MicroRNAs in the p53 network: micromanagement of tumour suppression

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.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).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.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.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.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.