p53 regulates autophagic activity in senescent rat mesenchymal stromal cells
p53 regulates autophagic activity in senescent rat mesenchymal stromal cells
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p53调节衰老大鼠间充质基质细胞的自噬活性
DOI：
10.1016/j.exger.2016.01.004
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发表时间：
2016-03-01
影响因子：
3.9
通讯作者：
Hu, Chengjun
中科院分区：
文献类型：
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作者：
Zheng, Yong;Lei, Yueshan;Hu, Chengjun
抑癌蛋白p53在细胞衰老的调控中起着重要作用，其功能主要是通过调控其下游基因来实现的。新出现的证据表明，衰老和自噬似乎是由重叠的信号通路调节的。此外，在衰老细胞中已经观察到自噬标志物。本研究旨在探讨p53基因的表达模式和功能对骨髓间充质干细胞（BMSCs）自噬和复制性衰老的影响。我们发现，超过85%的BMSCs在第6代（衰老BMSCs）时SA-β-gal染色阳性，衰老相关基因（p16（ink 4a）和p21（waf 1））表达增加。这些结果伴随着p53的上调、哺乳动物雷帕霉素靶蛋白（mTOR）的下调和Rb的磷酸化。与第2代BMSCs相比，衰老BMSCs表现出增加的单丹酰尸胺（MDC）染色和自噬相关基因（LC 3和atg 12）水平。敲除p53可减轻BMSC衰老过程中的衰老状态并降低自噬活性，同时伴有mTOR和Rb磷酸化水平的显著上调。这些结果表明，当BMSCs进入复制衰老状态时，自噬增加，并且p53在这种状态下的自噬上调中起关键作用。(C)2016 Elsevier Inc. All rights reserved.
The tumor suppressor protein p53 is an important player in the regulation of cell senescence, its functions are largely carried out by modulating its downstream genes. Emerging evidence has suggested that senescence and autophagy appear to be regulated by overlapping signaling pathways. Furthermore, autophagy markers have been observed in senescent cells. In this study, we sought to explore the effects of the expression pattern and function of p53 on the activity of autophagy and replicative senescence in bone marrow derived mesenchymal stromal cells (BMSCs). We found that more than 85% of BMSCs stained positive for SA-beta-gal at passage 6 (senescent BMSCs) with increased expressions of senescence related genes (p16(ink4a) and p21(waf1)). These results were accompanied by the up-regulation of p53, down-regulation of mammalian target of rapamycin (mTOR) and phosphorylation of Rb. Senescent BMSCs displayed an increased monodansylcadaverine (MDC) staining and autophagy related genes (LC3 and atg12) level compared with BMSCs at passage 2. Knockdown of p53 alleviated the senescent state and reduced autophagic activity during the progression of BMSC senescence, which was accompanied by significantly up-regulated levels of mTOR and phosphorylation of Rb. These results demonstrate that autophagy increases when BMSCs enter the replicative senescence state, and p53 contributes a crucial role in the up-regulation of autophagy in this state. (C) 2016 Elsevier Inc. All rights reserved.