miR-34 and p53: New Insights into a Complex Functional Relationship

• Published in: PloS one 2015-07, Vol.10 (7), p.e0132767-e0132767
• Main Authors: Navarro, Francisco, Lieberman, Judy
• Format: Article
• Language: English
• Subjects: Apoptosis; Biotechnology; Cancer; Cell cycle; Cell Cycle Proteins; Cells (Biology); Chromosomes; DNA Damage; Gene expression; Gene Knockout Techniques; Gene Regulatory Networks; Genome, Human; Genotoxicity; HCT116 Cells; Human behavior; Humans; MCF-7 Cells; Metastasis; MicroRNA; MicroRNAs; MicroRNAs - metabolism; miRNA; Nuclear Proteins - metabolism; p53 Protein; Post-translation; Proteins; Proto-Oncogene Proteins - metabolism; Senescence; Sirtuin 1 - metabolism; Transcription; Transcription, Genetic; Transcriptional Activation - genetics; Transcriptome - genetics; Tumor cell lines; Tumor proteins; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0132767

miR-34, a tumor suppressor miRNA family transcriptionally activated by p53, is considered a critical mediator of p53 function. However, knockout of the mouse miR-34 family has little or no effect on the p53 response. The relative contribution of different miR-34 family members to p53 function or how much p53 relies on miR-34 in human cells is unclear. Here we show that miR-34a has a complex effect on the p53 response in human cells. In HCT116 cells miR-34a overexpression enhances p53 transcriptional activity, but the closely related family members, miR-34b and miR-34c, even when over-expressed, have little effect. Both TP53 itself and MDM4, a strong p53 transactivation inhibitor, are direct targets of miR-34a. The genes regulated by miR-34a also include four other post-translational inhibitors of p53. miR-34a overexpression leads to variable effects on p53 levels in p53-sufficient human cancer cell lines. In HCT116, miR-34a overexpression increases p53 protein levels and stability. About a quarter of all mRNAs that participate in the human p53 network bind to biotinylated miR-34a, suggesting that many are direct miR-34a targets. However, only about a fifth of the mRNAs that bind to miR-34a also bind to miR-34b or miR-34c. Two human cell lines knocked out for miR-34a have unimpaired p53-mediated responses to genotoxic stress, like mouse cells. The complex positive and negative effects of miR-34 on the p53 network suggest that rather than simply promoting the p53 response, miR-34a might act at a systems level to stabilize the robustness of the p53 response to genotoxic stress.