Transcriptional activation of the senescence regulator Lsh by E2F1
Transcriptional activation of the senescence regulator Lsh by E2F1
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E2F1 对衰老调节因子 Lsh 的转录激活
DOI：
10.1016/j.mad.2011.03.004
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发表时间：
2011-04-01
影响因子：
5.3
通讯作者：
Tong, Tanjun
中科院分区：
文献类型：
--
作者：
Niu, Jing;Chen, Tianda;Tong, Tanjun
Lsh是一种与SNF 2家族染色质重塑ATP酶相关的蛋白质，是一种主要的表观遗传调节因子，对DNA甲基化和组蛋白重复元件乙酰化至关重要。Lsh通过将HDAC募集到p（16 IN 4Ka）启动子来抑制内源性p16（INK 4a）表达，这反过来延迟细胞衰老。然而，在细胞衰老过程中Lsh表达的分子机制，管理损失尚未得到阐明。在这里，我们调查的人LSH启动子的转录调控。我们发现最小的Lsh启动子位于转录起始位点的-216和-119之间，并含有两个推定的E2 F结合位点。异位E2 F1在转录和翻译水平上增加Lsh的表达。E2 F1通过结合两个推定结合位点中的每一个与Lsh启动子物理相互作用，并反式激活Lsh启动子。E2 F1还诱导2BS细胞中的Lsh蛋白表达并反式激活Lsh启动子。与此同时，与年轻细胞相比，衰老细胞中E2 F1诱导的Lsh启动子活性降低。这些结果表明，E2 F1在人Lsh基因的转录调控中起着至关重要的作用，衰老细胞中Lsh表达的降低与E2 F1的抑制有关。出版社：Elsevier爱尔兰Ltd.
Lsh, a protein related to the SNF2 family of chromatin-remodeling ATPases, is a major epigenetic regulator that is essential for DNA methylation and histone acetylation at repetitive elements. Lsh represses endogenous p16(INK4a) expression by recruiting HDAC to the p(16IN4Ka) promoter, which in turn delays cell senescence. However, the molecular mechanisms that govern loss of Lsh expression during cellular senescence have yet to be elucidated. Here we investigate the transcriptional regulation of the human Lsh promoter. We find that the minimal Lsh promoter is located between positions -216 and -119 relative to the transcription start site, and contains two putative E2F binding sites. Ectopic E2F1 increases expression of Lsh at both transcriptional and translational levels. E2F1 physically interacts with the Lsh promoter by binding to each of the two putative binding sites and transactivates the Lsh promoter. E2F1 also induces Lsh protein expression and transactivates the Lsh promoter in 2BS cells. At the same time, E2F1-induced Lsh promoter activity is reduced in senescent cells compared to young cells. These results indicate that E2F1 plays a crucial role in transcriptional control of the human Lsh gene and the decrease of Lsh expression in senescent cells is related to the repression of E2F1. Published by Elsevier Ireland Ltd.