ESE-3, an Ets family transcription factor, is up-regulated in cellular senescence
ESE-3, an Ets family transcription factor, is up-regulated in cellular senescence
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DOI：
10.1111/j.1349-7006.2007.00543.x
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发表时间：
2007-09-01
期刊：
影响因子：
5.7
通讯作者：
Ishikawa, Fuyuki
中科院分区：
文献类型：
--
作者：
Fujikawa, Makoto;Katagiri, Toyomasa;Ishikawa, Fuyuki
正常细胞在受到各种压力后不可逆转地停止分裂。这种状态被称为细胞衰老，最近被证明在体内起到了肿瘤抑制机制的作用。衰老的细胞表现出一系列共同的特征，但导致这种状态的分子机制尚不清楚。研究表明，p38是一种应激诱导的丝裂原活化蛋白激酶(MAPK)，在多种环境下诱导细胞衰老中起着关键作用。为了更好地了解衰老诱导途径，对p38异位激活的正常人成纤维细胞进行了微阵列分析。研究发现，ESE-3、抑制素βA、RGS5、SSAT和DIO2基因在RasV12、H_2O_2和端粒缩短诱导的衰老细胞中表达上调，而在静止期和生长活跃的细胞中表达上调，提示这些基因可作为不同类型细胞衰老的分子标记。ESE-3的异位表达导致细胞生长受阻，p16(INK4a)表达上调，p21不表达，SA-β-Gal活性升高。相反，当异位表达时，RGS5、SSAT和抑制素βA受体基因的构成活性形式不会诱导这种衰老表型。在报告实验中，ESE-3的表达增加了p16(INK4a)启动子的活性，重组ESE-3蛋白与启动子中存在的Ets结合序列结合。这些结果表明，ESE-3作为p38的下游分子在诱导细胞衰老中发挥作用。
Normal cells irreversibly stop dividing after being exposed to a variety of stresses. This state, called cellular senescence, has recently been demonstrated to act as a tumor-suppressing mechanism in vivo. A common set of features are exhibited by senescent cells, but the molecular mechanism leading to the state is poorly understood. It has been shown that p38, a stress-induced mitogen-activated protein kinase (MAPK), plays a pivotal role in inducing cellular senescence in diverse settings. To better understand the senescence-inducing pathway, microarray analyses of normal human fibroblasts that ectopically activated p38 were performed. It was found that five genes encoding ESE-3, inhibin beta A, RGS5, SSAT and DIO2 were up-regulated in senescent cells induced by RasV12, H2O2 and telomere shortening, but not in quiescent or actively growing cells, suggesting that these genes serve as molecular markers for various types of cellular senescence. The ectopic expression of ESE-3 resulted in retarded growth, up-regulation of p16(INK4a) but not of p21, and increased levels of SA-beta-gal activity. In contrast, RGS5, SSAT and the constitutive active form of the inhibin beta A receptor gene did not induce such senescence phenotypes when ectopically expressed. ESE-3 expression increased the activity of the p16(INK4a) promoter in a reporter assay, and recombinant ESE-3 protein bound to the Ets-binding sequences present in the promoter. These results suggest that ESE-3 plays a role in the induction of cellular senescence as a downstream molecule of p38.