p53 activates the PANK1/miRNA-107 gene leading to downregulation of CDK6 and p130 cell cycle proteins.
p53 activates the PANK1/miRNA-107 gene leading to downregulation of CDK6 and p130 cell cycle proteins.
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DOI：
10.1093/nar/gkq796
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发表时间：
2011-01
影响因子：
14.9
通讯作者：
Engeland K
中科院分区：
文献类型：
--
作者：
Böhlig L;Friedrich M;Engeland K
抑癌基因p53是细胞周期阻滞和细胞凋亡的重要调控因子，它作为转录因子调控许多基因。我们通过微阵列分析鉴定了所有人类p53调控的mRNA，并寻找含有内含子miRNA的蛋白质编码基因。其中，该分析产生了泛酸激酶1（PANK 1）基因及其内含子miRNA-107。我们发现，miRNA-107和PANK 1在不同的细胞系统中受到p53的共调节。PANK 1蛋白，催化辅酶A生物合成的限速步骤，也被p53上调。我们观察到p53通过PANK 1启动子中的结合位点直接激活PANK 1和miRNA-107的转录。此外，p53在DNA损伤后被募集到PANK 1启动子。为了更深入地了解miRNA-107的功能，我们研究了其潜在的靶基因。细胞周期调节因子在预测的miRNA-107靶点中显著富集。我们发现了G1/S进展的两个重要调节因子CDK 6和RB相关2基因RBL 2（p130）的miRNA-107依赖性调节。CDK 6和p130蛋白在miRNA-107表达后下调。我们的研究结果揭示了一种新的miRNA依赖的信号通路，导致下调细胞周期蛋白的转录抑制的情况下。
The tumor suppressor p53 is a central regulator of cell-cycle arrest and apoptosis by acting as a transcription factor to regulate numerous genes. We identified all human p53-regulated mRNAs by microarray analyses and searched for protein-coding genes which contain intronic miRNAs. Among others, this analysis yielded the panthothenate kinase 1 (PANK1) gene and its intronic miRNA-107. We showed that miRNA-107 and PANK1 are coregulated by p53 in different cell systems. The PANK1 protein, which catalyzes the rate-limiting step of coenzyme A biosynthesis, is also upregulated by p53. We observed that p53 directly activates PANK1 and miRNA-107 transcription through a binding site in the PANK1 promoter. Furthermore, p53 is recruited to the PANK1 promoter after DNA damage. In order to get more insight into miRNA-107 function we investigated its potential target genes. Cell-cycle regulators are significantly enriched among predicted miRNA-107 targets. We found miRNA-107-dependent regulation of two important regulators of G1/S progression, CDK6 and the RB-related 2 gene RBL2 (p130). CDK6 and p130 proteins are downregulated upon miRNA-107 expression. Our results uncover a novel miRNA-dependent signaling pathway which leads to downregulation of cell cycle proteins in the absence of transcriptional repression.
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