The M-type receptor PLA2R regulates senescence through the p53 pathway
The M-type receptor PLA2R regulates senescence through the p53 pathway
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DOI：
10.1038/embor.2008.255
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发表时间：
2009-03-01
期刊：
影响因子：
7.7
通讯作者：
Bernard, David
中科院分区：
文献类型：
--
作者：
Augert, Arnaud;Payre, Christine;Bernard, David
衰老是由端粒侵蚀、致癌或氧化应激等各种应激引起的稳定的增殖停滞。令人信服的证据表明，它是阻止肿瘤发展的屏障。因此，描述有利于逃避衰老的新机制可以揭示肿瘤发生的新见解。为了确定控制衰老程序的新基因，我们在原代人类成纤维细胞中进行了功能丧失的遗传筛选。我们报道，M型受体PLA2R(磷脂酶A2受体)的敲除可以防止复制性衰老的开始，并减少应激诱导的衰老。有趣的是，PLA2R在复制性衰老过程中表达增加，其异位表达导致早衰。我们发现PLA2R以一种活性氧物种-DNA损伤-P53依赖的方式调节衰老。综上所述，我们的研究确认PLA2R是一个潜在的新的肿瘤抑制基因，在通过激活P53途径诱导细胞衰老中起关键作用。
Senescence is a stable proliferative arrest induced by various stresses such as telomere erosion, oncogenic or oxidative stress. Compelling evidence suggests that it acts as a barrier against tumour development. Describing new mechanisms that favour an escape from senescence can thus reveal new insights into tumorigenesis. To identify new genes controlling the senescence programme, we performed a loss-of-function genetic screen in primary human fibroblasts. We report that knockdown of the M-type receptor PLA2R ( phospholipase A2 receptor) prevents the onset of replicative senescence and diminishes stress-induced senescence. Interestingly, expression of PLA2R increases during replicative senescence, and its ectopic expression results in premature senescence. We show that PLA2R regulates senescence in a reactive oxygen species-DNA damage-p53-dependent manner. Taken together, our study identifies PLA2R as a potential new tumour suppressor gene crucial in the induction of cellular senescence through the activation of the p53 pathway.