title: miR-34 and p53: New Insights into a Complex Functional Relationship.
abstract: 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.
authors.affiliation: Cellular and Molecular Medicine Program, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Francisco
authors.initials: F
authors.lastname: Navarro
authors.affiliation: Cellular and Molecular Medicine Program, Boston Children's Hospital, Boston, Massachusetts, United States of America; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
mesh_terms: D018797:Cell Cycle Proteins; D004249:DNA Damage; D055786:Gene Knockout Techniques; D053263:Gene Regulatory Networks; D015894:Genome, Human; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D059467:Transcriptome / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C447939:SIRT1 protein, human; D056564:Sirtuin 1