摘要
通过对676条人microRNA进行筛选,共得到了53条新的具有p53-DNA结合位点且调控p53上游转录因子和下游靶基因的microRNA.结合已有蛋白质互作关系与microRNA调控信息,构建了p53-microRNA相互作用网络图,其中FAS受多条microRNA调控,FAS是介导细胞凋亡的关键因子,因此,FAS-microRNA的相互作用可能在细胞凋亡途径中起着关键的作用.随后,提出了microRNA参与p53调控的假设机制,认为p53调控靶基因与microRNA的同时也受上游转录因子与microRNA的调控,从而形成了以p53为中心的一种平衡,当这种调控平衡一旦被打破则会引起信号通路的紊乱,从而可能引发相应的疾病.对这53条microRNA进行靶基因预测,共得到15500个靶基因,对这些基因的出现频率进行聚类分析共得到27个簇,将出现频率大于10的基因进行功能注释分析,发现多数基因功能属于近来发现的p53靶基因新的功能分类——细胞粘连和细胞运动,目前研究认为,p53通过与这些具有细胞粘连和运动功能的靶基因结合来抑制肿瘤的迁移.通过对15500个基因进行功能注释分析,得到了30条感兴趣的参与细胞周期调控、细胞凋亡和细胞增殖的microRNA,其中有9条microRNA于3种生物学进程均有参与,这9条microRNA分别是:hsa-mir-181a-1、hsa-mir-181b-1、hsa-mir-181c、hsa-mir-181d、hsa-mir-195、hsa-mir-497、hsa-mir-495、hsa-mir-543和hsa-mir-548c.这暗示着这9条microRNA在p53信号通路的调节中可能起着关键的作用,它们互相作用共同调节着多个p53信号环路.最后在36个物种的基因组中对这30条microRNA进行了同源性搜索与保守性分析,结果发现有10条高度保守的且为目前数据库所未收录的microRNA.这10条microRNA分别是:hsa-mir-497、hsa-mir-495、hsa-mir-543、hsa-mir-19a、hsa-mir-19b-1、hsa-mir-200b、hsa-mir-448、hsa-mir-28、hsa-mir-455和hsa-mir-590.
53 new microRNAs which have p53-DNA binding sites and regulated the p53 upstream transcription factor and downstream target genes were screened from 676 human microRNAs. The microRNAs and p53 protein interaction networks was constructed through mined the known interaction of p53 and p53-microRNAs. Remarkably, FAS was found, which is a key factor in the apoptotic pathway regulated by a number of microRNAs. The interaction of FAS-microRNAs maybe play a key role in the apoptotic pathway. A presumptive p53-microRNA regulatory mechanism was proposed： p53 as a transcription factor regulated the target genes and direct regulatory microRNAs, whereas it also is regulated by upstream transcription factor and microRNAs. So, a balance which p53 located in the center would be formed by the factors of p53 pathway, the disease would be caused when this balance is broken. A total of 15 500 genes were predicted as targets of these 53 microRNAs and they are classed by 27 clusters according to the frequency of gene in all the 15 500 genes. Function annotation analysis of genes frequency more than 10 revealed a novel p53 functions, including cell adhesion and migration which suggested that p53 can suppress metastasis through direct transcriptional regulation of this new category of molecular targets. 30 microRNAs which involved in cell cycle, apoptosis and cell proliferation were explored through gene functional enrichment analysis, noticeably, 9/30 microRNAs （hsa-mir-181a-1, hsa-mir-181b-1, hsa-mir- 181 c, hsa-mir- 181 d, hsa-mir- 195, hsa-mir-497, hsa-mir-495, hsa-mir-543 and hsa-mir-548c） regulated all three biological process, which implies that these 9 microRNAs maybe play a key role in the regulation of p53 signaling pathway and feedback loops through interaction of microRNAs. Finally, the homology and conservation of 30 microRNAs were analyzed in the 36 species and 10 new highly conserved microRNAs （hsa-mir-497, hsa-mir-495, hsa-mir-543, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-200b, hsa-mir-448, hsa-mir-28, hsa-mir-455 an
出处
《生物化学与生物物理进展》
SCIE
CAS
CSCD
北大核心
2009年第9期1154-1164,共11页
Progress In Biochemistry and Biophysics
基金
国家高技术研究发展计划(863)资助项目(2006AA06Z353)~~
