Differential Regulation of microRNAs by p53 Revealed by Massively Parallel Sequencing: miR-34a is a p53 Target That Induces Apoptosis and G1-arrest

In a genome?wide screen for microRNAs regulated by the transcription factor encoded by the p53 tumor suppressor gene we found that after p53?activation the abundance of thirty-four miRNAs was significantly increased, whereas sixteen miRNAs were suppressed. The induction of miR?34a was most pronounced among all differential regulations. Also expression of the primary miR?34a transcript was induced after p53 activation and by DNA damage in a p53?dependent manner. p53 occupied an evolutionarily conserved binding site proximal to the first non-coding exon of miR?34a. Ectopic miR?34a induced apoptosis and a cell cycle arrest in the G1-phase, thereby suppressing tumor cell proliferation. Other p53?induced miRNAs identified here may also have tumor suppressive potential as they are known to suppress the anti?apoptotic factor Bcl2 (miR?15a/16) and the oncogenes RAS and HMGA2 (let?7a). Our results for the first time directly integrate the regulation of miRNA expression into the transcriptional network regulated by p53. siRNAs corresponding to p53?induced miRNAs may have potential as cancer therapeutic agents as RNA interference based therapies are currently emerging.