. The EMBO Journal (2012) 31, 95-109. doi: 10.1038/emboj.2011.370; Published online 14 October 2011