Pathway analysis of senescence-associated miRNA targets reveals common processes to different senescence induction mechanisms
Pathway analysis of senescence-associated miRNA targets reveals common processes to different senescence induction mechanisms
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DOI：
10.1016/j.bbadis.2009.02.003
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发表时间：
2009-04-01
影响因子：
6.2
通讯作者：
Keith, W. Nicol
中科院分区：
文献类型：
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作者：
Lafferty-Whyte, Kyle;Cairney, Claire J.;Keith, W. Nicol
衰老诱导的机制包括端粒磨损、氧化应激、癌基因表达和DNA损伤信号传导。对这些刺激作出反应并产生复杂衰老细胞表型所需的细胞变化的调节具有许多不同的机制。miRNAs提供了一种机制，通过这种机制，在多个途径上具有不同功能的基因可以同时受到调节。在这项研究中，我们研究了12个先前被鉴定为衰老调节因子的miRNAs。利用其靶基因的通路分析，我们测试了miRNA调控在衰老诱导中的相关性。我们的分析强调了这些衰老相关的miRNAs（SA-miRNAs）调节细胞周期，细胞骨架重塑和增殖信号的潜力，逻辑上需要创建一个衰老细胞。对来自探索不同衰老刺激的研究的公开可用的基因表达数据的重新分析也揭示了它们调节核心衰老过程的潜力，无论刺激如何。我们还鉴定了理论上由SA-miRNA调控的刺激特异性凋亡存活途径。此外，miR-499和miR-34 c具有调节我们研究的所有4种衰老诱导类型的潜力的观察结果突出了它们作为衰老诱导的新型药物靶点的未来潜力。(C)2009爱思唯尔有限公司版权所有。
Multiple mechanisms of senescence induction exist including telomere attrition, oxidative stress, oncogene expression and DNA damage signalling. The regulation of the cellular changes required to respond to these stimuli and create the complex senescent cell phenotype has many different mechanisms. MiRNAs present one mechanism by which genes with diverse functions on multiple pathways can be simultaneously regulated. In this study we investigated 12 miRNAs previously identified as senescence regulators. Using pathway analysis of their target genes we tested the relevance of miRNA regulation in the induction of senescence. Our analysis highlighted the potential of these senescence-associated miRNAs (SA-miRNAs) to regulate the cell cycle, cytoskeletal remodelling and proliferation signalling logically required to create a senescent cell. The reanalysis of publicly available gene expression data from studies exploring different senescence stimuli also revealed their potential to regulate core senescence processes, regardless of stimuli. We also identified stimulus specific apoptosis survival pathways theoretically regulated by the SA-miRNAs. Furthermore the observation that miR-499 and miR-34c had the potential to regulate all 4 of the senescence induction types we studied highlights their future potential as novel drug targets for senescence induction. (C) 2009 Elsevier B.V. All rights reserved.