文章：

p53网络中的MicroRNA：肿瘤抑制的微观管理

MicroRNAs in the p53 network: micromanagement of tumour suppression

原文发布日期：2012-08-17

DOI: 10.1038/nrc3318

类型: Review Article

开放获取: 否

要点：

1. p53 regulates the expression not only of protein-coding genes but also of non-coding RNAs, among which microRNAs (miRNAs) have been characterized as mediators of tumour suppression by p53 in the past 5 years. For example, the genes encoding the miR-34, miR-200, miR-15/16 and miR-192/194/215 families, as well as miR-145 and miR-107, are directly induced by p53.
2. p53 also regulates the processing of precursor miRNAs, either directly by binding to DROSHA or indirectly, as mutant p53 binds to and inactivates p63 and thereby downregulates the expression of DICER1. Furthermore, p53 may affect miRNA target gene selection by regulating mRNA-binding proteins, such as RNA-binding-motif protein 38 (RBM38).
3. p53-regulated miRNAs mediate tumour suppression and stress responses by regulating multiple key processes, such as cell cycle progression, migration, epithelial–mesenchymal transition, stemness, metabolism, differentiation and cell survival. miRNAs achieve this by directly targeting the translation and mRNA stability of central components of these processes.
4. In response to stress, such as oncogene activation and DNA damage, p53-regulated miRNAs are engaged in diverse types of feedforward and feedback loops that mediate amplification, robustness, fine-tuning and buffering of signals, and collectively contribute to appropriate cellular reactions. Accordingly, the expression and activity of p53 itself is also under the control of miRNAs.
5. Genes encoding p53-regulated miRNAs are often targets for inactivation by genetic and epigenetic mechanisms in human tumours, indicating that they are tumour suppressor genes.
6. Reintroduction of p53-regulated miRNAs into tumours with p53 mutation or miRNA inactivation may have therapeutic value, as this was shown to be effective in preclinical tumour models. Detection of the inactivation of p53-induced miRNAs in biopsy samples or body fluids may have diagnostic and/or prognostic value.

要点翻译：

1. p53不仅调控蛋白质编码基因的表达，还调控非编码RNA的表达。其中，microRNAs（miRNAs）在过去五年中被证实是p53抑制肿瘤的介质。例如，编码miR-34、miR-200、miR-15/16和miR-192/194/215家族以及miR-145和miR-107的基因均受p53直接诱导。
2. p53还通过直接结合DROSHA或间接方式调控前体miRNA的加工——突变型p53通过结合并抑制p63，进而下调DICER1的表达。此外，p53可通过调控RNA结合蛋白（如RNA结合基序蛋白38/RBM38）影响miRNA靶基因的选择。
3. p53调控的miRNAs通过调节细胞周期进程、迁移、上皮-间质转化、干性、代谢、分化和细胞存活等多个关键过程，介导肿瘤抑制和应激反应。miRNAs通过直接靶向这些过程中核心组分的翻译及mRNA稳定性来实现这一功能。
4. 在应答癌基因激活和DNA损伤等应激时，p53调控的miRNAs参与多种前馈与反馈循环，介导信号的放大、稳定性维持、微调与缓冲，共同确保细胞产生适切的反应。相应地，p53自身的表达与活性也受miRNAs的调控。
5. 编码p53调控miRNAs的基因在人类肿瘤中常因遗传或表观遗传机制失活，表明这些基因具有肿瘤抑制功能。
6. 在p53突变或miRNA失活的肿瘤中重新引入p53调控的miRNAs可能具有治疗价值，临床前肿瘤模型已证实该策略的有效性。在活检组织或体液中检测p53诱导miRNAs的失活状态可能具备诊断和/或预后价值。

英文摘要：

In recent years, microRNAs (miRNAs) have been identified as mediators of tumour suppression and stress responses exerted by the p53 tumour suppressor. p53-regulated miRNAs contribute to tumour suppression by controlling the expression of central components of multiple processes, including cell cycle progression, epithelial–mesenchymal transition, stemness, metabolism, cell survival and angiogenesis. The expression and activity of p53 itself is also under the control of miRNAs. Finally, genetic and epigenetic alterations identified in the p53–miRNA network indicate that these pathways are important for the initiation and progression of tumours. In the future, knowledge about the p53–miRNA network may be able to be exploited for diagnostic and therapeutic approaches in cancer prevention and treatment.

摘要翻译： 

近年来，microRNAs（miRNAs）已被确认为p53肿瘤抑制因子所发挥的肿瘤抑制和应激反应的中介分子。p53调控的miRNAs通过控制包括细胞周期进程、上皮-间充质转化、干细胞特性、代谢、细胞存活和血管生成等多个过程的核心组分的表达，从而促进肿瘤抑制。p53自身的表达和活性也受到miRNAs的调控。最后，在p53-miRNA网络中发现的遗传和表观遗传学改变表明，这些通路对于肿瘤的发生和进展具有重要意义。未来，关于p53-miRNA网络的知识可能会被用于癌症预防和治疗的诊断和治疗方法中。

原文链接：

MicroRNAs in the p53 network: micromanagement of tumour suppression