The tumor suppressors p53, p63, and p73 are regulators of microRNA processing complex.
The tumor suppressors p53, p63, and p73 are regulators of microRNA processing complex.
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DOI：
10.1371/journal.pone.0010615
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发表时间：
2010-05-12
期刊：
影响因子：
3.7
通讯作者：
Boominathan L
中科院分区：
文献类型：
--
作者：
Boominathan L
已知肿瘤抑制因子 p53、p73 和 p63 具有转录因子的功能。它们会促进生长停滞或细胞凋亡，具体取决于 DNA 损伤。许多 microRNA (miRNA) 已被证明可以作为 p53 的转录靶标，它们似乎可以帮助 p53 促进生长停滞和细胞凋亡。然而，p53/p63/p73 调节 miRNA 加工复合物的问题迄今为止尚未得到深入解决。使用 Target scan、Mami 和 Diana 软件进行比较/计算基因组分析，以识别调节 miRNA 加工复合物的 miRNA。在这里，我首次提出证据表明肿瘤抑制因子 p53、p63 和 p73 既可以作为 miRNA 加工组件的正调节因子，也可以作为负调节因子。使用精心策划的 p53 依赖性 miRNA 表达数据来识别靶向 miRNA 处理复合体成分的 p53-miR。该分析表明 miRNA 加工复合物的大部分成分（mRNA 的 3'UTR）都是 p53-miR 的靶标。值得注意的是，这些数据揭示了 p53-miR 在靶向 miRNA 加工复合物的许多成分方面的保守性质。 p53/p73/p63 似乎调节 miRNA 加工的主要成分，例如 Drosha-DGCR8、Dicer-TRBP2 和 Argonaute 蛋白。特别是，p53/p73/p63 似乎调节 miRNA 的加工，例如 let-7、miR-200c、miR-143、miR-107、miR-16、miR-145、miR-134、miR-449a、miR-503 和 miR-21。有趣的是，p63−/− 和dicer−/− 小鼠之间似乎存在表型相似性，表明p63 和dicer 可以相互调节。此外，p63、p73 和 DGCR8 蛋白包含保守的相互作用结构域。此外，miRNA 加工机制的许多组件（包括 dicer 和 P2P-R）的启动子含有 p53-RE，表明它们可能是 p63/p73/p53 的直接转录靶标。总之，这项研究提供了 p53、p63 和 p73 如何调节 miRNA 加工组件的机制见解；以及 p53、TA-p63 和 TA-p73 调节 miRNA 如何抑制肿瘤发生、EMT、转移和癌症干细胞增殖。
The tumor suppressors p53, p73, and p63 are known to function as transcription factors. They promote either growth arrest or apoptosis, depending upon the DNA damage. A number of microRNAs (miRNAs) have been shown to function as transcriptional targets of p53 and they appear to aid p53 in promoting growth arrest and apoptosis. However, the question of p53/p63/p73 regulating the miRNA processing complex has not been addressed in depth so far. Comparative/computational genomic analysis was performed using Target scan, Mami, and Diana software to identify miRNAs that regulate the miRNA processing complex. Here, I present evidence for the first time that the tumor suppressors p53, p63, and p73 function as both positive and negative regulators of the miRNA processing components. Curated p53-dependent miRNA expression data was used to identify p53-miRs that target the components of the miRNA-processing complex. This analysis suggests that most of the components (mRNAs' 3′UTR) of the miRNA processing complex are targeted by p53-miRs. Remarkably, this data revealed the conserved nature of p53-miRs in targeting a number of components of the miRNA processing complex. p53/p73/p63 appears to regulate the major components of the miRNA processing, such as Drosha-DGCR8, Dicer-TRBP2, and Argonaute proteins. In particular, p53/p73/p63 appears to regulate the processing of miRNAs, such as let-7, miR-200c, miR-143, miR-107, miR-16, miR-145, miR-134, miR-449a, miR-503, and miR-21. Interestingly, there seems to be a phenotypic similarity between p63−/− and dicer−/− mice, suggesting that p63 and dicer could regulate each other. In addition, p63, p73, and the DGCR8 proteins contain a conserved interaction domain. Further, promoters of a number of components of the miRNA processing machinery, including dicer and P2P-R, contain p53-REs, suggesting that they could be direct transcriptional targets of p63/p73/p53. Together, this study provides mechanistic insights into how p53, p63, and p73 regulate the components of the miRNA processing; and how p53, TA-p63, and TA-p73 regulated miRNAs inhibit tumorigenesis, EMT, metastasis, and cancer stem cell proliferation.
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