Contribution of p16INK4a and p21CIP1 pathways to induction of premature senescence of human endothelial cells:: permissive role of p53
Contribution of p16INK4a and p21CIP1 pathways to induction of premature senescence of human endothelial cells:: permissive role of p53
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DOI：
10.1152/ajpheart.00364.2005
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发表时间：
2006-04-01
影响因子：
4.8
通讯作者：
Goligorsky, MS
中科院分区：
文献类型：
--
作者：
Chen, J;Huang, X;Goligorsky, MS
p16（INK4a）和p21（CIP1）通路在诱导人内皮细胞过早衰老中的作用：p53的允许作用[J]中国生物医学工程学报，2016,31(2):559 - 561。2005年10月21日首次出版；doi: 10.1152 / ajpheart。00364.2005. -我们之前发现非酶化糖化胶原I (GC)，模拟糖尿病微环境，可以诱导早期传代人脐静脉内皮细胞（HUVECs）衰老表型。在本研究中，我们探讨了细胞周期检查点通路在启动gc诱导的内皮细胞过早衰老中的功能参与。与天然胶原相比，暴露于GC后，早期传代HUVECs显示p53， p21(CIP1) （p21）和p16(INK4a) (p16) mRNA表达增加。转染p16、p21和p53增强的绿色荧光蛋白（EGFP）重组质粒24小时后，HUVECs进入G(1)期细胞周期阻滞。在第3天和第5天，转染p16-EGFP的HUVECs衰老细胞比例增加，这种增加在gfp阳性细胞群中更为明显，衰老细胞占68%。转染p21也能诱导衰老，但仅在第5天。p16和p21共转染无加性效应。转染p21或p53可诱导HUVECs细胞凋亡。接下来，我们通过小干扰RNA策略抑制内源性p53、p21、p16或视网膜母细胞瘤（Rb）基因的表达，并研究它们对p16和p21引发的内皮细胞衰老的影响。分析表明，抑制p53表达可消除p16过表达引起的衰老。矛盾的是，当p21被抑制时，这种效应没有被观察到。另一方面，Rb的抑制消除了p16或p21过表达引发的衰老。综上所述，p53/p21通路主要负责gc诱导的细胞凋亡，但p53/p21和p16通路的协同激活通过rb依赖机制负责gc诱导的内皮细胞衰老。
Contribution of p16(INK4a) and p21(CIP1) pathways to induction of premature senescence of human endothelial cells: permissive role of p53. Am J Physiol Heart Circ Physiol 290: H1575-H1586, 2006. First published October 21, 2005; doi: 10.1152/ajpheart. 00364.2005. - We have previously found that nonenzymatically glycated collagen I (GC), mimicking diabetic microenvironment, can induce senescent phenotype in early passage human umbilical vein endothelial cells (HUVECs). In the present study, we explored the functional involvement of cell cycle checkpoint pathways in initiating GC-induced premature endothelial cell senescence. When compared with native collagen, early passage HUVECs showed increased p53, p21(CIP1) (p21), and p16(INK4a) (p16) mRNA expression after exposure to GC. Twenty-four hours after transfection of p16, p21, and p53-enhanced green fluorescent protein (EGFP) recombinant plasmids, HUVECs entered G(1)-phase cell cycle arrest. By days 3 and 5, HUVECs transfected with p16-EGFP showed an increased proportion of senescent cells, and this increase was more prominent in the GFP-positive cell population, which exhibited 68% of senescent cells. Transfection of p21 also induced senescence but only by day 5. Cotransfection of p16 and p21 showed no additive effect. Transfection of p21 or p53 induced apoptosis in HUVECs. Next, we suppressed endogenous p53, p21, p16, or retinoblastoma (Rb) gene expression through small interference RNA strategy and investigated their influence in p16- and p21-initiated endothelial cell senescence. Analysis indicated that suppression of p53 expression can abolish senescence induced by p16 overexpression. Paradoxically, this effect was not observed when p21 was suppressed. On the other hand, suppression of Rb eliminated senescence initiated by either p16 or p21 overexpression. In summary, the p53/p21 pathway is mainly responsible for GC-induced apoptosis, but the coordinated activation of the p53/p21 and p16 pathway is responsible for GC-induced endothelial cell senescence through a Rb-dependent mechanism.